458
Neuronal Surface Antibody-Mediated Autoimmune Encephalitis Jenny J. Linnoila, MD, PhD 1
Myrna R. Rosenfeld, MD, PhD 2'3’4
1 Departm ent of Neurology, Massachusetts General Hospital, Boston, Massachussetts 2 Departm ent of Neurology, Hospital Clinic /In s titu t d’ lnvestigacio Biomedica August Pi i Sunyer (IDIBAPS), Barcelona, Spain 3 Centre de Recerca Biomedica CELLEX, Lab Neuroimmonologia P3A, Barcelona, Spain 4 Departm ent of Neurology, University of Pennsylvania; Philadelphia, Pennsylvania 5 Institucio Catalana de Recerca i Estudis Avangats (ICREA) at Institut d ’ lnvestigacio Biomedica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Josep Dalmau, MD, PhD3’4’5
Address fo r correspondence Josep Dalmau, MD, PhD, Institucio Catalana de Recerca i Estudis Avangats (ICREA) at Institut d’ lnvestigacio Biomedica August Pi i Sunyer (IDIBAPS), Barcelona, Spain 08036 (e-mail: [email protected]).
Semin Neurol 2014;34:458-466.
Abstract
In the past few years, many autoimmune encephalitides have been identified, with specific clinical syndromes and associated antibodies against neuronal surface antigens. There is compelling evidence that many of these antibodies are pathogenic and most of these encephalitides are highly responsive to immunotherapies. The clinical spectra of some of these antibody-mediated syndromes, especially those reported in only a few patients, are evolving. Others, such as anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, are well characterized. Diagnosis involves recognizing the specific syn dromes and identifying the antibody in a patient’s cerebrospinal fluid (CSF) and/or serum. These syndromes are associated with variable abnormalities in CSF, magnetic resonance imaging, and electroencephalography. Treatment is often multidisciplinary
Keywords ► autoimmune
and should be focused upon neutralizing the effects of antibodies and eliminating their source. Overlapping disorders have been noted, with some patients having more than
► limbic ► encephalitis ► neuronal antibodies
one neurologic autoimmune disease. In other patients, viral infections such as herpes simplex virus encephalitis trigger robust antineuronal autoimmune responses.
Encephalitis is commonly encountered in neurology.1 When the etiology is unclear, the cause is typically labeled “viral” or “idiopathic.” In the past few years, it has become evident that many of these encephalitides are autoimmune in origin, and represent specific clinical syndromes associated with anti bodies that target neuronal surface antigens.2-4 It has been demonstrated in vitro and in vivo that some of these cell surface-targeted antibodies are pathogenic and reversibly disrupt the structure and function of their target neuronal proteins.5-10 This in large part explains the responsiveness of patients’ symptoms to immunotherapy. These syndromes have a variable association with cancer and may be confused with the classic antibody associated paraneoplastic neuro
Issue Theme Neurorheumatology; Guest Editor, Tracey A. Cho, MD, MA
logic disorders (PNDs).11 However, in a classic PND of the central nervous system (CNS), the associated antibodies usually target intracellular neuronal proteins and are markers of paraneoplasia without being pathogenic. The neuronal damage in PNDs of the central nervous system (CNS) is T-cell mediated and mostly irreversible, resulting in the generally limited neurologic recovery of the patients, even with maximal treatment.12 As more autoimmune encephalitis (AE) with antibodies to neuronal cell surface antigens are identified, it can be difficult to keep track of newly described clinical associations and concepts that are still evolving. Because most of these syn dromes are treatment responsive and if left undertreated can
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http ://d x.d o i.o rg / 10.1055/s-0034-1390394. ISSN 0271-8235.
Neuronal Surface Antibody-Mediated Autoimmune Encephalitis
result in serious disability or death, it is important to prompt ly recognize and treat them. This review aims to provide a practical overview of the evaluation, diagnosis, and treatment of AE associated with antibodies against neuronal cell surface antigens.
Diagnosis Recognizing A utoim m u n e Encephalitis
Diagnosing AE involves familiarizing oneself with the various syndromes that have been described in detail elsewhere,4,5,9,13-22 and thus are only briefly summarized below and in -Table 1, with an emphasis on defining features. Many AE share overlapping clinical features, and knowing their characteristic or distinctive signs helps to differentiate them. However, there has been a growing tendency for some syndrome definitions to be used imprecisely. For instance, limbic encephalitis is a well-defined disorder characterized by subacute short-term memory loss, confusion, and mood/ behavioral changes, such as depression, irritability, and hal lucinations, with or without seizures.23,24 In the literature,
Linnoila et al.
the term limbic encephalitis is frequently misused to describe any sort of autoimmune encephalopathy, which can misdirect the differential diagnosis.25 Some AE have been described in only a few patients, and it is possible that their full clinical spectra remain to be defined. In contrast, other disorders, such as anti-N-methyl-D-aspartate (NMDA) receptor enceph alitis, have been comprehensively described,26 and an atypi cal symptom could be unrelated or perhaps part of an overlapping but independent disorder, discussed further below. In itia l Studies in th e W o rk u p o f A utoim m une Encephalitis
The initial workup for autoimmune encephalitis is similar to that for other encephalitides, including standard Woodwork, routine cerebrospinal fluid (CSF) analysis with IgG index and oligoclonal bands (OCBs), magnetic resonance imaging (MRI) of the brain, and electroencephalography (EEG). The CSF, MRI, and EEG results can be variable for the different AE,13 as noted below. Some of the variability relates to the point in the clinical course that the studies are done. For instance, a
Table 1 Antineuronal antibody-associated autoimmune encephalitis syndromes
Antigen
Clinical syndrome
Tumor
Additional
NMDAR (GluNI)
Anti-NMDAR encephalitis: Psychiatric manifestations, insomnia, reduction of verbal output, seizures, amnesia, move ment disorders, catatonia, autonomic instability, coma
Age-dependent: ~10-45%, rare in children, ovarian teratomas, rarely carcinomas
~50% Viral prodrome; EEG: “ delta brush pat tern" in ~30% of pa tients; relapses 12% at 2 years
AMPAR
Limbic encephalitis; may occur with pure psychiatric manifestations
70% (Lung, breast, thymoma)
Relapses common
GABABR
Limbic encephalitis, orominent seizures
50% (Lung, neuroendocrine)
Status epilepticus
LGI1
Limbic encephalitis, focal faciobrachial seizures, REM sleep behavior disorder, myoclonus
Neuronal Surface Antibody-Mediated Autoimmune Encephalitis Jenny J. Linnoila, MD, PhD 1
Myrna R. Rosenfeld, MD, PhD 2'3’4
1 Departm ent of Neurology, Massachusetts General Hospital, Boston, Massachussetts 2 Departm ent of Neurology, Hospital Clinic /In s titu t d’ lnvestigacio Biomedica August Pi i Sunyer (IDIBAPS), Barcelona, Spain 3 Centre de Recerca Biomedica CELLEX, Lab Neuroimmonologia P3A, Barcelona, Spain 4 Departm ent of Neurology, University of Pennsylvania; Philadelphia, Pennsylvania 5 Institucio Catalana de Recerca i Estudis Avangats (ICREA) at Institut d ’ lnvestigacio Biomedica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Josep Dalmau, MD, PhD3’4’5
Address fo r correspondence Josep Dalmau, MD, PhD, Institucio Catalana de Recerca i Estudis Avangats (ICREA) at Institut d’ lnvestigacio Biomedica August Pi i Sunyer (IDIBAPS), Barcelona, Spain 08036 (e-mail: [email protected]).
Semin Neurol 2014;34:458-466.
Abstract
In the past few years, many autoimmune encephalitides have been identified, with specific clinical syndromes and associated antibodies against neuronal surface antigens. There is compelling evidence that many of these antibodies are pathogenic and most of these encephalitides are highly responsive to immunotherapies. The clinical spectra of some of these antibody-mediated syndromes, especially those reported in only a few patients, are evolving. Others, such as anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, are well characterized. Diagnosis involves recognizing the specific syn dromes and identifying the antibody in a patient’s cerebrospinal fluid (CSF) and/or serum. These syndromes are associated with variable abnormalities in CSF, magnetic resonance imaging, and electroencephalography. Treatment is often multidisciplinary
Keywords ► autoimmune
and should be focused upon neutralizing the effects of antibodies and eliminating their source. Overlapping disorders have been noted, with some patients having more than
► limbic ► encephalitis ► neuronal antibodies
one neurologic autoimmune disease. In other patients, viral infections such as herpes simplex virus encephalitis trigger robust antineuronal autoimmune responses.
Encephalitis is commonly encountered in neurology.1 When the etiology is unclear, the cause is typically labeled “viral” or “idiopathic.” In the past few years, it has become evident that many of these encephalitides are autoimmune in origin, and represent specific clinical syndromes associated with anti bodies that target neuronal surface antigens.2-4 It has been demonstrated in vitro and in vivo that some of these cell surface-targeted antibodies are pathogenic and reversibly disrupt the structure and function of their target neuronal proteins.5-10 This in large part explains the responsiveness of patients’ symptoms to immunotherapy. These syndromes have a variable association with cancer and may be confused with the classic antibody associated paraneoplastic neuro
Issue Theme Neurorheumatology; Guest Editor, Tracey A. Cho, MD, MA
logic disorders (PNDs).11 However, in a classic PND of the central nervous system (CNS), the associated antibodies usually target intracellular neuronal proteins and are markers of paraneoplasia without being pathogenic. The neuronal damage in PNDs of the central nervous system (CNS) is T-cell mediated and mostly irreversible, resulting in the generally limited neurologic recovery of the patients, even with maximal treatment.12 As more autoimmune encephalitis (AE) with antibodies to neuronal cell surface antigens are identified, it can be difficult to keep track of newly described clinical associations and concepts that are still evolving. Because most of these syn dromes are treatment responsive and if left undertreated can
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http ://d x.d o i.o rg / 10.1055/s-0034-1390394. ISSN 0271-8235.
Neuronal Surface Antibody-Mediated Autoimmune Encephalitis
result in serious disability or death, it is important to prompt ly recognize and treat them. This review aims to provide a practical overview of the evaluation, diagnosis, and treatment of AE associated with antibodies against neuronal cell surface antigens.
Diagnosis Recognizing A utoim m u n e Encephalitis
Diagnosing AE involves familiarizing oneself with the various syndromes that have been described in detail elsewhere,4,5,9,13-22 and thus are only briefly summarized below and in -Table 1, with an emphasis on defining features. Many AE share overlapping clinical features, and knowing their characteristic or distinctive signs helps to differentiate them. However, there has been a growing tendency for some syndrome definitions to be used imprecisely. For instance, limbic encephalitis is a well-defined disorder characterized by subacute short-term memory loss, confusion, and mood/ behavioral changes, such as depression, irritability, and hal lucinations, with or without seizures.23,24 In the literature,
Linnoila et al.
the term limbic encephalitis is frequently misused to describe any sort of autoimmune encephalopathy, which can misdirect the differential diagnosis.25 Some AE have been described in only a few patients, and it is possible that their full clinical spectra remain to be defined. In contrast, other disorders, such as anti-N-methyl-D-aspartate (NMDA) receptor enceph alitis, have been comprehensively described,26 and an atypi cal symptom could be unrelated or perhaps part of an overlapping but independent disorder, discussed further below. In itia l Studies in th e W o rk u p o f A utoim m une Encephalitis
The initial workup for autoimmune encephalitis is similar to that for other encephalitides, including standard Woodwork, routine cerebrospinal fluid (CSF) analysis with IgG index and oligoclonal bands (OCBs), magnetic resonance imaging (MRI) of the brain, and electroencephalography (EEG). The CSF, MRI, and EEG results can be variable for the different AE,13 as noted below. Some of the variability relates to the point in the clinical course that the studies are done. For instance, a
Table 1 Antineuronal antibody-associated autoimmune encephalitis syndromes
Antigen
Clinical syndrome
Tumor
Additional
NMDAR (GluNI)
Anti-NMDAR encephalitis: Psychiatric manifestations, insomnia, reduction of verbal output, seizures, amnesia, move ment disorders, catatonia, autonomic instability, coma
Age-dependent: ~10-45%, rare in children, ovarian teratomas, rarely carcinomas
~50% Viral prodrome; EEG: “ delta brush pat tern" in ~30% of pa tients; relapses 12% at 2 years
AMPAR
Limbic encephalitis; may occur with pure psychiatric manifestations
70% (Lung, breast, thymoma)
Relapses common
GABABR
Limbic encephalitis, orominent seizures
50% (Lung, neuroendocrine)
Status epilepticus
LGI1
Limbic encephalitis, focal faciobrachial seizures, REM sleep behavior disorder, myoclonus
