Autoantibody-Mediated Encephalitis

Differential diagnosis in patients with impaired consciousness of unclear origin

Background: Acute and subacute disturbances of wakefulness and cognitive function are common neurological manifestations in the hospital and in outpatient care. An important element of the differential diagnosis was described only a few years ago: autoimmune encephalitis, a condition whose diagnosis and treatment pose an interdisciplinary challenge.

Methods: This review is based on pertinent publications from the years 2005–2017 that were retrieved by a selective search in PubMed, and on the authors’ personal experience and case reports.

Results: The incidence of autoimmune encephalitis in Germany is estimated at 8–15 cases per million persons per year. In some patients with psychotic manifestations or impaired consciousness of acute or subacute onset, an autoimmune pathogenesis can be demonstrated by the laboratory detection of autoantibodies against neuronal target antigens (e.g., glutamate receptors). Testing of this type should be performed in patients with inflammatory changes in the cerebrospinal fluid or on magnetic resonance imaging (MRI), or those who have had an otherwise unexplained first epileptic seizure or status epilepticus. The cumulative sensitivity of testing for all potentially causative antineuronal antibodies in patients with clinically defined autoimmune encephalitis is estimated at 60–80 %. Figures on cumulative specificity are currently unavailable.

Conclusion: The detection of antineuronal antibodies in patients with the corresponding appropriate symptoms implies the diagnosis of autoimmune encephalitis. Observational studies have shown that rapidly initiated immunosuppressive treatment improves these patients’ outcomes. Further studies are needed to determine the positive predictive value of antineuronal antibody detection and to develop further treatment options under randomized and controlled conditions.

Acute or subacute disorders of wakefulness (quantitative impairment of consciousness, ICD-10 R40.-) and qualitative impairment of consciousness (confusion, impaired orientation, amnesia syndromes; ICD-10 R41.-) are frequently occurring causes of hospitalization. In a large neurological emergency department, quantitative disorders of consciousness were the cardinal symptom in every fifth patient seen (reduced vigilance 9%, epileptic seizures 11%) (1). Around 20 to 30% of all hospital inpatients, 50% of elderly patients, and up to 70% of intensive care patients suffer from delirium, i.e., acute deterioration of alertness, organized cognition, memory, attentiveness, and perception (2, e1–e3). Particularly with delirium syndromes the causes are unclear and the treatment principally comprises supportive measures, e.g., management of systemic infections or electrolyte shifts (3).

Recently an additional differential diagnosis has been described, namely a group of previously unknown immune-mediated forms of encephalitis with autoantibodies against neuronal antigens (4). These diseases are rare, but can be clearly delineated from noninflammatory causes with the aid of a rigorous diagnostic work-up for antibodies. Their detection and diagnosis is of great importance, as immune therapy is a causal, frequently successful form of treatment (5). Owing to the wide heterogeneity of immune-mediated forms of encephalitis, these diseases demand close interdisciplinary cooperation on the part of neurologists, intensive care specialists, oncologists, pediatricians, gynecologists, and psychiatrists (eBoxes 2 and 3).

eBox 2

Case 1

eBox 3

Case 2

The aim of this review is to impart basic familiarity with autoimmune encephalitis and the diagnostic options for this group of diseases. The following questions are answered:

• What symptoms and findings may point to the presence of underlying autoimmune encephalitis?
• In which patients is an antibody diagnostic work-up for autoimmune encephalitis appropriate and how should it be carried out?
• What factors and sources of error must be considered in interpreting the results?

Methods

The PubMed database (www.pubmed.gov) was surveyed for relevant scientific research. The search strategy is described in eBox 1.

eBox 1

Supplementary information on method

Results

Clinical symptoms

Many forms of autoimmune encephalitis manifest as “limbic encephalitis,” i.e., psychiatric symptoms or qualitative impairment of consciousness in combination with epileptic seizures and memory disorders (4). Because the seizures are often not generalized (6), but occur focally as psychomotor episodes with isolated impaired consciousness and disorientation (dyscognitive seizures) (7), these patients often receive an incorrect diagnosis of delirium, encephalopathy, or neurodegenerative dementia (5).

The year 2016 saw the publication of the first consensus criteria for the diagnosis of possible autoimmune encephalitis prior to knowledge of the antibody results (8). The principal warning signs are rapidly progressive (<3 months) qualitative or quantitative impairment of consciousness, lethargy, personality changes, and deterioration of short-term memory. Further diagnostic “red flags” are newly occurring epileptic seizures, psychiatric symptoms, changes in magnetic resonance tomography (MRI) findings in the temporal lobes (bilateral alterations of the mesial portions of the lobes on T2-weighted MRI), inflammatory changes of the cerebrospinal fluid (CSF), and alterations on electroencephalography (EEG) (epilepsy-typical potentials or regional decelerations) (8). In particular, an unprovoked first occurrence of status epilepticus should prompt suspicion of autoimmune encephalitis until another cause is demonstrated (9). In many patients, however, especially the elderly, the memory deterioration takes place over a period exceeding 3 to 6 months and the initially mostly focal epileptic seizures may be misconstrued by the patients and their relatives (10, 11, e4, e5).

Antineuronal antibodies

It has been known since the 1960s that limbic forms of encephalitis may occur as paraneoplastic neurological syndromes (e6). In these cases the patients are often found to have antibodies to neuronal intracellular antigens (onconeural antibodies) (e7), are mostly elderly, almost always have a malignant tumor, and respond only poorly to immunotherapy (Table).

Table

In 2005, previously unknown antineuronal antibodies were detected in patients with severe encephalitis and benign ovarian teratomas who responded well to immunotherapy. These antibodies were directed at structures located on the surface of axons and dendrites (e8). In time, the N-methyl-D-aspartate (NMDA) receptor was identified as the underlying target antigen (12). Thirteen further “neuronal surface antigens” were identified in the following few years, mostly receptors or synaptic scaffolding proteins (Table) (13).

Incidence of autoimmune encephalitis

From what is known so far, autoimmune encephalitis is a rare disease. Its precise incidence in Germany has not yet been investigated. The German Network for Research on Autoimmune Encephalitis (GENERATE e. V.) estimates the incidence at 8 to 15 patients/1 000 000 inhabitants/year. Data from southern England suggest a similar figure (14). However, studies on the frequency of autoimmune encephalitis specifically in inpatients or outpatients with acutely or subacutely impaired consciousness are lacking as yet in Germany. Probably some members of this group of patients suffer from unrecognized autoimmune encephalitis. For example, an autoimmune or paraneoplastic etiology was found in 13 to 37% of patients with newly occurring, unprovoked, refractory status epilepticus (9, 15, 16). It can therefore be assumed that a meaningful number of undetected cases exist and that the incidence of autoimmune encephalitis is actually higher than previously thought.

Pathophysiology

In some patients the primary trigger factor for autoimmune encephalitis is a (usually previously undetected) tumor that is expressing the target antigen, e.g., ovarian teratoma in the case of anti-NMDA receptor encephalitis (17, 18). The cause of cases of autoimmune encephalitis in which no tumor is demonstrated is unclear, although viral infection (e.g., after herpes [HSV-I] encephalitis) and genetic predisposition have been postulated (19–21) (Figure 1).

Figure 1

Pathomechanism of synaptic encephalitis: the example of anti-NMDA receptor encephalitis

In a second step, probably unrelated events (e.g., systemic infections) (22) lead to migration of autoantibody-producing activated B lymphocytes across the blood–brain barrier into the brain (18). The antibodies that are then produced there exert a direct effect by binding to their target antigens (17, 23, 24). This effect is dose dependent and reversible, comparable with pharmacological inhibition (25, 26) (Figure 1). Therefore, the symptoms of most forms of autoimmune encephalitis with synaptic antibodies can be reversed by early treatment (13).

Diagnosis

Cerebral imaging and the general CSF findings—leukocyte count, cytology, and analysis of autochthonous immunoglobulin synthesis—are important for the demonstration of autoimmune encephalitis (24). Both investigations serve above all to narrow down the differential diagnoses (Box). The finding of bilateral temporomesial hyperintensities on T2/FLAIR MRI sequences may point to limbic encephalitis, but in most cases conventional imaging reveals only unspecific changes or a lack of abnormalities (27).

Box

Differential diagnoses of autoimmune encephalitis

If the CSF shows signs of inflammation with pleocytosis or detection of isolated oligoclonal bands and infection has been excluded, the encephalitis may be of autoimmune origin (Box). In autoimmune encephalitis the leukocyte count may be as high as 100/µl, or occasionally even 500/µl, and isolated oligoclonal bands are often present in the CSF (8, 28). In general, however, these inflammatory CSF changes are observed more frequently in acute cases (e.g., anti-NMDA receptor encephalitis) (28) and much less often in subacute/chronic autoimmune encephalitis (11). Therefore, while a constellation of CSF findings pointing to inflammation in a patient with impaired consciousness should always prompt consideration of underlying autoimmune encephalitis, the absence of such signs does not rule out encephalitis. Indeed, for some subforms, e.g., LGI1 encephalitis (LGI1: leucine-rich glioma inactivated protein 1), absence of these signs is typical (5, 11).

The international consensus, however, is that early diagnostic work-up for autoimmune encephalitis by means of antibody determination is required in all cases of acute or subacute qualitative or quantitative impairment of consciousness in which there is no convincing alternative etiology (Figure 2) (8). This is particularly true in the presence of the following:

Figure 2

Proposed diagnostic algorithm for investigation of autoimmune encephalitis (AE) (based on [8])

• An inflammatory CSF syndrome
• Prominent epileptic seizures
• MRI findings suggestive of unilateral or bilateral involvement of the limbic system (mesial temporal lobes) (8).

Antibody detection

As specific biomarkers, antineuronal antibodies in serum and CSF are of key importance (8). Proof of their presence enables both delineation from other differential diagnoses and also identification of the subform of autoimmune encephalitis involved. This differentiation is important for the prognosis and the recognition of a possible tumor association (Table).

In some forms of autoimmune encephalitis, autoantibody testing possesses high diagnostic sensitivity and specificity (e.g., CSF sampling in anti-NMDA receptor encephalitis: specificity 100%, sensitivity 100% [98.5 to 100.0%]) (23). Predictive values cannot currently be ascertained owing to lack of data on prevalence of the antibodies in patients with impaired consciousness from other causes.

However, autoantibodies cannot always be demonstrated in cases where clinical findings indicate that autoimmune encephalitis is probable (8). For this reason the cumulative sensitivity of comprehensive antibody testing for all potential neuronal antibodies is lower (estimated at 60 to 80%) in clinically defined autoimmune encephalitis. No data are yet available on cumulative specificity.

The following aspects have to be taken into account when testing for autoantibodies:

• Standardized commercial test systems are now available for specific detection of the most frequently occurring antibodies (Table). The examinations can thus be performed in any laboratory where the staff are familiar with autoimmune diagnostic methods (immunofluorescence, ELISA, immunoblotting). Because symptoms overlap among the various disease presentations, and owing to the multiplicity of newly identified autoantibodies, generation of an autoantibody profile (Figure 2) with inclusion of neuronal tissue is superior to the testing of individual antibodies. In a retrospective study of 2716 requests for analysis (2608 results negative, 108 positive), around 30% of the positive tests identified antibodies other than those suspected (29).
• In certain subforms serum testing without accompanying CSF analysis is considerably less sensitive and specific (e.g., anti-NMDA receptor encephalitis: 16% false-negative results for serum testing alone) (23). For this reason it is recommended to test for antibodies in both CSF and serum in parallel.
• Our own observations, in agreement with published data (30), show that isolated analysis of serum for antibodies to neuronal surface antigens using transfected cells can result in false-positive rates of 1 to 2%. Therefore any low-titer detection of these antibodies in serum (<1:40) that is not backed up by corresponding findings in the CSF should be viewed skeptically and the findings should be double-checked by means of other techniques at a laboratory with special expertise in autoimmune encephalitis (Figure 2) (17, 23).
• The autoantibodies associated with encephalitis belong, without exception, to immunoglobulin (Ig) class G (24). The diagnostic value of antineuronal antibodies of classes IgA and IgM is unclear. For example, IgA or IgM antibodies to NMDA receptors in serum are found in up to 10% of patients with various neuropsychiatric illnesses—and in the same proportion of healthy persons (30).
• In patients with anti-NMDA receptor encephalitis there is a correlation between disease activity and antibody titer in CSF but not in serum (23). However, the titer depends on the test system used, so this correlation may not be found in routine diagnostic practice. Moreover, persistence of the given antibodies has been described in the remission phase for patients with LGI1 encephalitis and anti-NMDA receptor encephalitis (11, 31).
• The most frequently occurring antineuronal antibodies can be detected with the currently available test kits, but there are no validated systems for many less common target antigens. Furthermore, increasing numbers of new antigens are being identified (32–34, e9). In patients with clinical suspicion of autoimmune encephalitis, this diagnostic gap can be bridged to some extent by means of special immunohistochemical methods, but these can usually only be carried out in specialized laboratories. These investigations, using specific tissue slices prepared in such a way as to preserve the integrity of membrane proteins, represent an expanded search system for new antibodies and simultaneously serve to verify and confirm known antibodies (Figure 2, eFigure) (13, 17). Therefore, clinically suspected autoimmune encephalitis can only be considered seronegative if this tissue-based screening test also yields no evidence of antineuronal antibody activity (8).
• Not infrequently, other systemic (e.g., antinuclear antibodies, ANA) or organ-specific (e.g., anti-thyroperoxidase, TPO) autoantibodies are detected in patients with autoimmune encephalitis. Findings of this kind, which point to a general autoimmune diathesis, may give rise to incorrect diagnoses (such as neuropsychiatric lupus erythematosus or Hashimoto encephalitis) in the absence of knowledge of the specific antineuronal antibodies and disease pattern. These diseases should thus only be considered after comprehensive testing for antineuronal antibodies, including extended serological tests (8).

eFigure

Experimental analyses

In summary, the following are required for rational antibody diagnosis in patients with qualitative or quantitative impairment of consciousness:

• General familiarity with the clinical warning signs of underlying autoimmune encephalitis on the part of the treating physician
• Consensus among hospital staff or provision by the laboratory of an antibody panel for standardized, syndrome-oriented antibody testing
• Cooperation with a laboratory experienced in the diagnosis of autoimmune encephalitis
• Close communication between treating physician and laboratory in the event of atypical clinical signs with a positive antibody constellation, or high clinical suspicion without antibody detection.

Treatment and prognosis

No randomized controlled trials on the topic of treatment for autoimmune encephalitis have been published. Encephalitis with antibodies to neuronal surface antigens generally have a good prognosis provided it is detected promptly and treated at an early stage (28). However, the prognosis in individual cases varies depending on the target antigen of the autoantibody, the presence or absence of associated tumors, the patient’s age, and the severity of the disease (10, 11, 28). For instance, 77 to 98% of patients with anti-NMDA receptor encephalitis are able to live independently by 2 years after diagnosis (multicenter observational study with 577 patients, evidence level III) (28). However, multimodal imaging and neuropsychological testing demonstrated long-term impairment of memory function (35, 36). In LGI1 encephalitis, structural damage to the hippocampus often leads to permanent cognitive deficits (37). These persisting deficits can, however, be prevented by early immunotherapy after the first epileptic seizures (retrospective cohort study, n = 80, 56% cognitive deficits without immunotherapy, 1.3% with immunotherapy, evidence level III) (6). In general, early and adequate immunotherapy seems to be one of the most important prognostic factors (11, 28).

While the swiftest possible initiation of treatment—usually intravenous steroid pulse therapy and plasma exchange—and resection of any underlying tumor are of primary importance, patients who do not respond positively should be given rituximab or cyclophosphamide as early as possible (8, 28). Those who remain refractory to this treatment have benefited from IL6 blockade (tocilizumab) or plasma cell-specific therapy (proteasome inhibitors) (38, 39). Nevertheless, it is not uncommon for a patient to need several months of convalescence with intensive rehabilitation (11, 28). Most cases of monophasic autoimmune encephalitis do not require immune therapy stretching over a period of years (evidence level V), but such measures can be considered in the event of repeated recurrence (evidence level V) (40). All the treatments described above are off label.

Despite all the laboratory tests that have recently become available, autoimmune encephalitis is still not infrequently seronegative (8). However, many of these patients benefit from immunotherapy. Therefore, all patients with high clinical suspicion of autoimmune encephalitis, even those who are seronegative, should be given immunotherapy (8). Clinical criteria for probabe seronegative autoimmune encephalitis have recently been published, but the diagnosis should be made only after exclusion of rarely occurring autoantibodies (Figure 2) (8).

Crucial for the collection of data on the whole spectrum of autoimmune encephalitis are national and international networks and registers for this group of diseases (e.g., the German Network for Research on Autoimmune Encephalitis, GENERATE e. V.; www.generate-net.de [in German]).

Conflict of interest statement
Prof. Wandinger worked for Euroimmun up to December 2012. He has received payment for a lecture from the laboratory Dr. Fenner und Kollegen.

Dr. Leypoldt has received payments for lectures from Grifols, Teva, Roche, Biogen, Merck, and Fresenius.

All three authors—Prof. Wandinger, Dr. Leypoldt, and Prof. Junker—are employed at a university institute where the work includes investigation of antineuronal antibodies.

Manuscript submitted on 19 December 2017, revised version accepted on 4 June 2018

Translated from the original German by David Roseveare

Corrresponding author
Prof. Dr. med. Klaus-Peter Wandinger
Institut für Klinische Chemie
Universitätsklinikum Schleswig-Holstein, Campus Lübeck
Ratzeburger Allee 160, 23538 Lübeck, Germany

►Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref4018

eBoxes, eFigure:
www.aerzteblatt-international.de/18m0666

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