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Psychosomatics 2017:58:228–244 © 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Review Article

Autoimmune Encephalopathy for


Psychiatrists: When to Suspect
Autoimmunity and What to Do Next

Mark Oldham, M.D.

Objective: To provide a critical review of autoimmune connective tissue disease and other vasculitides. These
encephalopathy—broadly defined as neuropsychiatric may present variously such as with unexplained delir-
features directly related to an autoimmune process— ium, cognitive decline, or depression. Autoimmune
relevant for psychiatric practice. Methods: We con- encephalitis may be diffuse or localized as in limbic,
sulted rheumatology textbooks to define the scope of brainstem, or basal ganglia encephalitis. Unexplained
autoimmune conditions and identified recent reviews of delirium, psychosis, catatonia, strokes, and seizures are
rheumatic conditions, autoimmune vasculitis, and among common presenting symptoms. Conclusions:
autoimmune encephalitis. We integrated these with Prompt identification and management of autoim-
primary reports to provide a clinically relevant overview munity are critical for optimal outcomes. The fact that
of autoimmune encephalopathy. We focus on clinical undiagnosed and, therefore, untreated autoimmunity
features that should raise suspicion for autoimmunity. leads to debilitation demands vigilance for these con-
Results: Despite outlying conditions, 2 categories of ditions. Close attention to the unusual nature and course
autoimmune encephalopathy are described: (1) neu- of neuropsychiatric symptoms, associated neurological
ropsychiatric symptoms associated with rheumatic features, and review of systems as reviewed here should
conditions and (2) antibody-associated autoimmune guide the skillful clinician.
encephalitis. Rheumatic conditions principally include (Psychosomatics 2017; 58:228–244)

Key words: autoimmune encephalopathy, encephalitis, rheumatic disease, anti-NMDA receptor, limbic
encephalitis, paraneoplastic encephalitis.

INTRODUCTION in autoimmune conditions makes recognition difficult.


Delayed diagnosis may lead debilitating symptoms to
Autoimmune encephalopathy is increasingly recog- persist or recur for decades,3 and neurocognitive
nized for its early psychiatric symptoms.1,2 It should
be noted that many of the citations herein are from
Received February 6, 2017; revised February 22, 2017; accepted
neurological sources, which prefer the term encephal- February 22, 2017. From the Yale School of Medicine (MO), New
opathy. Encephalopathy is not operationalized, so Haven, CT. Send correspondence and reprint requests to Mark
it is used here in its broadest sense to include Oldham, M.D., Yale School of Medicine, 20 York St, Fitkin 615,
New Haven, CT 06510; e-mail: mark.oldham@yale.edu
any clinically significant neuropsychiatric features. © 2017 The Academy of Psychosomatic Medicine. Published by
However, the heterogeneity of symptoms encountered Elsevier Inc. All rights reserved.

228 www.psychosomaticsjournal.org Psychosomatics 58:3, May/June 2017


Oldham

decline may become irreversible with prolonged brain nature of neuropsychiatric symptoms may alert clini-
inflammation.4 The fact that prompt recognition of an cians to possible autoimmunity; diagnosis requires
autoimmune etiology can lead to effective treatment objective findings. Critically, computed tomography
demands that psychiatric clinicians maintain a high and magnetic resonance imaging (MRI) are insuffi-
degree of suspicion for autoimmunity, especially in ciently sensitive to rule out autoimmune encephalop-
unusual neuropsychiatric syndromes. Here, we identify athy. In fact, reviews indicate that a single brain MRI
key clinical features that raise suspicion for autoim- may have less than 50% sensitivity for detecting several
munity, provide an overview of autoimmune encepha- of these conditions.10
lopathies for the psychiatric clinician, and conclude with Many rheumatic conditions have been associated
recommendations on evaluation and management. with neuropsychiatric symptoms; however, multi-
organ involvement, complex histopathology, and
TWO CATEGORIES OF AUTOIMMUNE overlap syndromes make rheumatic conditions diffi-
ENCEPHALOPATHY cult to classify. Given intraclass and intrasyndrome
diversity in these conditions, each syndrome has a
Despite several outlying conditions, 2 categories of unique pattern of associations with neuropsychiatric
encephalopathy due to the direct effect of autoim- symptoms (Table 1).
munity are recognized: (1) rheumatic conditions with The neuropsychiatric features of AAE often
neuropsychiatric symptoms and (2) antibody- reflect brain regions affected, which may be diffuse
associated autoimmune encephalitis (AAE). Rheu- or focal (Table 2). Diffuse encephalitis implies broad or
matic conditions with neuropsychiatric symptoms multifocal inflammation. It may affect brain only
include collagen vascular disease, vasculitides with (encephalitis), extend to the meninges (meningoence-
cerebral involvement, and outliers such as neuro- phalitis), or extend to the spinal cord (encephalomye-
sarcoidosis. These syndromes are defined by the nature litis). Brain involvement presents with delirium and
and extent of systemic disease. Although psychiatric seizures. Involvement of the meninges and spinal cord
symptoms may be the presenting feature, systemic causes meningismus and localizing neurological def-
evidence of disease is typically evident concurrent with icits, respectively.
psychiatric symptoms.5 Delirium and cognitive Focal encephalitis may involve the medial temporal
impairment are the most common neuropsychiatric lobes (typically bilateral in AAE; limbic encephalitis),
presentations, but other psychiatric syndromes, such basal ganglia (basal ganglia encephalitis), or brainstem
as depression and anxiety disorders, are defined.6,7 (brainstem encephalitis or rhombencephalitis). Limbic
AAEs describe conditions of brain inflammation encephalitis is known for its common triad of ante-
associated with IgG autoantibodies targeting either rograde amnesia, seizures, and psychiatric symptoms
neuronal surface epitopes or intracellular antigens. ranging from personality change to delirium. Features
Antineuronal surface epitope antibodies are infre- of brainstem encephalitis are variable because inflam-
quently paraneoplastic, whereas anti-intracellular mation may involve any number of closely nestled
antigen antibodies are often known as onconeural brainstem tracts and nuclei. Cranial nerve palsies are
antibodies for their close association with malig- seen in three-quarters of all patients with brainstem
nancy.8 Importantly, proposed diagnostic criteria encephalitis, but the presence of altered arousal, long
for AAE identify psychiatric symptoms as a primary tract signs, cerebellar ataxia, or fever varies with
criterion for diagnosis. These criteria also allow for cause.11 Basal ganglia encephalitis is a poorly under-
probable diagnosis and treatment of many types of stood syndrome that causes dystonia, parkinsonism,
AAE while awaiting antibody confirmation.9 chorea, emotional dysregulation, or psychosis.12 Ence-
phalitis lethargica may be one subtype.13
CLINICAL OVERVIEW
FEATURES THAT SUGGEST
Autoimmune encephalopathy usually has a subacute AUTOIMMUNITY
onset, progressing over the course of 1–3 months,
though it may present acutely as in the case of acute Unusual psychiatric symptoms often cue suspicion of
disseminated encephalomyelitis. Further, the atypical an underlying autoimmune process (Table 3). These

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Autoimmune Encephalopathy for Psychiatrists

TABLE 1. Rheumatic Conditions With Psychiatric Relevance (References in Text)


Connective tissue General features Psychiatric features
disease
Systemic lupus Z4 of 11 diagnostic criteria Neurolupus case definitions:
erythematosus Serological markers: Cognitive impairment
ANA Mood disorder
Anti-Sm Anxiety disorder
Anti-dsDNA Psychotic disorder
Encephalopathy

Antiphospholipid Primary or comorbid with other rheumatic disease Strokes


Ab syndrome (e.g., lupus) or cancer

Sjögren syndrome Sicca syndrome (dry eyes and mouth) Meningoencephalitis, limbic encephalitis, and
brainstem encephalitis reported
Serological markers: Though not case definitions as in lupus, cognitive
Anti-SS-A (Ro) impairment, mood disorders, and anxiety disorders
Anti-SS-B (La) are common

Polymyositis Anti-Jo antibodies Progressive multifocal leukoencephalopathy due to


corticosteroid use reported

Vasculitis syndrome Systemic features Psychiatric features

Large-sized vessels
Takayasu arteritis Constitutional symptoms: dizziness, fever, myalgia, Anergic depression
arthralgia, and upper extremity claudication Posterior reversible encephalopathy syndrome
reported
Giant cell arteritis Amaurosis fugax, headache, and jaw claudication Rare delirium, delusions, and memory impairment

Medium-sized vessels
Polyarteritis nodosa Involves kidneys, skin, and peripheral neuropathy Encephalopathy
Kawasaki disease Pediatric fever plus Z4 of 5: Encephalopathy or listlessness
Conjunctivitis
Orolingual erythema
Swollen, red hands/feet
Truncal rash
Cervical lymphadenopathy

Small-sized vessels
ANCA-associated Leukocytoclastic vasculitis Rare encephalopathy
(also “pauci- Conflicting evidence suggests ANCA-negativity associated
immune”) with CNS involvement
Immune complex Leukocytoclastic vasculitis Rare encephalopathy due to systemic inflammation
(rare CNS deposition)

Variable-sized vessels
Behçet syndrome Painful oral ulcers (necrotic base, red halo; Z3/y), genital Brainstem encephalitis with reduced arousal and fever
ulcers, eye lesions, and skin lesions
Cogan syndrome Keratitis and pseudo-Ménière disease Cerebral vasculitis
Primary angiitis of May occur with β-amyloid deposition Multifocal strokes, headache, cognitive impairment,
the CNS and personality change

Unclassified
Susac syndrome Branch retinal artery infarct (100%), hearing loss, headache Encephalopathy, multifocal vasculitis
“Snowballs” in corpus callosum on T2/FLAIR MRI
Histology: gass plaques
Sweet syndrome Fever, painful red plaques or nodules, elevated ESR, CRP, or Benign recurrent encephalitis
WBC with neutrophilic predominance

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Oldham

TABLE 1 (Continued )
Connective tissue General features Psychiatric features
disease
Outliers
Sarcoidosis Granulomatous disease with central pulmonary involvement Cognitive impairment
in 90% Personality change
Relapsing Auricular, nasal, and respiratory chondritis, audiovestibular Brainstem encephalitis, cerebral arteritis
polychondritis damage, ocular inflammation, seronegative inflammatory
polyarthritis
Scleromyxedema Flesh-colored papules due to mucin deposition, myositis, Unexplained delirium
dysphagia, and restrictive lung disease
Serology: IgG paraproteinemia with gamma light chains
Auto-anti- Severe thrombocytopenia and macroangiopathic hemolytic Delirium
ADAMTS13 anemia
Ab Cerebrovascular events more common
ADEM Multifocal neurological deficits Encephalopathy

ADEM ¼ acute demyelinating encephalomyelitis; anti-dsDNA ¼ anti–double stranded DNA; ANA ¼ antinuclear antibodies; ANCA
¼ anti-neutrophil cytoplasmic antibodies; CNS ¼ central nervous system; CRP ¼ C-reactive protein; ESR ¼ erythrocyte sedimentation rate;
FLAIR ¼ fluid-attenuated inversion recovery.

can include delirium whose first-line workup is unre- may lead to elevated CRP and normal ESR, in part
vealing, catatonic features not attributable to a pri- because CRP rises more acutely in response to
mary psychiatric disorder especially when comorbid inflammation,21 and cases with normal CRP and
with delirium,14 subacute anterograde amnesia,9 per- ESR are reported.22 Similarly, cerebral vasculitis
sonality change,9 abnormal age of symptom onset may present with normal ESR, CRP, or both.23,24
such as late-onset mania,15 multisymptom presenta- The syndrome of inappropriate antidiuretic hormone
tions particularly with early neurocognitive decline secretion can suggest intracranial or thoracic pathol-
and nonauditory hallucinations,16 abrupt or florid ogy, and progressive hypoventilation of unclear cause
symptom onset,17 rapid progression of symptoms,18 may be due to anti–N-methyl-D-aspartate receptor
fluctuating symptoms that change over days to (NMDAR) antibody encephalitis. Because rheumatic
weeks,10 or symptoms resistant to conventional psy- conditions rarely present with isolated neuropsychi-
chiatric interventions.4 atric symptoms, evaluation for systemic features of
Neurological examination may provide important rheumatic disease is warranted.
clues to underlying cause. Focal neurological signs The value of a detailed review of systems and
may define involved central nervous system (CNS) medical and family histories bears reinforcing. Viral
regions (e.g., cranial nerve palsy accompanying brain- prodromes are seen in more than half of patients with
stem encephalitis), or they may reflect the extent of anti-NMDAR antibody encephalitis. Diffuse arthral-
inflammation (e.g., meningismus due to meningeal gia is common in connective tissue disease, sicca
involvement). Seizures in the context of altered men- syndrome in Sjögren syndrome, and headache in
tation may herald encephalitis or cerebral vasculitis.19 cerebral vasculitis. Systemic vasculitis often causes
Although generalized tonic-clonic seizures declare inanition, fever, and myalgias. Personal or family
themselves, nonconvulsive seizures can manifest with history of autoimmunity or cancer associated with
paraictal catatonia, intermittent unresponsiveness, or paraneoplastic syndromes should be inquired.
stereotypies.20 Long-term video electroencephalogra- Patients with unexplained delirium and tobacco
phy is often necessary to characterize epileptic events. use history should also be assessed for recent unin-
Medical evaluation may similarly suggest auto- tended weight loss, cough, and hemoptysis: tobacco
immunity. Elevations in the inflammatory markers, can cause small cell lung cancer that metastasizes to
erythrocyte sedimentation rate (ESR), and C-reactive brain and is associated with paraneoplastic
protein (CRP) are expected. However, acuity of illness encephalomyelitis.

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Autoimmune Encephalopathy for Psychiatrists

TABLE 2. Antibody-Associated Autoimmune Encephalitis


Neuronal surface Clinical syndromes Notable features
antigens
NMDA receptor, Diffuse encephalitis (DE), limbic encephalitis (LE) Triphasic illness
NR1 subunit Viral prodrome
Psychiatric features
Neurological and medical complications
Teratoma in approximately half of women
Tumor rare in men and children
Relapses in 10-20%
May be postinfectious (HSV1, VZV, and β-hemolytic
Strep)
AMPA, GluA1, or DE or LE Lung, breast, and thymoma (50%)
GluA2
mGlu1 Cerebellar ataxia, rare encephalopathy Lymphoma, leukemia, and prostate
May be postinfectious (VZV)
mGlu5 LE Ophelia syndrome defined by LE plus Hodgkin lymphoma
GAD-65* LE or cerebellar ataxia (?) Antibody titer associated with likelihood of
neuropsychiatric presentation
Stiff person syndrome (SPS) Often co-occurs with other autoantibodies
Thymoma or small cell (25%)
LGI1 (Kv1.1) LE, faciobrachial dystonic seizures Tumor rare
Caspr2 (Kv1.1 or Neuromyotonia, Morvan syndrome, less common LE Thymoma, endometrial carcinoma (30%)
Kv1.2)
Contactin 2 (Kv1.1) Poorly characterized Unclear
DPPX (Kv4.2) Delirium, amnesia, and depression Dysautonomia with severe diarrhea
Tumors not reported
GABAA Encephalitis, prominent seizures Lung, breast, thymoma, and Hodgkin lymphoma (450%)
GABAB Encephalitis, prominent seizures Lung and neuroendocrine (50%)
Glycine-α1 Hyperekplexia, SPS Tumor rare
IgLON5 REM sleep behavior disorder, insomnia, sleep apnea, and Tumors not reported
dysautonomia
D2 Basal ganglia encephalitis with movement disorder and Tumors not reported
psychosis May be postinfectious (β-hemolytic Strep)
Neurexin 3α Delirium Prodromal fever, headache, GI symptoms

Intracellular Paraneoplastic syndromes Tumors


epitopes

Classic antibodies
Anti-Hu (ANNA-1) Encephalomyelitis (EM), LE Small cell,† thymoma
Anti-Ri (ANNA-2) Dementing illness/EM, brainstem encephalitis (BE), LE, Gyn, breast adenocarcinoma, small cell†
cerebellar degeneration (CD)
Anti-Yo (PCA-1) CD Gyn, breast adenocarcinoma
Anti-CV2/CRMP5 EM with subacute dementia and personality change, LE, Small cell,† thymoma
CD, and chorea
Anti-Ma1 or Ma2 Cognitive impairment/EM, LE, BE, and hypothalamic Testicular germ cell tumor, non–small cell lung cancer
encephalitis
Amphiphysin Cognitive impairment/EM, LE Small cell,† breast adenocarcinoma

Nonclassic antibodies
ANNA-3 EM Small cell†
PCA-2 LE, BE, CD Small cell†
AGNA (SOX1) LE, CD Small cell†

Outlying syndromes Clinical syndromes Notable features

Hashimoto Encephalopathy with seizures, myoclonus, Steroid-responsive


encephalopathy hallucinations, or stroke-like episodes
Anti-TPO (85%)

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Oldham

TABLE 2 (Continued )
Neuronal surface Clinical syndromes Notable features
antigens
Anti-TG (70%)
Gluten Cognitive impairment Associated migraines and white matter hyperintensities
encephalopathy
Antigliadin Ab
Bickerstaff BE Associated with Miller-Fisher syndrome, which is a
encephalitis variant of Guillain-Barre syndrome
Albuminocytologic dissociation in CSF
Antibody-negative Variable Diagnosis requires:
AAE Neuropsychiatric features
2 of 3 objective findings
Other syndromes ruled out

AAE ¼antibody-associated autoimmune encephalitis; AGNA ¼ antiglial nuclear antibody (here, specifically antibodies to SOX1);
ANNA ¼ antineuronal nuclear antibodies; anti-TPO ¼ antithyroid peroxidase; BE ¼ brainstem encephalitis; CD ¼ cerebellar degeneration;
CSF ¼ cerebrospinal fluid; DE ¼ diffuse encephalitis; EM ¼ encephalomyelitis; HSV ¼ herpes simplex virus; IgLON5 ¼ immunoglobulin
LON family of cell adhesion molecules member 5; LE ¼ limbic encephalitis; PCA-1 ¼ prostate cancer antigen; REM ¼ rapid eye movement;
SPS ¼ stiff person syndrome; VZV ¼ varicella zoster virus.
n
Intracellular antigen.

Small cell tumor may be pulmonary or extrapulmonary.

SPECIFIC CONDITIONS neurolupus.26 Antiphospholipid antibodies, found in half


of patients with lupus, have been inconsistently associated
Rheumatic Conditions With Neuropsychiatric with neuropsychiatric syndromes.27 These antibodies
Symptoms confer hypercoagulability and may cause strokes, seiz-
ures, headache, or vascular cognitive impairment. Contra-
Unlike AAE, which involves direct CNS inflamma- dictory evidence suggests an association between
tion (i.e., encephalitis), rheumatic conditions tend to antiribosomal P protein antibodies and psychosis.26
cause neuropsychiatric symptoms by inflammation of Drug-induced lupus, which presents with antihistone
connective tissue and, in particular, blood vessels antibodies in 495% of cases, has a lower prevalence of
(Table 2). The neurophysiology of connective tissue neuropsychiatric features. Psychotropics that cause drug-
disease remains incompletely understood. Neuropsychi- induced lupus include bupropion, chlorpromazine, lith-
atric symptoms may be the result of vasculopathy- ium, olanzapine, and valproic acid.
related brain ischemia, systemic inflammation disrupting Neuropsychiatric symptoms are seen in a fifth of
neurotransmission, or neurological inflammation itself. patients with Sjögren syndrome, and among the fea-
Vasculitis may occur in connective tissue disease or as an tures of neuro-Sjögren are cognitive impairment (50%),
independent autoimmune vasculitis syndrome. Finally, mood disorders (26%), and anxiety disorders (12%).16
outlying rheumatic conditions with neuropsychiatric Rarely, Sjögren syndrome has been reported in asso-
import such as neurosarcoidosis are described. ciation with autoimmune encephalitis, which may be
either a focal limbic or brainstem encephalitis or diffuse
encephalitis of brain, meninges, or spinal cord.28
Rheumatic Conditions: Connective Tissue Disease
Psychiatric presentations in other connective tissue
Neuropsychiatric lupus, historically lupus cerebritis, disease, such as polymyositis, systemic scleroderma,
occurs in roughly half of patients with systemic lupus or rheumatoid arthritis, remain poorly characterized.
erythematosus.25 Of the 19 neuropsychiatric case defini-
tions for neurolupus,7 headache is the most common (87% Rheumatic Conditions: Cerebral Vasculitis
of patients with lupus) followed by cognitive impairment
(46%), mood disorders (26%), and anxiety disorders Vasculitis syndromes are categorized by size of
(12%).16 At least 20 antibodies have been associated with affected vessels and by organs involved.29 Given the

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Autoimmune Encephalopathy for Psychiatrists

TABLE 3. Clinical Features That Raise Suspicion for psychiatric involvement may include torpor, depres-
Autoimmune Cause sion, or anergia, and cases of posterior reversible
Psychiatric Personality change encephalopathy syndrome have been described.34
symptoms Multisymptom presentations Giant cell arteritis, also called temporal arteritis,
Nonauditory hallucinations
principally affects temporal arteries causing amaurosis
History Viral prodrome fugax, jaw claudication, and headache localized to the
Severe diarrhea temples with associated tenderness to touch. Though
Fever psychiatric presentations are rare, it has been reported
Personal/family history of autoimmunity
Personal/family history of neoplasm
to cause delirium, delusions, and impaired memory.35
associated with paraneoplastic syndromes The 2 medium-sized vasculitis syndromes include
Current or significant history of tobacco use polyarteritis nodosa and Kawasaki disease. Polyarter-
Natural history Abnormal age of symptom onset
itis nodosa preferentially affects kidneys, skin, and the
Abrupt or florid symptom onset peripheral nervous system, causing neuropathy. CNS
Rapid symptom progression involvement is a late finding and presents with
Changing neuropsychiatric symptoms
systemic features including fever, malaise, myalgias,
Treatment resistance
and wasting syndrome.36 CNS symptoms are expected
Neuropsychiatric Unexplained delirium to cause delirium, focal deficits, or seizures. Kawasaki
symptoms Premature cognitive impairment disease is typically a time-limited vasculitis of child-
Subacute anterograde amnesia
Catatonic features
hood. Psychiatric features are rare but may include
REM sleep behavior disorder delirium or torpor.
Small-vessel vasculitides are characterized by
Neurological Seizures
features Unexplained stroke-like events, particularly
leukocytoclastic inflammation and include (1) 3
multifocal anti-neutrophil cytoplasmic antibodies (ANCA)–
Headache associated vasculitides and (2) 4 syndromes related
Localizing neurological signs including
to immune complex deposition including cryoglobu-
cranial nerve palsies
Sensorimotor findings linemic vasculitis. Systemic features of these condi-
Movement disorder tions are the rule though they may rarely present as
delirium or stroke syndromes of unclear etiology.
Medical features Hyponatremia
Central sleep apnea
Cryoglobulinemia deserves note for its 3 subtypes.
Dysphagia Type 1 is defined by monoclonal antibody elaboration
Dysautonomia due to liquid neoplasia. In this syndrome, accumulat-
ing antibodies in the blood cause hyperviscosity, which
REM ¼ rapid eye movement.
in turn causes ischemia because of vessel sludging.
Patients may have headache, retinopathy, spontane-
ous mucosal bleeding, vertigo, delirium, or coma.37
multisystemic nature of these syndromes, clinical Neuropathology of cryoglobulinemia types 2 and
features are determined by the distribution of inflamed 3 may occur due to immune complex deposition.
vessels. Ultimate pathology is due to end-organ Vasculitides of variable-sized vessels include Beh-
ischemia. CNS involvement leads to strokes including çet and Cogan syndromes. Behçet syndrome, charac-
subcortical infarcts presenting as psychiatric syn- terized by uveitis and ulceration of the mouth and
dromes.30 Vasculitis outside the CNS can cause organ genitals, involves cerebral vessels in 5–30% of patients.
failure resulting in psychiatric symptoms, and systemic Acute neuro-Behçet syndrome presents with menin-
inflammation itself can cause delirium.31,32 goencephalitis and has a predilection for the brain-
The 2 large-vessel syndromes are Takayasu arter- stem, whereas chronic neuro-Behçet causes progres-
itis and giant cell arteritis. Takayasu affects the aorta sive neurocognitive impairment associated with ataxia
and main branches in patients younger than 40 years and dysarthria.38 Cerebral inflammation in neuro-
of age and presents with nonspecific symptoms includ- Behçet may also lead to dural sinus thrombosis or
ing dizziness, fever, myalgia, arthralgia, and upper other stroke-like syndromes.39 A quarter of patients
extremity claudication.33 Common reasons for with Cogan syndrome are estimated to have cerebral

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Oldham

involvement.40 Delirium can occur because of diffuse myositis. Associated clinical features include dyspha-
encephalitis, but stroke syndromes are more common. gia and restrictive lung disease, and serology usually
Primary angiitis of the CNS is defined by vasculitis reveals IgG paraproteinemia with gamma light
restricted to the CNS. Its most common presenting chains.49 Anti-ADAMTS13 autoantibodies cause
symptoms are headache, encephalopathy, and com- acquired thrombotic thrombocytopenic purpura, a
monly multifocal strokes suggesting diffuse cerebro- medical emergency defined by severe thrombocytope-
vascular involvement.41 The index diagnostic criterion nia and microangiopathic hemolytic anemia due to
includes unexplained neuropsychiatric symptoms, but shearing of red blood cells. Thrombotic thrombocy-
diagnosis requires angiographic or histopathological topenic purpura presents with neuropsychiatric fea-
evidence of CNS angiitis. Subacute headache with tures in two-thirds of cases; in half of the cases it
progressive subcortical cognitive impairment and involves seizures or cerebrovascular accidents, the
evidence of systemic or cerebrospinal fluid (CSF) other half with nonfocal symptoms including delirium
inflammation raise suspicion for primary angiitis of or headache.50
the CNS. Cerebral amyloid angiopathy may present Finally, encephalopathy may follow infections as
with a syndrome of CNS angiitis indistinguishable in the case of acute demyelinating encephalomyelitis,
from primary angiitis of the CNS but whose course is Bickerstaff brainstem encephalitis (described later), or
inexorable due to progressive amyloid deposition.41 several AAE syndromes (Table 1).51 For instance,
Two additional autoimmune cerebral vasculitis anti-NMDAR antibody encephalitis has been
syndromes of psychiatric relevance are Susac and reported as the cause of encephalitis following herpes
neuro-Sweet syndrome. Susac syndrome, also retino- simplex virus encephalitis.52 Acute demyelinating
cochleocerebral syndrome, is a vasculitis affecting encephalomyelitis is an immune-mediated demyeli-
retinal, inner ear, and cerebral arteries, and accord- nating disorder that presents with delirium. Its asso-
ingly causes vision loss, sensorineural hearing loss, and ciated multifocal neurological deficits should alert
often unexplained encephalopathy with headache.42 It clinicians to diffuse CNS disease.53 Symptoms may
classically presents with “snowballs” in the corpus be severe, but outcome is generally favorable. A severe
callosum on T2-weighted brain MRI.43 Neuro-Sweet form of acute demyelinating encephalomyelitis,
syndrome presents as acute encephalitis or meningitis though, acute hemorrhagic leukoencephalitis is not
in patients with abrupt-onset fever and characteristic uncommonly fatal, and those that survive are func-
painful, erythematous plaques or nodules on the tionally devastated.51
skin.44 Unlike small-vessel vasculitides mentioned
earlier, histopathology reveals neutrophilic infiltrate
without leukocytoclastic vasculitis. Antibody-Associated Autoimmune Encephalitis:
Neuronal Cell Surface Antibodies
Rheumatic Conditions: Outliers
Neuronal surface autoantibodies, most of which
Sarcoidosis is a noncaseating granulomatous dis- alter channel activity, cause downstream effects that
ease with pulmonary involvement in 90% of patients. are reversible with antibody removal.54 These anti-
Extrapulmonary disease is common and involves the bodies have varied associations with malignancy.8
nervous system in up to 15% of patients. The most Furthermore, given the reliance on case series,
common feature of neurosarcoid is cranial neuro- reported clinical associations remain provisional,
pathy. Roughly 1 in 5 with neurosarcoid presents with and recognition bias currently prevents a clear picture
cognitive or behavioral features.45 Relapsing poly- of disease spectrum. Interestingly, though the number
chondritis, which usually first presents with auricular of identified synaptic antigens continues to expand,
chondritis, has been reported as a rare cause of limbic most center on the excitatory neurotransmitter gluta-
encephalitis, cerebral vasculitis, or meningoencepha- mate (NMDA, AMPA, mGluR5, and GAD-65
litis with fever.46–48 [enzyme that converts glutamate to gamma-amino-
Scleromyxedema is a dermatological condition butyric acid {GABA}]), the inhibitory neurotransmit-
with hallmark flesh-colored papules because of mucin ters GABA/glycine (GABAA, GABAB, and glyα1),
deposition that may cause unexplained delirium and and voltage-gated potassium channel complexes

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Autoimmune Encephalopathy for Psychiatrists

(Kv1.1, Kv1.2, and Kv4.2), and many of these are clonic. Faciobrachial dystonic seizures, characterized
often co-localized within synapses.55 by brief, recurrent synchronous arm and ipsilateral
The most commonly described AAE is anti- facial twitch, are considered pathognomonic for anti-
NMDAR antibody encephalitis. In upwards of 80% LGI1 antibody syndrome.66 Antibodies against
of patients with this condition, patients present to Caspr2 are a cause of neuromyotonia that presents
psychiatric providers first,20,56,57 and an estimated as muscle hyperexcitability with fasciculations appear-
40% are admitted to a psychiatric hospital at presen- ing as a “bag of worms” rippling under the skin. They
tation.58 In fact, psychiatric and behavioral distur- also cause the broader Morvan syndrome that is
bances account for most symptom burden in adults.4 defined by neuromyotonia, insomnia, dysautonomia,
Anti-NMDAR antibody encephalitis typically causes and delirium. Anti-Caspr 2 antibodies may cause
diffuse encephalitis though limbic encephalitis may limbic encephalitis though less commonly than anti-
occur.20 Onset begins with a viral prodrome in more LGI1 antibodies. Clinical associations with anti-
than half of patients. This is followed by psychiatric contactin 2 remain unclear. Finally, antibodies to
symptoms including psychosis, mania, depression, or dipeptidyl-peptidase-like protein-6 (DPPX), the reg-
catatonia. The condition often progresses to seizures, ulatory unit of a separate potassium channel Kv4.2,
dysautonomia, and hypoventilation.59 Despite initial have also been implicated in AAE. Most of these
reports of concurrent ovarian teratoma, subsequent patients have some combination of amnesia, delirium,
reports have suggested this relationship to be weaker psychosis, or depression.67 A key clinical finding for
than initially thought. Further, only a small propor- this condition is dysautonomia that presents variously
tion of men and children have an associated tumor.4 as severe diarrhea, gastroparesis, bladder dysfunction,
Four other glutamate-related targets include the or temperature dysregulation.
AMPA receptor, mGlu1, mGluR5, and GAD-65. Antibodies to epitopes associated with inhibitory
Anti-AMPAR antibodies target either ionotropic neurotransmitter activity—GABAA, GABAB, and
glutamate receptor 1 (GluA1) or 2 (GluA2). Like glycine α1—are described infrequently. Autoantibod-
anti-NMDAR antibodies, these antibodies are asso- ies to GABAA can cause rapidly progressive severe
ciated with limbic encephalitis or diffuse encephali- delirium and treatment-refractory seizures. Several
tis.60,61 Autoantibodies to metabotropic Glu1 such patients have required pharmacologically
(mGlu1) receptors preferentially cause cerebellar dys- induced coma for seizure control.68 Anti-GABAB
function, with only 3 of 11 patients described exhibit- antibodies cause limbic encephalitis with prominent
ing cognitive impairment and 1 with paranoia and seizures as well.69 Although also a cause of limbic
auditory hallucinations.62 Anti-mGlu5 receptor anti- encephalitis, antibodies to glycine α1 have a unique
bodies are a biomarker for Ophelia syndrome, char- association with progressive encephalomyelitis with
acterized by Hodgkin lymphoma and limbic rigidity and myoclonus.70 Glycine is the major inhib-
encephalitis including hallucinations.63 GAD-65 is a itory neurotransmitter in the spinal cord, explaining
unique target because it is intracellular, yet anti-GAD- why these antibodies may also cause hyperekplexia
65 antibodies seldom suggest cancer. Although the (i.e., brisk startle) and stiff person syndrome.
pathogenicity of such antibodies remains controver-
sial, it is curious that antibody titer correlates with the Antibody-Associated Autoimmune Encephalitis:
likelihood of limbic encephalitis or cerebellar ataxia.64
Known as a single entity until 2010, anti-voltage- Intracellular Epitopes
gated potassium channel complex (anti-VGKCC) Antibodies against intracellular antigens do not
antibody encephalitis is now know to comprise anti- directly cause neuropsychiatric symptoms. Rather,
bodies targeting at least 3 antigens: LGI1, Caspr2, and associated neuropsychiatric symptoms are attributed
contactin 2.18 Each of these 3 antigens represents a to cytotoxic T-cell response.71 Small cell cancer,
distinct accessory protein in the Kv1.1 or Kv1.2 thymoma, breast cancer, and Hodgkin lymphoma
VGKCC. The binding sites of an additional 20% of have well-documented associations with paraneoplas-
anti-VGKCC antibodies remain undefined.65 Anti- tic CNS syndromes.72 CNS paraneoplastic syndromes
LGI1 antibodies are closely associated with limbic are categorized as classic or nonclassic,73 and classic
encephalitis and seizures, including generalized tonic- syndromes relevant for psychiatric features include

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Oldham

encephalomyelitis and limbic encephalitis. Brainstem described; such cases have included both limbic
encephalitis is a nonclassic syndrome and may be a encephalitis and panencephalitis.80 Early identifica-
cause of unexplained confusion.74 Paraneoplastic anti- tion of autoimmune encephalitis is critical because
bodies are similarly divided into classic or nonclassic prompt treatment is consistently associated with
(Table 2). Identifying the clinical syndrome is the first improved neurocognitive and functional outcomes.81
step, followed by serological investigation for associ- To avoid further delay in treatment, a probable
ated antibodies and a workup for occult malignancy diagnosis of antibody-negative autoimmune encepha-
guided by the antibody identified. litis may be given if a patient has symptoms of
encephalitis (short-term memory impairment, altered
Antibody-Associated Autoimmune Encephalitis: mentation, or psychiatric symptoms [This diagnostic
criterion is broad though, by analogy with other
Outliers defined syndromes, delirium, or features described
Three other AAE deserve mention: Hashimoto under the first paragraph of the section Features That
encephalopathy (HE), gluten encephalopathy, and Suggest Autoimmunity may be considered.]) and at
Bickerstaff brainstem encephalitis. The first of these, least 2 of the following 3 findings are present (brain
HE, is also known by the more illustrative name MRI suggestive of encephalitis; CSF pleocytosis,
steroid-responsive encephalopathy associated with oligoglonal bands, or elevated IgG index; or brain
thyroid antibodies.75 At least 85% of patients with biopsy with evidence of inflammation), and other
HE have antithyroid peroxidase antibodies and 70% defined syndromes mentioned earlier are excluded.9
have antithyroglobulin antibodies. Notably, 1 in 10
healthy adults in the community will be positive for WORKUP
one or both antibodies.9 The index criterion for HE is
broad: encephalopathy with seizures, myoclonus, Rather than conducting the “million-dollar workup”
hallucinations, or stroke-like episodes. Psychiatric for each patient, we recommend thoughtful testing
symptoms, including depression, psychotic mania, guided by clinical syndromes (i.e., concurrent features
rapidly progressive dementia, or even a decades- that suggest, for instance, limbic encephalitis) and
long schizophrenia-like illness, have been reported further guided by detailed psychosocial and medical
as the presenting feature of HE.75 Patients are typically history. Table 4 organizes common clinical findings
euthyroid or mildly hypothyroid at presentation, and that may suggest specific autoimmune encephalopa-
symptoms generally respond within days to high-dose thies. Guidance on performing medical workup for
corticosteroids. altered mental status is beyond the scope of this
Less common than gluten ataxia, gluten encephal- article,82,83 and specialized workup should be com-
opathy occurs in association with antigliadin anti- pleted and interpreted by providers with expertise in
bodies (either IgG or IgA). This form of cognitive those conditions. Here, we provide general consider-
impairment can occur in either celiac disease or ations for investigating autoimmunity as the cause of
nonceliac gluten sensitivity.76 Interestingly, white unexplained neuropsychiatric symptoms.9,19,30,84
matter hyperintensities are found in this condition, Where a rheumatic condition is suspected, evi-
and these patients may present with migraine-like dence of systemic disease should guide consideration
headaches along with peripheral neuropathy. Symp- of specific disease states. Nonspecific features includ-
toms typically improve with a gluten-free diet.77,78 ing arthralgias, fatigue, or weight loss may be seen
Lastly, Bickerstaff brainstem encephalitis, along with with systemic inflammation. Serological evaluation
Miller-Fisher syndrome, comprise the anti-GQ1b for rheumatic disease includes antinuclear antibodies
antibody syndrome where Bickerstaff encephalitis with reflex extractible nuclear antigen panel (i.e., anti-
describes central involvement and Miller-Fisher SS-A, anti-SS-B, anti-Scl-70, anti-Jo-1, anti-RNP, and
peripheral involvement.79 Beyond reduced arousal, anti-Sm). Anti–double stranded DNA antibodies may
clinical features of Bickerstaff encephalitis include also be seen in lupus, and antihistone antibodies
external ophthalmoplegia and ataxia. suggest drug-induced lupus. Additional laboratory
Seronegative autoimmune encephalitides exist tests may include cytoplasmic ANCA or perinuclear
whose corresponding antibodies are yet to be ANCA for ANCA-associated small-vessel vasculitis,

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Autoimmune Encephalopathy for Psychiatrists

TABLE 4. Clinical Features That May Suggest Specific Autoimmune Encephalopathies

History and review of systems


Constitutional
Unintended weight loss Paraneoplastic syndrome, systemic vasculitis
Viral prodrome Anti-NMDAR, postinfectious encephalitis
Fulminant progression Acute hemorrhagic leukoencephalitis (i.e., severe ADEM)
REM sleep behavior disorder Anti-IgLON5, -LGI1
Recently stopped immunosuppression Immune reconstitution inflammatory syndrome (IRIS)
Recently started antiretroviral therapy IRIS
Heavy smoking Small-cell-related paraneoplastic syndrome, cerebral Buerger

Neuromuscular
Myasthenia gravis Anti-Caspr2
Refractory epilepsy Anti-GABAA or -GABAB
Strokes Vasculitis, antiphospholipid antibody syndrome

Head, ears, eyes, nose, and throat


Photosensitivity Lupus, Cogan syndrome
Dry eyes and mouth Sjögren syndrome
Jaw claudication and amaurosis fugax Giant cell arteritis
Painful oral ulcers Beçhet syndrome
Visual field deficit and hearing Susac syndrome
impairment
Dizziness Takayasu arteritis, Cogan syndrome
Headache Vasculitis (giant cell arteritis with temporal headache)
Migraines Antigliadin antibody

Gastrointestinal
Diarrheal prodrome Anti-DPPX
Chronic GI symptoms Antigliadin antibody

Cardiopulmonary
Dyspnea Connective tissue disease, sarcoidosis, scleromyxedema, and relapsing polychondritis

Musculoskeletal
Raynaud phenomenon Connective tissue disease, cryoglobulinemia
Arthralgia Connective tissue disease, vasculitis
Myalgia (often proximal) Connective tissue disease, vasculitis

Obstetric
Recurrent spontaneous abortion Antiphospholipid antibody syndrome

Mental status examination


Catatonia Encephalitis
Dense anterograde amnesia Limbic encephalitis (consider antibody-associated autoimmune encephalitis)
Prominent psychosis Anti-AMPAR

Laboratory evidence
Hyponatremia SIADH due to cerebral process (nonspecific)
Blood dyscrasia Thrombocytopenia or hemolytic anemia in lupus, macroangiopathic hemolytic anemia in
vasculitides
Renal impairment (otherwise unexplained) Lupus and vasculitis (often small-vessel vasculitides)
Pulmonary granuloma Sarcoidosis
Albuminocytologic dissociation in CSF Anti-GQ1b (i.e., Miller-Fisher/Bickerstaff)

Physical findings
General
Dysautonomia Anti-NMDAR, -DPPX, -Caspr2, and IgLON5

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Oldham

TABLE 4. Continued

Head, ears, eyes, nose, and throat


Cranial nerve palsies Brainstem encephalitis or ADEM
Symmetric ophthalmoplegia Bickerstaff
Interstitial keratitis (eye pain and redness) Cogan syndrome, relapsing polychondritis
Vestibular disturbance Cogan syndrome, relapsing polychondritis
Auricular chondritis Relapsing polychondritis
Nasal chondritis Relapsing polychondritis
Oral ulcers Lupus or Beçhet syndrome

Cardiopulmonary
Pericarditis or pleurisy Lupus
Hypventilation Anti-NMDAR
Dry cough Sarcoidosis, paraneoplastic syndrome associated with small cell lung cancer

Neuromuscular
Meningismus Meningoencephalitis (broad differential though ruling out infection is paramount)
Quadriparesis Bickerstaff or other brainstem encephalitis
Faciobrachial dystonic seizures Anti-LGI1
Neuromyotonia (“bag of worms” Anti-Caspr2
appearance)
Cerebellar ataxia Paraneoplastic cerebellar degeneration, brainstem encephalitis, and antigliadin antibodies
Seizure Broad differential but may suggest temporal lobe involvement such as limbic encephalitis
Dystonia, parkinsonism, and myoclonus Basal ganglia encephalitis, antiglycine α1
Chorea Basal ganglia encephalitis, anti-CV2/CRMP5
Myalgia (typically proximal) Connective tissue disease, vasculitis
Hyperekplexia Antiglycine α1

Dermatologic
Malar (butterfly) or discoid rash Lupus
Livedo reticularis or racemosa Vasculitis, antiphospholipid antibody syndrome (including Sneddon syndrome)
Digital necrosis Cryoglobulinemia
Painful red plaques and nodules Sweet syndrome
Flesh-colored papules Scleromyxedema

Genitourinary
Genital ulceration Beçhet syndrome

ADEM ¼ acute demyelinating encephalomyelitis; CSF ¼ cerebrospinal fluid; IgLON5 ¼ immunoglobulin LON family of cell adhesion
molecules member 5; NMDAR ¼ N-methyl-D-aspartate receptor; REM ¼ rapid eye movement.

angiotensin converting enzyme activity or chest X-ray tomography angiogram) provides radiographic evi-
for sarcoidosis, serum or urinary protein electropho- dence of cerebral vasculitis. Definitive diagnosis of
resis or both with immunofixation for confirmation to vasculitis not uncommonly requires biopsy.
assess for oligoclonal bands, or serum cryoglobulins to AAE may be suggested by leukocytosis, lympho-
rule out cryoglobulinemia. cytosis, or other evidence of systemic inflammation
Cerebral vasculitis is suggested by headache, such as tachycardia or fever. Most patients have
seizures, cognitive and personality change, and cere- elevated CRP and ESR, but these are not universal.
brovascular events—either transient ischemic attacks Routine electroencephalogram should be considered
or strokes. Standard assessment for thrombophilia is to rule out nonconvulsive seizures or evidence of
warranted for cerebrovascular events. Brain MRI with encephalopathy.85 Long-term monitoring with
and without contrast, electroencephalography, and video-electroencephalogram may be performed where
lumbar puncture additionally assess for evidence of clinical suspicion for occult epileptic activity is high.
cerebral inflammation. Cerebral angiography (arterio- Sensitivity of brain MRI for individual subtypes of
gram, magnetic resonance angiography, or computed AAE varies, but where present, findings include

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Autoimmune Encephalopathy for Psychiatrists

hyperintensities on T2-weighted or fluid-attenuated neutralize or remove circulating antibodies, they are


inversion recovery sequences. Lumbar puncture best reserved for conditions with pathogenic antibodies
should be considered to evaluate for leukocytes in (e.g., those that target neuronal surface antigens).91
the CSF (operationalized as Z5/mm3)9 and particu- IVIg or therapeutic plasma exchange may be
larly lymphocytic pleocytosis. Oligoclonal bands or used as acute monotherapy where steroids are
elevated IgG index in the CSF may provide further contraindicated.84
evidence in support of AAE. Antibodies may be Up to half of patients with AAE have a satisfactory
produced by intrathecal lymphocytes, so CSF is response to acute, first-line therapy, but maintenance
preferred for send-out evaluation of antibody panels.86 immunotherapy is recommended for 6 months or
Academic centers such as the Mayo Clinic offer longer for continued symptom improvement and
thorough antibody panels defined by clinical scenario relapse prevention.81 It usually involves a gradual
(e.g., encephalopathy, paraneoplastic syndromes, or steroid taper and initiation of second-line agents, chiefly
early/rapidly progressive dementia). rituximab and cyclophosphamide. The antimetabolites
(azathioprine, mycophenolate mofetil, and methotrexate)
MANAGEMENT OF PSYCHIATRIC are used less frequently. Readers are referred to recent
SYMPTOMS reviews that outline treatment algorithms and immuno-
therapy regimens used for AAE.9,73,81,84
A patient with autoimmunity should be managed by a Paradoxically, corticosteroids initiated to treat
clinician with expertise treating the condition in autoimmune conditions with neuropsychiatric symp-
question. Additionally, because managing autoim- toms may themselves cause neuropsychiatric symp-
munity involves immunosuppression, ruling out con- toms. Steroid-induced neuropsychiatric symptoms are
current infection is critical87 (discussed in Ref. 88 for dose-dependent and commonly present within days of
thorough review of encephalitic causes). Best evidence starting therapy.92 The temporal association between
management recommendations for autoimmune ence- neuropsychiatric symptoms (improvement, worsen-
phalopathies rely on observational studies and expert ing, or change in character) and corticosteroids
opinion.84 (initiation or dose change) often illuminates whether
Management of neuropsychiatric symptoms asso- symptoms are due to underlying autoimmunity or an
ciated with rheumatic conditions involves immuno- adverse effect of treatment. Where steroid dose reduc-
therapy tailored to specific autoimmune condition plus tion or switch to alternative immunotherapy is infea-
symptomatic treatment of neuropsychiatric symp- sible, management of steroid-induced symptoms is
toms. See, for instance, clinical guidelines for manag- symptomatic. Of note, rituximab may rarely cause the
ing neurolupus.89 Most cerebral vasculitides are devastating condition progressive multifocal
treated with corticosteroids, often combined with leukoencephalopathy.
other agents such as cyclophosphamide.30 No randomized trials for autoimmune encephal-
AAE treatment involves acute and maintenance opathy treatment have been conducted. Response rates
immunotherapy,84 and neurological examination to symptomatic treatment are lower in this population
should be completed before starting treatment to gauge than in primary psychiatric disorders.10,93 Encephalitis
response and inform subsequent treatment decisions. and vasculitis commonly cause seizures, so mood-
High-dose corticosteroids are first-line along with stabilizing antiepileptics, such as valproic acid or
removal of associated tumor where identified, espe- carbamazepine, and benzodiazepines may be preferred
cially ovarian teratomas associated with anti-NMDAR for agitation. Atypical neuroleptics are generally pre-
antibody encephalitis. Onconeural antibodies strongly ferred to typical antipsychotics for reduced risk of
suggest malignancy, but paraneoplastic syndromes are extrapyramidal symptoms. Even still, recent findings
likely to precede tumor identification for months to suggest that features of neuroleptic malignant syn-
years.74 Steroids may be combined with intravenous drome may be seen in upwards of half of patients with
immunoglobulin (IVIg) or, less commonly, therapeutic anti-NMDAR antibody encephalitis treated with either
plasma exchange, but clinical decisions are strongly typical or atypical neuroleptics.58 This should also be
influenced by physician specialty and geography.90 borne in mind when treating steroid-induced psychosis.
Because IVIg and therapeutic plasma exchange Catatonia warrants treatment with benzodiazepines,

240 www.psychosomaticsjournal.org Psychosomatics 58:3, May/June 2017


Oldham

and electroconvulsive therapy has been used success- on the differential for all psychiatric symptoms,
fully in this population. unusual syndromes demand further consideration.
Disease course and degree of recovery are dictated Where possible, clinical syndromes should be charac-
by the underlying autoimmune condition, and this terized with ample guidance from history and neuro-
limits generalizability of comments. Nevertheless, logical examination. Current reports of autoimmune
many autoimmune encephalopathies are incompletely encephalopathies should be considered preliminary.
resolved with treatment, leaving patients with chronic Autoimmunity as a cause of neuropsychiatric features
neuropsychiatric symptoms and functional impair- continues to gain greater awareness, and this aware-
ment. For instance, although roughly 4 in 5 patients ness is expected to lead to a clearer understanding of
with anti-NMDAR antibody encephalitis may be their clinical diversity. Many of the syndromes cata-
functionally independent at 2-year follow-up, many loged here rely on case reports and series, so reporting
of these patients still have persisting impairment.4 bias must be acknowledged. Most importantly, iden-
Interventions to improve quality of life in postautoim- tifying an autoimmune cause for neuropsychiatric
mune encephalopathy population deserve further features offers therapeutic inroads, offering both an
investigation. answer and hope of recovery to patients and their
families.
CONCLUSIONS
Acknowledgments: M.O. expresses his deep grat-
Many autoimmune conditions have relevance for itude to Hochang Ben Lee, M.D., and to Paul Desan,
psychiatric clinicians, particularly those practicing in M.D., Ph.D., for their investments in professional
medical settings. Although secondary causes should be development and encouragement in this manuscript.

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