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Steven Vernino, MD, PhD University of Texas Southwestern Medical Center Dallas, TX Introduction Neurologists are often consulted to evaluate patients with subacute encephalopathy, defined as the onset of cognitive and behavioral disturbances over days or weeks. Toxic/metabolic encephalopathy and infectious causes of meningoencephalitis must be foremost in the differential diagnosis. Once these are excluded, an autoimmune process may be suspected on the basis of clinical presentation, brain MRI, electrodiagnostic studies and laboratory tests on serum and CSF. Specifically, the presence of certain serum or CSF autoantibodies and elevated CSF protein with normal cell count (or a mild lymphocytic pleocytosis only) should raise the possibility of an autoimmune/inflammatory disorder. Autoimmune causes of encephalopathy have been recognized for many decades. However, recent observations and improved diagnostic testing have made this an exciting and evolving area in neurology. Accurate and prompt diagnosis of autoimmune encephalopathy is important since effective treatment may be available, and permanent impairment will result if the encephalopathy is left untreated. It is particularly important to differentiate these disorders from rapidly progressive dementia due to prionopathy or other degenerative conditions. Treatable autoimmune encephalopathies are probably more common than appreciated. Once considered extremely rare, autoimmune encephalitis is now known to be relatively frequent, often unrelated to cancer, and sometimes very responsive to treatment. New diagnostic methods, in the form of serological testing in the blood and CSF, have widened the clinical spectrum of the autoimmune encephalopathies. Various autoimmune and inflammatory conditions may be considered in the differential diagnosis of a progressive dementia or subacute encephalopathy as listed in Table 1. Many of the autoimmune encephalopathies present with classic features of limbic encephalitis; confusion, short-term memory loss, behavior change (depression, apathy, irritability), seizures (frequently temporal complex partial type. MRI imaging studies, electroencephalography and CSF analysis help to confirm the diagnosis, but the abnormalities on these ancillary studies are often non-specific, in the sense that it is difficult to distinguish paraneoplastic from non-paraneoplastic forms of limbic encephalitis. Some forms of autoimmune encephalopathy, have recognizable characteristic clinical features (Table 2) that segregate according to serological associations (antibodies). In the absence of distinctive diagnosis or serological confirmation, a clinical response to immunotherapy may be the only evidence of an autoimmune cause and can define the syndrome as steroid-responsive encephalopathy (SRE). Paraneoplastic Limbic Encephalitis Paraneoplastic limbic encephalitis (PLE) is characterized by the triad of short-term memory impairment, temporal lobe seizures and psychiatric symptoms (commonly depression, psychosis or change in personality).1 As with most paraneoplastic syndromes, there is a slight female predominance. Two thirds of patients have overt seizures (usually complex partial temporal lobe seizures) which may be difficult to control, and nearly all patients will show abnormalities on electroencephalography.2 Sometimes, patients present initially with unexplained seizure rather than cognitive complaints. In others, brief complex partial seizures may be subtle and unrecognized, and the behavioral and cognitive presentation can mimic a rapidly progressive dementia. The differential diagnosis includes primary psychiatric illness, viral encephalitis, Creutzfeld-Jakob disease (CJD), vasculitis, and non-paraneoplastic autoimmune encephalopathies (Table 2).3 Certain additional clinical features should increase the suspicion of a paraneoplastic cause. The presence of other progressive neurological symptoms (especially sensory neuropathy or gastrointestinal dysmotility) could be explained by a second coexisting paraneoplastic syndrome. Other systemic symptoms (unexplained weight loss, night sweats) or laboratory findings (elevated sedimentation rate, hyponatremia) may signify the presence of occult cancer.

© 2012 The American Academy of Neurology Institute.

The pathology of PLE is focused in the anteromedial temporal cortex, hippocampus, and amygdala although adjacent limbic structures (hypothalamus and insular cortex) may be involved, and the process may be quite asymettrical.2 MRI typically shows non-enhancing signal changes in the mesial temporal lobes. Positron emission tomography of the brain may show hypermetabolism in the same region.4, 5 Later in the disease course, marked hippocampal atrophy often develops, associated with permanent cognitive impairment and epilepsy. The electroencephalogram is abnormal and often shows epileptiform activity in the mesial temporal lobes as well as diffuse slowing.2 Cerebrospinal fluid examination is important to rule out infectious causes (especially herpes simplex encephalitis) that may have a similar clinical and radiographic presentation. A variety of autoantibody markers are associated with PLE including ANNA-1 and anti-Ma2 (see Table 3). Recently, antibodies against NMDA receptors and other synaptic proteins have been identified as important serological markers (as described below).5, 6 The autoantibody findings are very useful in directing the search for occult malignancy, but up to 30% of patients with PLE and cancer have negative antibody studies.2 In those cases, a search for malignancy must be conducted according to the patient’s individual cancer risk factors. The most common tumors associated with PLE are small-cell lung carcinoma (SCLC),2, 7, 8 testicular cancer,9, 10 thymoma,11, 12 breast cancer, and ovarian teratoma.6 Since the syndrome usually occurs prior to the cancer diagnosis, these patients present to neurologists rather than oncologists. In most instances, the cancer is limited in stage and can be difficult to detect even when suspected. In cases of occult SCLC, imaging the chest with FDG-PET scan appears to be more sensitive than computed tomography alone.13 Although PLE may be associated with neuronal specific antibodies, cytotoxic T-cell autoimmunity is considered to be the main pathophysiology. Thus, permanent neuronal loss may occur. PLE may stabilize or partially improve following treatment of the cancer or treatment with immunomodulatory therapies, but most patients are left with residual memory impairment and seizures. High dose steroids sometimes produce a meaningful response. Hence, a response to steroids does not rule out a paraneoplastic disorder. Autoimmune encephalopathy with antibodies against potassium channel complex proteins Antibodies reactive with neuronal voltage-gated potassium channels (VGKC) were initially identified in patients with Isaacs syndrome, or autoimmune neuromyotonia.14 Subsequently VGKC antibodies were reported in patients with limbic encephalitis, most of whom did not have cancer.15-17 Recent experiments have demonstrated that most of the antibodies in the serum of patients with these disorders do not bind directly to the VGKC. Instead, serum of patients with limbic encephalitis and VGKC antibodies are most often directed against LGI1 (leucine-rich glioma-inactivated).18, 19 LGI1 is a secreted protein that interacts with several transmembrane synaptic proteins to form a protein complex. This complex helps to organize presynaptic VGKC and postsynaptic neurotransmitter receptors (such as AMPA-type glutamate receptors). Mutations of LGI1 are associated with epilepsy. The clinical presentation of limbic encephalitis associated with LGI1 antibodies has some distinctive features.3, 20 The clinical and radiological findings at presentation in these patients are often indistinguishable from those of paraneoplastic limbic encephalitis, consisting of subacute cognitive impairment with behavioral changes and temporal lobe seizures, high T2 and FLAIR signal in the mesial temporal lobes and temporal lobe EEG abnormalities. Unique features of this disorder are the frequent association with hyponatremia, a strong male predominance, and often rapid and dramatic response to treatment with high dose steroids or plasma exchange (Table 2). When limbic encephalitis is associated with very high levels of LGI1 (VGKC complex) antibodies, no other paraneoplastic neurological symptoms, and no other paraneoplastic autoantibodies, most cases are not paraneoplastic.3, 20 However, some patients with limbic encephalitis associated with lung cancer or thymoma may have VGKC complex antibodies,21 so the presence of these antibodies and the lack of any paraneoplastic antibodies does not preclude the consideration of occult cancer. Other patients with antibodies against the VGKC complex, especially those with neuromyotonia, have antibodies that bind to Caspr2 (contactin-associated protein). The normal function of Caspr2 is to anchor VGKC in the juxtaparanodal region of myelinated axons. Patients with Caspr2 (VGKC complex) antibodies may develop peripheral nerve hyperexcitability (neuromyotonia), but many will also have central nervous system features. This may be indistinguishable from the limbic encephalitis seen in paraneoplastic context or in association with LGI1 antibodies. More typically, these patients have a less specific encephalopathy along with features of peripheral © 2012 The American Academy of Neurology Institute.

nerve hyperexcitability or peripheral neuropathy. The French physician Augustin Marie Morvan first used the term “la chorée fibrillaire” in 1870 to describe a syndrome characterized by peripheral nerve hyperexcitability, dysautonomia, insomnia, and fluctuating delirium.22 The current use of the term “Morvan syndrome” describes the association of acquired neuromyotonia (involuntary rippling, twitching and stiffness of muscles), myokymia, severe insomnia, hyperhidrosis and encephalopathy.23-25 The typical cognitive presentation of Morvan syndrome includes confusion, hallucinations and fluctuating cognition. Needle electromyography (EMG) typically reveals spontaneous muscle fiber activity with fasciculations, multiplets, myokymia and neuromyotonic discharges. The classic diagnosis of Morvan syndrome should be reserved for patients in whom at least 4 cardinal features develop: myokymia or neuromyotonia, dysautonomia (typically with hyperhidrosis, hypersalivation, labile hypertension), severe insomnia, and fluctuating encephalopathy with vivid hallucinations. Unlike limbic encephalitis, the head MRI in Morvan syndrome is usually normal. The majority of patients are male and the age of onset is younger than PLE. The diagnosis can be confirmed by demonstrating myokymia and neuromyotonia by EMG, absence of normal sleep architecture on polysomnography, and serum VGKC complex (Caspr2 of LGI1) antibodies. In addition to limbic encephalitis, various forms of degenerative dementia might be considered in the differential diagnosis; fatal familial insomnia (because of the complete insomnia), CJD (because of the cognitive presentation) and Lewy body dementia (because of the fluctuating symptoms, hallucinations and sleep disturbance). The key distinguishing clinical feature to recognize in Morvan syndrome is the spontaneous neuromuscular and autonomic hyperactivity. Autoimmune encephalitis with NMDA receptor antibodies This disorder has only been recognized since 2007,6 and yet it is now recognized as one of the most common forms of autoimmune encephalopathy. The disorder classically affects young women (median age 19 years), but there is an extremely broad range of age, sex and ethnicity. One study found that 1% of all young adults (18-35 years) admitted to an intensive care unit because of encephalitis had NMDA-R antibodies.26 This disorder represents a characteristic syndrome which is quite different from limbic encephalitis. The presentation is a complex subacute syndrome with a flu-like prodrome (fever, headache, malaise) followed by psychiatric symptoms (anxiety, depression) or frank psychosis (bizarre behavior with delusions and hallucinations), often leading to a psychiatric evaluation for schizophrenia. Patients usually progress to develop orofacial or limb dyskinesias. Then, they may appear as catatonic, in an unresponsive, mute, state with eyes open and increased muscle tone. This can progress to coma with central hypoventilation, requiring intensive care management and intubation. Seizures and autonomic instability (dramatic fluctuations of heart rate, blood pressure and temperature) can occur. Brain MRI is often normal, but about 25% have typical findings of limbic encephalitis, and rarely cortical FLAIR abnormalities are seen. The EEG shows diffuse delta-theta slowing. Cerebrospinal fluid analysis shows lymphocytic pleocytosis and increased protein concentration. Diagnosis of this disorder can be confirmed by demonstration of serum and/or CSF antibodies to NMDA glutamate receptor. The antibodies target extracellular epitopes contained in the NR1 subunit of the NMDAR,6 a receptor subtype that is predominantly concentrated in the hippocampus and forebrain. Classically, the disorder affects young women with ovarian teratoma. However, as experience grows, it has become clear that many cases of NMDA-R antibody encephalitis are not associated with cancer. In women older than 18 years, the incidence of teratoma is about 55%. Anti-NMDA-R encephalitis with typical features can occasionally occur in men, and many recent cases have been described in children without cancer.29 Among men, about 5% are found to have testicular germ-cell tumors or other neoplasms.27 Psychiatric problems may dominate in children, making the diagnosis more challenging. Hypoventilation and dysautonomia appear to be less prominent in children. Prompt identification of the disorder followed by removal of the teratoma and immunotherapy seems to result in gradual recover over weeks in the majority of paraneoplastic cases.28 Most women will not respond to immunotherapy if the teratoma is not removed. Thus, every effort should be made to detect an occult malignancy. Any cystic and persistent abnormalities of the ovary need to be evaluated aggressively and removed (even if small in size and lacking malignant features by imaging). Young women with a non-paraneoplastic form of autoimmune encephalitis can present with similar clinical features and may respond well to immunotherapy. As with the paraneoplastic form, full recovery can occur but often requires weeks or months.

© 2012 The American Academy of Neurology Institute.

Autoimmune encephalopathy associated with antibodies against other synaptic receptors Some patients with classic features of limbic encephalitis have none of the previously recognized serological markers for paraneoplastic or autoimmune limbic encephalitis. In a significant number of these patients, immunohistochemical studies revealed antibodies (from serum or CSF) that bind to synaptic regions in neuronal tissue sections. Very recently, some of these have been identified as antibodies against synaptic neurotransmitter receptors, AMPAR (AMPA-type glutamate receptor) or GABABR (metabotropic GABA receptor). So far, these antibodies have only been identified in small case series. Clinically, the patients are very similar to those with LGI1 antibodies in terms of symptoms and imaging abnormalities (Table 2) except that many cases are associated with cancer. Among cases of paraneoplastic limbic encephalitis associated with small-cell lung carcinoma, GABABR antibodies are found in many of the cases that are seronegative for the recognized neuronal nuclear and cytoplasmic paraneoplastic antibodies (like anti-Hu). Patients with GABABR antibodies reported thus far seem to be characterized by prominent and early onset seizures. AMPAR antibodies, on the other hand, have been associated with a prominent psychiatric presentation of limbic encephalitis and association with several different malignancies. Other antibodies directed against synaptic receptors are likely to be identified as markers and possible mediators of autoimmune encephalopathy. For example, antibodies against GlyR (glycine receptor) have been identified in a handful of patients. The encephalopathy in those patients consisted of behavior alterations in association with hyperekplexia, atypical stiff person syndrome, or seizures. Steroid-responsive encephalopathy Non-paraneoplastic forms of autoimmune encephalopathy may lack the characteristic features of limbic encephalitis. Various terminologies are used, including non-vasculitic autoimmune inflammatory meningoencephalitis,30 steroid-responsive encephalopathy, and Hashimoto encephalopathy.31, 32 Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), often referred to as “Hashimoto’s encephalopathy”, was initially described by Lord Brain.33 The name reflects the presence of thyroid autoimmunity, often without clinical or biochemical evidence of thyroid dysfunction, in these patients. Patients may have serum antibodies against either thyroperoxidase (TPO) or thyroglobulin (formerly known as thyroid microsomal antibodies). The titer of the thyroid antibodies does not correlate with severity or any clinical features. While overt thyroid dysfunction is uncommon at the time of neurological presentation, many patients will develop hypothyroidism sometime later in the clinical course. Evidence of thyroid autoimmunity, however, is non-specific and quite common among all patients with autoimmune neurological disorders. A direct causal relationship between thyroid antibodies and encephalopathy is unlikely.34 Anti-thyroid antibodies may also be found in CSF of patients with SREAT.35 Again, however, the presence and level of the CSF antibodies does not appear to correlate with clinical features of the disease. The brain MRI is often normal. The typical presentation of SREAT is a subacute cognitive disorder with fluctuating symptoms (which may present as stroke-like events), tremor, myoclonus, and neuropsychiatric features. Patients are predominantly women, and there is a wide age range in reported cases likely reflecting the demographics of autoimmune thyroiditis. Nonspecific CSF evidence of inflammation (high protein) is common and similar to other forms of autoimmune encephalopathy. When abnormal, MRI may show changes in subcortical white matter or meningeal enhancement.34, 36 These MRI changes may resolve with successful treatment. Ultimately, there are no specific clinical, laboratory or neuroimaging findings for this entity. The differential diagnosis includes CJD (because of the myoclonus and cognitive features), CNS vasculitis (because of the stroke-like events), primary psychiatric disease and paraneoplastic encephalitis. The presence of thyroid antibodies does not obviate the need to consider these alternate diagnoses. Patients typically improve with corticosteroid therapy but may relapse.34, 37 It is still unclear whether steroid responsiveness should be a necessary criteria to make this diagnosis. Treatment with intravenous immunoglobulin, azathioprine or other immunosuppressants may work for refractory cases. There have also been a few reported cases of response to plasma exchange.38 When all antibody tests (thyroid, VGKC-complex and paraneoplastic) are negative, the empiric use of steroids in patients with unexplained encephalopathy remains controversial. We have often advocated a short trial of high © 2012 The American Academy of Neurology Institute.

dose intravenous steroids (1 gram methylprednisolone daily for 5 days) when there is no evidence of infection or metabolic disturbance and the rapidity of onset is inconsistent with a degenerative disorder. For the diagnosis of steroid-responsive encephalopathy, the clinical response should be unequivocal and persist for a week or more beyond the time of treatment. Treatment considerations Autoimmune encephalopathy is becoming increasingly recognized as a potential cause of progressive cognitive deterioration. The evaluation of cases of rapid onset encephalopathy and dementia should include spinal fluid evaluation, MRI brain imaging and EEG. Several treatable syndromes have characteristic clinical features, and antibody studies help confirm a diagnosis of autoimmune encephalopathy in some cases. The spectrum of autoimmune encephalopathies is quite diverse. Although our ability to identify these disorders has improved (especially with the advent of additional specific serological markers), clear guidelines on immunotherapy are not yet established. The clinician must start be assessing the likelihood of a paraneoplastic cause and initiate a thorough cancer evaluation if indicated. Various forms of immunotherapy are available, including corticosteroids, intravenous immunoglobulin, plasma exchange, and oral immunosuppressant drugs. Patients with SCLCassociated paraneoplastic limbic encephalitis often have a poor response to treatment, but may stabilize. Those with antibodies against synaptic proteins (LGI1, NMDAR, AMPAR, GABABR) often show a favorable response to immunotherapy, although recovery may be prolonged. Steroid-responsive encephalopathy (such as SREAT), by definition, has a good clinical response to initial treatment. Future studies will certainly shed more light on the pathogenesis of these autoimmune encephalopathies. Further improvements in diagnostic and treatment options are expected in the next few years. Table 1. Autoimmune and inflammatory causes of rapidly progressive dementia Paraneoplastic Limbic Encephalitis small-cell lung carcinoma testicular cancer thymoma teratoma other tumors (breast, lymphoma, non-small cell lung) Non-paraneoplastic Limbic Encephalitis with VGKC complex (LGI1 and Caspr2) antibodies with NMDA-R antibodies with antibodies to other synaptic receptors Morvan syndrome Steroid-responsive encephalopathy (SRE) with anti-thyroid antibodies (Hashimoto encephalopathy) Post-infectious autoimmune encephalopathy “Encephalitis lethargica” “Cognitive” presentation of multiple sclerosis Inflammatory vasculopathies (occasionally present as progressive dementia) CNS vasculitis Retinocochleocerebral (Susac’s) syndrome Lupus cerebritis Sjögren’s syndrome Antiphospholipid antibody syndrome

© 2012 The American Academy of Neurology Institute.

Table 2. Clinical features of autoimmune encephalopathies*
Paraneoplastic LE # of reported cases Usual age (years) Sex distribution Memory loss Seizures Psychiatric Hyperhidrosis Movement disorder Other unique features High CSF protein Hyponatremia MRI > 100 50 – 75 60% female +++ Common Occasional No No sensory or autonomic neuropathy 80% 25% FLAIR signal in mesial temporal lobes (MTL) Lung, breast, testicular LE with LGI1 antibody > 100 44 – 79 65% male +++ 40% Occasional with seizures No Encephalopathy with Caspr2 antibody ~ 40 37 – 76 85% male ++ Common Frequent** ++ No Insomnia**, myokymia 30% ND Normal or FLAIR signal in MTL (40%) Thymoma (20%) NMDA-R antibody encephalitis > 100 2 – 70 (median 20) 85% female ++ 50% Common + Dyskinesias Hypoventilation GABABR antibody encephalitis ~25 50 – 70 50:50 + Prominent No No AMPA-R antibody encephalitis ~25 40 – 80 90% female + 50% Common No No SREAT (“Hashimoto”) > 100 12 – 84 70% female ++ Uncommon Uncommon No Tremor Episodic aphasia 80% Uncommon Normal (60%) or nonspecific WM changes None

40% 80% Increased FLAIR signal in MTL (90%) Thymoma or lung (<20%)

95% No Nl or FLAIR signal in MTL or cortex (25%) Ovarian teratoma

90% ND MTL FLAIR signal (70%)

90% ND Increased FLAIR signal in MTL (90%) Lung, breast, thymoma

Tumor associations

SCLC (60%)

* Data represent a summary of English-language literature and the author’s experience syndrome ND = no data available Table 3: Autoantibodies in autoimmune encephalopathies
Clinical Presentation PLE PLE Antibody ANNA-1 (anti-Hu) CRMP-5 (anti-CV2)

** with Morvan

Interpretation Highly predictive of SCLC Highly predictive of SCLC or thymoma



Highly predictive of testicular cancer (men)


LGI1 or Caspr2

< 20% have SCLC or thymoma

Morvan syndrome


about 20% have SCLC or thymoma


NMDA receptor

Association with teratoma in young women


AMPA-R or GABABR thyroperoxidase (TPO) or thyroglobulin

60-70% have lung or breast cancer Predictive of ongoing or future thyroiditis & hypothroidism

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