The Emerging Link Between Autoimmune Disorders and Neuropsychiatric Disease

The NMDA-type glutamate receptor, long thought to be a crucial receptor in learning and memory, visual adaptation, synaptic plasticity, and disorders as diverse as schizophrenia, addiction, stroke, and Alzheimer's disease, is now also known to be a target of autoimmune dysfunction.⁹ Anti-NMDA receptor encephalitis was first described several years ago in multiple large studies that characterized the clinical syndrome in detail.^9–12 Clinicians all over the world have begun to diagnose mysterious cases of sudden behavioral change followed by profound neurologic deterioration by identifying anti-NMDA receptor antibodies in patients' CSF, and some have postulated this syndrome to be the biological underpinning for what was historically described as “demonic possession.”¹³ Patients are usually young women or children (although men have also been identified) who first present to a psychiatric setting with paranoid and delusional thinking, perceptual disturbances, agitation, changes in speech, and bizarre behavior (Table 1).^9,11 A viral prodrome often precedes psychiatric symptoms by a few weeks, but otherwise there is usually sparse past medical history. In most cases, patients rapidly deteriorate neurologically, with symptoms such as seizures, autonomic instability, dyskinesias, altered levels of consciousness with catatonic-like features, and hypoventilation that can require intubation. CSF findings include mild-to-moderate pleocytosis, but nearly half of patients have no abnormalities on brain MRI studies.⁹

Although anti-NMDA receptor encephalitis is not by definition associated with cancer, ∼50% of women with the disorder have an ovarian teratoma, with generation of antibodies in response to an antigen expressed by tumor cells.⁹ In girls younger than age 18 and in male patients of any age, even fewer have an identifiable tumor of any kind (Table 1).¹¹ Regardless of the inciting factor, the effect of the autoantibodies has been well described and is uniform. NMDA receptors are expressed throughout the brain, but immunostaining of rodent brain sections with patient antibodies demonstrates preferential labeling of hippocampus.⁹ The antibody specifically recognizes the NR1 subunit of the NMDA receptor, which is the obligate subunit and thus is present in all NMDA receptors. Binding of patient antibodies to the receptor results in internalization from the neuronal surface and reduced glutamatergic transmission, although this effect is reversible with removal of the autoantibody.^9,14

Despite the severity of neurologic symptoms, many patients respond well to treatment—likely a reflection of the reversible nature of the pathogenic cellular mechanisms. Thus, prompt recognition and diagnosis of anti-NMDA receptor encephalitis is essential. Patients with an ovarian teratoma or other tumor should have appropriate cancer care, usually with removal of the tumor and/or chemotherapy.¹⁵ In the absence of cancer (or after tumor treatment), patients are treated with immunotherapy such as intravenous immunoglobulin, corticosteroids, cyclophosphamide, and rituximab.⁹ Seventy-five to eighty percent of patients have full or substantial recovery, although usually after a prolonged hospital course. Behavioral and cognitive symptoms (disinhibition, poor attention, impulsivity) often persist for many months after the acute phase of illness, and about 20% of patients experience a relapsing course of disease.^7,9 Management of the acute and prolonged neuropsychiatric symptoms is receiving increased attention, and clinical experience suggests that despite a psychotic picture at times, high-potency dopaminergic blockade might not address symptoms as effectively as more sedating medications (MSK, JD, unpublished observations).¹⁶

Dysfunction of glutamatergic signaling can also result in limbic encephalitis when the immune system attacks AMPA-type glutamate receptors. AMPA receptors mediate the majority of fast excitatory synaptic transmission in the CNS, and disrupted AMPA receptor function is thought to be involved in learning and memory abnormalities,¹⁷ addiction,¹⁸ and depression,¹⁹ among other disorders. Anti-AMPA receptor autoantibodies bind the receptor, leading to a reversible internalization and removal from the synapse.²⁰ Patients are usually women older than 50 who present with subacute memory loss, confusion, agitated behavior, and seizures (Table 1); most also have an associated tumor of the breast, lung, or thymus.²⁰ MRI and CSF findings are typical of limbic encephalitis, and treatment is first oriented toward the tumor, followed by immunotherapy. Although patients respond well initially, this disorder is characterized by frequent relapse of short-term memory deficits and behavioral difficulties in the absence of detectable cancer recurrence, suggesting more prolonged autoimmune abnormalities.²⁰

Remarkably, in both anti-NMDA receptor and anti-AMPA receptor encephalitis, specific cases have been identified in which neuropsychiatric symptoms predominate without focal neurologic signs or progression to severe neurologic compromise. One case involved a 19-year-old man who presented with subacute cognitive changes and behavioral symptoms most consistent with a manic episode. In retrospect, his parents had noticed excessive blinking (facial dyskinesias), which they attributed to anxiety. He was found to be anti-NMDA receptor antibody-positive and responded well to immunotherapy and valproic acid without further neurologic decline (MSK, JD, unpublished observations). Other case reports describe patients with anti-AMPA receptor antibodies who had only rapidly progressive behavioral changes consistent with atypical psychosis that responded to corticosteroid therapy.²¹ Finally, Bataller and colleagues²² report on a 67-year-old woman found to have anti-AMPA receptor encephalitis, who initially experienced confusion, hypersomnia, visual hallucinations, and combativeness after surgery for breast adenocarcinoma. Two weeks after discharge, she was readmitted with memory impairment and depressed affect. After treatment with high-dose intravenous immunotherapy and chemotherapy, her memory symptoms improved, although apathy and depressed mood persisted after 3 months. One year after the initial presentation, her mood and her neuropsychological symptoms were normal aside from partial amnesia of the illness and the previous 2 years. These cases highlight emerging evidence that autoimmune processes might masquerade as psychiatric illnesses and, given the vastly different treatment options, emphasize the renewed need for large studies to determine the frequency of these syndromes in the psychiatric population.²³

In addition to modulation of glutamatergic signaling, recent work has described limbic encephalitis associated with anti-γ-aminobutyric acid type B (GABA_B) receptor autoantibodies (Table 1).²⁴ Disrupted GABA_B receptor signaling in rodents has been shown to result in seizures, memory dysfunction, anxiety, and alterations in mood.²⁵ Consistent with these findings, patients with anti-GABA_B receptor encephalitis present with prominent seizures, severe memory dysfunction, and confusion; some also experience perceptual disturbances, paranoia, and behavioral changes.²⁴ Affected patients are usually in their 60s and are equally divided between sexes. Anti-GABA_B receptor encephalitis occurs commonly with small-cell lung cancer, and more than half of patients improve with immunotherapy and tumor treatment. Interestingly, nearly half of these patients also harbor other autoantibodies, suggesting more generalized autoimmune dysfunction in this population.²⁴ Future work will help delineate the cellular mechanisms by which anti-GABA_B receptor autoantibodies result in the observed clinical syndrome.

Although multiple autoantibodies recognizing synaptic receptors have been described, recent work also implicates disruption of trans-synaptic scaffolding systems in certain autoimmune encephalitides. Trans-synaptic neuronal cell adhesion molecules are known to be crucial for proper synapse formation and adhesion, plasticity, and function.²⁶ In both developing and mature neurons, these molecules also serve to recruit and anchor pre- and postsynaptic proteins to appropriate synaptic localizations, allowing for normal synaptic transmission. In some instances, neuropsychiatric disorders such as autism and schizophrenia are postulated to result from genetic mutations in these neuronal cell-adhesion systems.^27,28 Recent discoveries now indicate that acquired autoimmune syndromes also target trans-synaptic signals. Leucine-rich glioma-inactivated 1 (LGI1) is a secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22 to create a trans-synaptic protein complex, which also includes potassium channels and AMPA-type glutamate receptors.^29,30 Mutations in LGI1 are known to cause autosomal-dominant partial epilepsy with auditory features,³¹ a syndrome characterized by temporal lobe seizures with prominent auditory hallucinations (Table 1).³² A classic limbic encephalitis previously thought to be caused by autoantibodies recognizing voltage-gated potassium channels (VGKC) is now known to result from autoantibodies targeting LGI1.^30,33 As described in detail as encephalitis attributed to anti-VGKC antibodies,³⁴ anti-LGI1 patients present most prominently with seizures, memory loss, and confusion. Other symptoms can include autonomic dysfunction (hyperhidrosis, hypersalivation) and behavioral changes such as apathy and irritability. MRI usually shows increased signal involving medial temporal lobes, although (uncharacteristic of classic limbic encephalitis) CSF is often normal. It is unclear why patients with anti-LGI1 antibodies do not often experience perceptual disturbances akin to those in patients with autosomal-dominant partial epilepsy with auditory features, although this difference is likely related to the acquired dysfunction of LGI1 later in life as opposed to a developmental abnormality. Like other autoimmune encephalopathies with extracellular antigen targets, anti-LGI1 encephalitis responds remarkably well to immunotherapy, with ∼80% of patients showing either full recovery or mild disability.^34,35

In addition to LGI1, current research suggests that another molecule involved in neuronal cell adhesion might be a target for autoimmune syndromes.^30,33 Contactin-associated protein-like 2 (Caspr2) has a role in clustering VGKC at the paranodal regions of myelinated axons.³⁶ Caspr2 is a member of the neurexin superfamily, which mediates cell–cell interactions in the CNS and in which mutations have been associated with schizophrenia, autism, and mental retardation.³⁷ Genetic-analysis experiments have described a cortical dysplasia/focal epilepsy syndrome caused by mutations in Caspr2.³⁸ Patients with these mutations present early in life (between ages 2 and 7) with intractable seizures, followed by diminished learning and social behaviors, with language regression. Other pervasive neuropsychiatric symptoms are autistic-like and include hyperactivity, inattention, and aggression. Autoantibodies recognizing Caspr2 have been described in autoimmune encephalitis, often in association with symptoms of peripheral nerve hyperexcitabilty such as neuromyotonia (difficulty in muscle relaxation), cramps, fasciculations, and muscle spasms (Table 1).^30,33,39 Taken together, these two autoimmune syndromes highlight the role of synaptic organizers in autoimmune encephalitis and open new avenues toward understanding the role of trans-synaptic signals in disease states.

A number of other multi-organ diseases appear to have autoimmune pathogenesis, with protean clinical manifestations that often include neuropsychiatric changes. Susac's syndrome, first described in 1979, consists of the triad of branch retinal arterial occlusions, hearing loss, and acute encephalopathy (Table 2).^52–54 Neuropsychiatric symptoms may be less global, however, and include personality changes, paranoia, and affective dysregulation early in the course, with memory abnormalities and increasing confusion as the syndrome progresses.^54,55 Focal neurologic findings and headache are also commonly observed.⁵⁴ Susac's syndrome usually affects young women, and a viral prodrome can precede other symptoms. MRI shows disseminated lesions in white and gray matter, with a predilection for corpus callosum involvement. EEG often reveals diffuse slowing, whereas CSF only reliably shows elevated protein (no definitive autoantibody has been identified as causative).^54,56 Fluorescein angiography and audiometry are normally part of the diagnostic process, as well. Susac's syndrome is thought to be a brain microangiopathy, with pathologic findings similar to those of autoimmune antiendothelial cell antibody syndromes.⁵³ Patients respond well if the syndrome is identified early and treated with immunosuppression,^54,55 further supporting the notion that Susac's syndrome is an autoimmune disorder.

Primary CNS vasculitis (also known as primary angiitis of the CNS) is a rare idiopathic vasculitis, with headache and encephalopathy as the most common initial symptoms (Table 2).^57–59 As with other vasculitides, this syndrome is thought to result from autoimmune dysfunction, based largely on the response to immunotherapy. Affected patients are usually middle-aged men (mean age, 50 years), with diffuse or focal neurologic findings resulting from injury to intracerebral vessels.⁵⁹ Psychiatric symptoms can include memory dysfunction, confusion, and affective changes.^57,59 Multifocal lesions or infarcts on MRI, inflammatory changes in CSF, and cerebral angiography showing vasculitic changes (alternating vessel narrowing and dilations) lead to diagnosis.⁶⁰ Although sensitivity varies among studies,⁵⁹ brain biopsy is generally considered the gold standard of diagnosis (particularly to rule out infectious processes) and often reveals granulomatous changes.^57,60 Treatment is with corticosteroids alone or in combination with cyclophosphamide.^59,60

Finally, illnesses such as CNS Whipple's disease, Sjögren's syndrome, and Behçet's disease may have prominent neuropsychiatric symptoms (Table 2). Whipple's disease is caused by infection with Tropheryma whipplei, but immune dysfunction is thought to play a role.⁶¹ With CNS involvement, oculomasticatory myorhythmia is pathognomonic,⁶² and patients commonly have cognitive changes, although other psychiatric findings (depression, anxiety, psychosis, personality change) are often found.⁶³ Case reports have described a patient with an amnestic syndrome⁶⁴ and another with Klüver-Bucy-like symptoms⁶⁵ in CNS Whipple's disease, which highlights the variable presentation in this disease. Sjögren's syndrome^66–69 and Behçet's disease^70–72—both autoimmune disorders—can involve the CNS as well, causing cognitive and personality changes (Table 2).