Update on the diagnosis and management of autoimmune encephalitis

Key points

• Autoimmune encephalitis should be a key part of the differential diagnosis in patients with alterations in cognition, consciousness, personality or behaviour.

• Antibody testing should be guided by recognisable clinical syndromes, but also should account for the expanding numbers of recognised antibodies and overlapping phenotypes.

• Autoimmune encephalitis may present sub-acutely with normal or subtly abnormal cerebrospinal fluid findings and neuroimaging.

• Despite severe symptoms and long intensive treatment unit stays, the outcome of autoimmune encephalitis is good in most cases if early immune therapy is given.

• The optimum first- and second-line treatment strategy for autoimmune encephalitis is unclear and well-designed clinical trials are needed.

Clinical syndromes

The spectrum of clinical presentations associated with AE is wide and partly reflects the antibody involved (Table 1). The most recognisable clinical syndromes are limbic encephalitis and NMDA-R (N-methyl-D-aspartate receptor) encephalitis.

Limbic encephalitis, reflecting inflammation of the medial temporal lobe, may present with changes in behaviour, seizures or memory difficulties. Two of the most common and well-characterised antibodies which are associated with limbic encephalitis are those directed against leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2). AE associated with LGI1 antibodies generally affects older patients and is unusual in those <40 years old. LGI1 antibodies may be associated with faciobrachial dystonic seizures: brief jerking movements affecting ipsilateral arm and face, which are highly specific to LGI1 and may precede the onset of encephalitis, but may not be present in many.³ Hyponatraemia is also a common finding.⁴ CASPR2 antibody encephalitis can present with a crossover of central and peripheral nervous system features including memory difficulties, sleep disturbances and peripheral nerve hyperexcitability syndromes. Testing for voltage gated potassium channel (VGKC)-complex antibodies should now be abandoned in favour of testing for LGI1 and CASPR2 antibodies, which target proteins associated with the ion channel. VGKC positivity in the absence of LGI1 or CASPR2 antibodies has been reported in a heterogenous group of clinical syndromes, but is not thought to be a true marker of disease.⁵

NMDA-R encephalitis most often affects children and younger adults, has a 4:1 female predominance and is associated with ovarian teratoma in around half of females. The disorder begins with abnormal behaviour, often with psychotic or affective features, developing by 1 month into a characteristic clinical picture. This may include seizures, movement disorder (classically orofacial dyskinesia, but limb dyskinesia/chorea is often predominant), reduced consciousness level and autonomic dysfunction (particularly bradycardia/tachycardia, hyperthermia and fluctuating blood pressure).⁶ NMDA-R encephalitis can occasionally be triggered by herpes simplex virus (HSV) encephalitis: in a recent prospective study of 51 patients with HSV encephalitis, 14 developed secondary autoimmune encephalitis associated with neuronal antibodies, although three also developed NMDA-R antibodies in the absence of clinical evidence of encephalitis.⁷

Other, more recently described syndromes are associated with antibodies against γ-aminobutyric acid receptors (GABAR) type A or B, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and dipeptidyl-peptidase-like protein 6 (DPPX; Table 1).

Clinicians should be aware of formes frustes within these classical syndromes, for example, some patients with incipient NMDA-R encephalitis may present with first episode psychosis or prominent movement disorder.

Diagnosis

Patients presenting with symptoms suggesting encephalitis should be admitted urgently and undergo lumbar puncture and neuroimaging. The main concern at the outset is to exclude an infective cause such as HSV, which can cause rapidly progressive brain oedema, necrosis and death. Aciclovir treatment in HSV encephalitis is a life-saving intervention. Several antibody-associated encephalitides, particularly NMDA-R encephalitis, can present similarly to primary psychiatric illness. ‘Red flag’ early features for AE include an infective prodrome, rapid progression, movement disorder, focal neurological signs, seizures or unexplained hyponatraemia.⁸

Although autoimmune encephalitis is now usually a positive diagnosis, other mimics of AE should be considered, including primary central nervous system (CNS) lymphoma, neurosarcoidosis, CNS vasculitis, tumours, genetic epilepsy syndromes, mitochondrial encephalomyopathies and prion disease.

CSF findings are often abnormal in AE, with a mild lymphocytic pleocytosis and/or moderately raised CSF protein. However, up to a third of patients have a completely normal CSF and so this does not exclude the diagnosis.⁹

Neuroimaging with magnetic resonance imaging (MRI) is essential, although this may also be normal in up to a third of cases.¹⁰ In general, MRI findings are nonspecific, although medial temporal lobe signal change frequently occurs in limbic encephalitis (eg Figs 1a and b).

• Download figure
• Open in new tab
• Download powerpoint

Fig 1.

a) T2 weighted axial magnetic resonance imaging LGI-1 antibody encephalitis showing high signal in left medial temporal lobe. b) Coronal T2 fluid-attenuated inversion recovery magnetic resonance imaging showing high signal in the left medial temporal lobe. c) Electroencephalography with N-methyl-D-aspartate receptor antibody encephalitis showing characteristic finding of extreme delta brush.

Electroencephalography (EEG) often identifies encephalopathic changes that can support the diagnosis but are nonspecific. Caution is required as psychiatric and antiepileptic drugs can cause similar features.¹¹ EEG can help to diagnose non-convulsive status epilepticus or to distinguish seizures (eg epilepsia partialis continua (EPC)) from a movement disorder. NMDA-R encephalitis may be associated with the characteristic EEG pattern of extreme delta brush (Fig 1c).

Antibody testing for encephalitis is a rapidly evolving area of neuroimmunology. Certain autoimmune encephalitides, particularly those associated with NMDA-R and LGI1 antibodies, present with recognisable clinical syndromes and diagnostic suspicion may already be high so that antibody testing can be targeted. In other cases that do not have distinguishing features, testing for a wider range of antibodies may be necessary, in consultation with a neurologist and neuroimmunology laboratory. Panels of immunofluorescence tests have been developed commercially and their role is still evolving, considering the balance between increased chance of detecting a pathogenic antibody versus the potential for false positives. Antibodies have hitherto mostly been tested in serum. However, intrathecal antibody synthesis occurs in most forms of AE and, particularly for NMDA-R antibodies, CSF testing is more sensitive and specific than serum and should be undertaken where clinical suspicion is high and in challenging cases.

Consensus criteria also allow for a diagnosis of ‘seronegative AE’, based on clinical features in the absence of antibodies which may respond to immune therapy (Box 1).^6,12

Because of the paraneoplastic associations of several antibodies, investigation for malignancy is crucial. Computed tomography (CT) of the chest, abdomen and pelvis is indicated in all patients with suspected AE. For those with particular associations, such as GABA_BR, positron-emission tomography is advised and, if negative, should be repeated at 3–6 months.¹³ Additionally, in NMDA-R encephalitis, because of the association with teratoma, ultrasound of the ovaries or testes should be performed.

Management and outcome

Evidence for optimal management of AE is largely based on retrospective studies, together with principles adapted from other antibody mediated diseases, eg myasthenia gravis. Patients with encephalitis should be managed at a centre with appropriate facilities and specialist expertise, ideally a regional neuroscience centre.

First-line therapy, aimed at reducing antibody levels rapidly, normally comprises intravenous corticosteroids often combined with intravenous immunoglobulin or plasma exchange. In those who fail to respond, more aggressive immune therapy is usually started, with concomitant higher risk of adverse effects, including cyclophosphamide or rituximab.¹⁴ In NMDA-R encephalitis, other agents such as bortezomib have been used in a small number of refractory cases. Relapses may occur when immune therapy is reduced, or may reflect tumour recurrence or persistence of missed tumour.¹⁵

Starting immune therapy early has been associated with improved outcome in NMDA-R encephalitis in retrospective series. Also, in those who fail to respond to first-line therapy, moving to more aggressive second-line treatments is associated with better outcome and reduced rate of relapse.¹⁶ In patients with ovarian teratoma, tumour resection is associated with faster rate of recovery and reduced relapse rate.¹⁶

LGI1 encephalitis generally responds well to first-line treatment, particularly corticosteroids, and outcomes are generally good, however, in the long-term cognitive problems are common.^17,18

Patients with autoimmune encephalitis often require extensive supportive care, including prolonged intensive care unit stays. Issues may include managing seizures, autonomic instability, infective complications, and agitation. Antipsychotic medications may be required, but should be used with caution due to the risk of extrapyramidal side effects or neuroleptic malignant syndrome, which may be higher in NMDA-R encephalitis.¹⁹

With appropriate treatment, outcome overall compares favourably with infective encephalitis, with >80% of patients with NMDA-R encephalitis having no more than slight disability (modified Rankin Scale 2) at 2 years.¹⁶ However, there is emerging evidence that subtle neurocognitive/psychosocial issues may be more prevalent than previously appreciated.²⁰ Support from psychology/counselling services and charitable groups, such as the Encephalitis Society, is vital in the recovery phase.

Funding

Mark A Ellul receives support from the Association of British Neurologists through a clinical research training fellowship. Benedict D Michael has received funding from the Medical Research Council, Wellcome Trust, British Medical Association, Academy of Medical Sciences and National Institute for Health Research.