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Paraneoplastic and autoimmune encephalitis

Paraneoplastic and autoimmune encephalitis
Authors:
Josep Dalmau, MD, PhD
Myrna R Rosenfeld, MD, PhD
Section Editor:
Patrick Y Wen, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: Jul 08, 2022.

INTRODUCTION — Encephalitis is an inflammatory condition of the brain with many etiologies. There are several types of encephalitis that are immune mediated, including the classic paraneoplastic encephalitis syndromes, often associated with antibodies against intracellular neuronal proteins (onconeuronal proteins), and the encephalitis syndromes associated with antibodies against neuronal cell surface/synaptic proteins, often referred to as "autoimmune encephalitis."

While the paraneoplastic encephalitis syndromes are invariably cancer related, the autoimmune encephalitis syndromes may occur in the presence or absence of cancer. Thus, nomenclature can be confusing, as the paraneoplastic encephalitis syndromes are autoimmune, and autoimmune encephalitis may be paraneoplastic. In this topic, the term "autoimmune encephalitis" refers specifically to those syndromes that are associated with antibodies to neuronal cell surface/synaptic proteins.

An overview of paraneoplastic syndromes and other paraneoplastic disorders are discussed separately. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle" and "Paraneoplastic cerebellar degeneration" and "Opsoclonus-myoclonus syndrome".)

PARANEOPLASTIC ENCEPHALITIS

Clinical features — Paraneoplastic encephalitis may manifest as limbic or brainstem encephalitis or be part of widespread involvement of the neuraxis, as in paraneoplastic encephalomyelitis. In the majority of cases, symptoms have an acute to subacute onset, and evaluation of the cerebrospinal fluid (CSF) often shows abnormalities such as pleocytosis, increased protein concentration, oligoclonal bands, and elevated immunoglobulin G (IgG) index, suggesting an inflammatory process. In more than half of patients, the neurologic syndrome develops before the cancer diagnosis is known.

Limbic encephalitis — Limbic encephalitis refers to an inflammatory process localized to structures of the limbic system (eg, hippocampus, amygdala, hypothalamus, cingulate gyrus, limbic cortex), although the pathologic, clinical, and radiologic findings are often not confined to these areas. Limbic encephalitis is considered a classical paraneoplastic syndrome, defined as a disorder that is commonly due to a paraneoplastic process. However, as noted below, limbic encephalitis is the main manifestation of several of the autoimmune encephalitis syndromes that may occur without a cancer association. (See 'Autoimmune encephalitis' below.)

Limbic encephalitis is characterized by acute or subacute mood and behavioral changes, short-term memory problems, focal seizures with impaired awareness (complex partial seizures), and cognitive dysfunction [1,2]. Hypothalamic dysfunction may also occur with manifestations such as hyperthermia, somnolence, and endocrine abnormalities. Symptoms typically evolve over days to weeks, but more indolent presentations over months have been described [1].

Electroencephalographic (EEG) findings include focal or generalized slowing and/or epileptiform activity, which is maximal in the temporal regions [2]. Magnetic resonance imaging (MRI) may show areas of T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity in the medial temporal lobes (image 1); contrast enhancement in these regions is infrequent. Positron emission tomography (PET) may demonstrate hypermetabolism in the medial temporal lobes; later in the course of disease, hypometabolism may be present [3].

MRI findings in the medial temporal lobes are reasonably sensitive but not specific for limbic encephalitis. Approximately 80 percent of patients with symptoms of limbic encephalitis, in whom the diagnosis is eventually confirmed during the course of disease, will have uni- or bilateral increased FLAIR signal in the medial temporal lobes on MRI. The other patients may show late changes or no changes on MRI.

The most frequent neoplasms associated with paraneoplastic limbic encephalitis are cancer of the lung (usually small cell lung cancer [SCLC]), seminoma and other testicular tumors, thymoma, breast cancer, and Hodgkin lymphoma. Neurologic symptoms typically precede discovery of the tumor by weeks or months.

The type of associated autoantibody varies with tumor type (table 1). With SCLC, most patients have anti-Hu (also known as antineuronal nuclear antibody type 1 [ANNA-1]) or CV2/collapsin-responsive mediator protein 5 (CRMP5) antibodies in their serum and CSF, and they are more likely to develop other manifestations of paraneoplastic encephalomyelitis [2,4]. Responses to treatment (in particular after successful treatment of the tumor) have been reported but are rare.

Limbic encephalitis and, less commonly, other syndromes are being reported in some patients with cancer who have been treated with immune checkpoint inhibitors. Some of these patients have anti-Hu, anti-Ma2, or other autoantibodies [5-8]. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Neurologic'.)

Brainstem encephalitis — Paraneoplastic brainstem dysfunction often occurs during the course of other paraneoplastic syndromes, such as limbic encephalitis, cerebellar degeneration, or encephalomyelitis [9]. In some patients, however, the neurologic symptoms and pathologic findings (such as perivascular and interstitial inflammatory infiltrates, gliosis, and loss of neurons) appear restricted to the brainstem (picture 1) [10]. The term "rhombencephalitis" is sometimes used to denote inflammatory conditions affecting the lower brainstem [11].

A wide spectrum of symptoms localized to the pons and/or medulla can develop in these patients, including supranuclear, internuclear, and nuclear extraocular movement deficits; opsoclonus; nystagmus; dysphagia; dysarthria; sensorineural deafness; trigeminal sensory loss; central hypoventilation; and vertigo [9,12,13].

Any of the antibodies seen in paraneoplastic encephalomyelitis can be associated with predominant brainstem dysfunction (table 1). Anti-Hu antibodies are more often associated with lower brainstem involvement, while anti-Ma2 antibodies commonly associate with upper brainstem findings.

Many different underlying tumors have been identified. Patients with SCLC typically have anti-Hu antibodies [9,13], while most patients with testicular cancer have anti-Ma2 antibodies [14]. Anti-Hu brainstem encephalitis has also been described in association with breast cancer, renal cell carcinoma, prostate adenocarcinoma, and, rarely, in patients who appear cancer free [13].

Encephalomyelitis — Paraneoplastic encephalomyelitis is characterized by involvement of several areas of the nervous system, including the temporal-limbic regions, brainstem, cerebellum, spinal cord, dorsal root ganglia, and autonomic nervous system [9,10]. The distribution of disease and symptoms varies.

Pathologic examination usually reveals perivascular and interstitial inflammatory infiltrates of T lymphocytes, gliosis, neuronophagic nodules, and loss of neurons. In addition to T cell infiltrates, B cells preferentially cluster around vessels and may be associated with plasma cell infiltrates [15,16]. The findings are typically more extensive than symptoms would suggest and may involve any area of the central nervous system (CNS), dorsal root ganglia, or autonomic neurons.

Most patients with paraneoplastic encephalomyelitis have anti-Hu antibodies (table 1) [9,17,18]. These antibodies are directed against neuron-specific ribonucleic acid (RNA)-binding nuclear proteins (picture 2) and are associated with paraneoplastic sensory neuronopathy as well as encephalomyelitis [9,17,19]. The expression of the target antigens is highly restricted to the nervous system and the tumor [10]. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Subacute sensory neuronopathy'.)

Virtually all cancer types have been associated with paraneoplastic encephalomyelitis or its variants (limbic encephalitis, brainstem encephalitis, myelitis) [9,10]. However, the underlying tumor is SCLC in approximately 75 percent of patients [9,17,18,20]. The tumor is frequently undiagnosed at the time that the neurologic syndrome develops and may be difficult to demonstrate because of its small size. This stands in direct contrast to the fact that most SCLCs are widely metastatic at diagnosis. (See "Pathobiology and staging of small cell carcinoma of the lung".)

Myelitis — Paraneoplastic myelitis occurs as part of encephalomyelitis, usually in association with SCLC. Patients often develop sensory neuronopathy (eg, involvement of the dorsal root ganglia) as well and have anti-Hu antibodies in their serum and CSF [9,10]. Motor neuron syndromes are also described.

Sensory neuronopathy differs from the usual peripheral neuropathy in that the sensory loss is not distal and symmetrical and may involve proximal areas such as the face and trunk. Limb ataxia is often prominent due to early loss of vibratory and position sensation. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle".)

Specific antibody-associated syndromes

Anti-Hu encephalomyelitis — Anti-Hu paraneoplastic syndromes are often multifocal, affecting temporal lobes, brainstem, cerebellum, dorsal roots, and/or autonomic nervous system [1,9,17,20]. In many patients, symptoms begin with, and may remain restricted to, the dorsal root ganglia, causing a subacute sensory neuronopathy [9,17] (see "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Subacute sensory neuronopathy'). Other patients with anti-Hu antibodies present with a more restricted brainstem or limbic encephalitis [9,13]. (See 'Limbic encephalitis' above and 'Brainstem encephalitis' above.)

SCLC is found in most patients with anti-Hu encephalitis [1,17,20]. Some patients have other cancer types; no cancer is found in approximately 15 percent of patients [17,20]. Some children with anti-Hu antibodies have opsoclonus-myoclonus and neuroblastoma, but more commonly, the encephalitis is not paraneoplastic. In one referral-based cohort, six of eight children with anti-Hu encephalitis were cancer free compared with none of 243 adults [21].

Early recognition of anti-Hu encephalomyelitis and prompt antitumor treatment are important in stabilizing or sometimes improving the neurologic symptoms. In one series of 200 patients with paraneoplastic encephalomyelitis and anti-Hu antibodies, antitumor treatment was associated with a significantly greater likelihood of neurologic improvement or stabilization (odds ratio [OR] 4.6) and a lower mortality rate (relative risk of death with no antitumor treatment 2.6) [17].

Immunotherapy (eg, corticosteroids, immune globulin, plasma exchange, etc), either given with antitumor treatment or alone, has also been associated with stabilization in a smaller proportion of patients [20,22]. One report describes improvement with rituximab in two patients with paraneoplastic encephalomyelitis associated with the anti-Hu antibody [23]. In children, the syndrome appears to be more treatment resistant and associated with long-term sequelae of intractable epilepsy and cognitive impairment [21].

Neurologic dysfunction is a frequent cause of death, particularly when there is brainstem and autonomic dysfunction [9]. However, prolonged survival can occur in association with regression of the tumor [17,24].

Ma2-associated encephalitis — Testicular cancer is associated with anti-Ma2 (also called anti-Ta) antibodies [14]. The Ma2 antigen is selectively expressed in neurons and the testicular tumor (picture 2). Ma2 shares homology with Ma1, a protein that is associated with other paraneoplastic neurologic syndromes, particularly brainstem and cerebellar dysfunction (table 1) [16,25].

The clinical presentation of anti-Ma2-associated encephalitis differs from classic paraneoplastic limbic encephalitis. In a series of 38 patients with anti-Ma2 encephalitis, 34 (89 percent) developed isolated or combined limbic (n = 27), diencephalic (n = 13), or brainstem encephalopathy (n = 25) [16]. MRI abnormalities were frequent in these brain regions, and inflammatory changes were typically present in the CSF. Four patients developed other syndromes, including two with a predominant cerebellar ataxia that remained stable for several years, and two with myelopathy.

Other prominent neurologic features included excessive daytime sleepiness and eye movement abnormalities, particularly a vertical gaze paresis that sometimes evolved to total external ophthalmoplegia. Three patients developed atypical parkinsonism, and two developed a severe hypokinetic syndrome. An additional case report describes an individual whose syndrome included amyotrophy of the upper extremities with an associated cervical cord lesion [26].

Testicular germ cell tumors are the most common associated neoplasms, identified in 18 of 34 patients found to have cancer in the above described series [16]. Orchiectomy may be required to reveal microscopic testicular germ cell neoplasia, as occurred in six men (age 26 to 40 years) with Ma2-associated encephalitis and no evidence of other cancer by rigorous testing [27]. All six men were identified to be at risk for testicular cancer because of new testicular enlargement, testicular microcalcifications, and/or cryptorchidism. Extragonadal germ cell tumors have also been described in association with this syndrome [28,29]. The diagnosis of testicular germ cell tumors is discussed separately. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors".)

Coexisting antibodies to Ma1 were seen in 15 of 34 patients with anti-Ma2 encephalitis and were significantly more common in patients with tumors other than testicular cancer (usually lung cancer) [16]. Compared with patients with antibodies only to Ma2, these patients are also more likely to develop ataxia and to have a worse prognosis.

Anti-Ma2-associated encephalitis is more responsive to oncologic and immunologic treatment than other types of paraneoplastic encephalomyelitis [28]. In the series cited above, neurologic improvement or stabilization occurred in 18 of 33 patients with outcome information [16]. Features significantly associated with improvement or stabilization included male sex, age 45 years or less, testicular tumor with complete response to treatment, absence of anti-Ma1 antibodies, and limited CNS involvement. However, a positive treatment response can occur in other patients as well [30].

Anti-CRMP5 encephalomyelitis — Antibodies to CRMP5 have been associated with paraneoplastic encephalitis. Cortical symptoms are often not confined to the limbic system; distinctive symptoms including cerebellar ataxia, chorea, cranial neuropathies, loss of olfaction and taste, and/or optic neuropathy have been described [31-35]. Other paraneoplastic syndromes associated with these antibodies include axonal sensorimotor neuropathy, uveitis, and optic neuritis.

The most common associated cancers are SCLC and thymoma. Improvement with anticancer therapy and corticosteroids has been described.

Others

Stiff-person syndrome – Stiff-person syndrome may occur in isolation or as part of encephalomyelitis. Paraneoplastic stiff-person syndrome is associated with antiamphiphysin antibodies and rarely with antibodies to glutamic acid decarboxylase (GAD) or the glycine receptors (GlyR) that are more commonly associated with the nonparaneoplastic syndrome [36-39]. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Stiff-person syndrome'.)

Anti-Ri encephalitis – Antibodies to Ri are found in patients with paraneoplastic opsoclonus-myoclonus and ataxia. These antibodies have also been described in some patients with paraneoplastic brainstem encephalitis with eye movement disorders, dysphagia, ptosis, laryngospasm, and/or jaw dystonia [40]. While most patients do not respond to therapy, as with other paraneoplastic neurologic disorders, there are reports of responses to early initiation of immunotherapy and tumor-directed treatment. (See "Opsoclonus-myoclonus syndrome", section on 'Pathogenesis'.)

Anti-KLHL11 encephalitis – Antibodies to Kelch-like protein 11 (KLHL11) have been described in patients with a predominant brainstem/cerebellar encephalitis that is frequently but not invariably associated with tumors, most commonly benign teratoma or a testicular tumor [41-43]. Both men and women can be affected and patients ranging in age from 9 to 76 years have been reported. These antibodies have also been described in patients with other types of autoimmune encephalitis, including anti-N-methyl-D-aspartate (NMDA) receptor and anti-Ma2 encephalitis [43]. In these patients, the presence of KLHL11 antibodies did not confer distinct clinical features.

AUTOIMMUNE ENCEPHALITIS

Clinical spectrum — The autoimmune encephalitis syndromes have a wide clinical spectrum that ranges from typical limbic encephalitis to syndromes with complex neuropsychiatric symptoms such as deficits of memory, cognition, psychosis, seizures, abnormal movements, or coma (table 1). For some autoimmune encephalitides, children and women are more often affected.

This group of disorders is associated with antibodies to neuronal cell surface/synaptic proteins [44]. The target antigens usually play critical roles in synaptic transmission and plasticity. These syndromes are variably associated with cancer, as noted below.

While patients are often severely affected, these disorders are highly responsive to immunomodulatory therapies. At this time, the treatment approach to these patients is largely based on the experience with patients with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, which is the largest group studied to date. As early initiation of treatment (immunotherapy and tumor-directed therapy, if present) has been shown to improve outcomes, speed recovery, and reduce the risk of relapses, it is important that these syndromes are promptly recognized.

Specific autoimmune encephalitis syndromes

Anti-NMDA receptor encephalitis — Anti-NMDA receptor encephalitis is associated with a predictable set of symptoms that combine to make up a characteristic syndrome [45-49].

Clinical features — Many patients present with prodromal headache, fever, or a viral-like process, followed in a few days by a multistage progression of symptoms that include:

Prominent psychiatric manifestations (anxiety, agitation, bizarre behavior, hallucinations, delusions, disorganized thinking, psychosis). In very rare instances the disease can be monosymptomatic (eg, manifesting as isolated psychosis), or psychiatric symptoms can be the only manifestation of a recurrence [50,51].

Sleep disorders, including sleep reduction at disease onset and hypersomnia during recovery [52].

Memory deficits.

Seizures.

Decreased level of consciousness, stupor with catatonic features.

Frequent dyskinesias: orofacial, choreoathetoid movements, dystonia, rigidity, opisthotonic postures.

Autonomic instability: hyperthermia, fluctuations of blood pressure, tachycardia, bradycardia, cardiac pauses, and sometimes hypoventilation requiring mechanical ventilation.

Language dysfunction: diminished language output, mutism, echolalia.

Children as young as eight months have been reported with this syndrome [47,53-56]; in the authors' experience, children as young as two months may be affected. In children, the symptoms are similar to those of the adults, with prominent early psychiatric symptoms in most patients; dysautonomia and hypoventilation are less frequent and severe. Presenting symptoms usually include acute behavioral change, seizures, language dysfunction, and prominent dyskinesias, including dystonia and chorea [57-59]. Although rare, approximately 5 percent of patients are >45 years of age [60]. In this group, the disease is less severe but outcomes tend to be worse, possibly due to delay in diagnosis and treatment.

Diagnosis and differential diagnosis — The disorder should be suspected in adults or children that develop the above clinical symptoms, usually accompanied by:

Cerebrospinal fluid (CSF) lymphocytic pleocytosis or oligoclonal bands (although basic CSF parameters can be normal initially).

EEG with infrequent epileptic activity, but frequent slow, disorganized activity that does not correlate with most abnormal movements. In one study, 7 of 23 adults had a unique electrographic pattern called extreme delta brush, a finding associated with a more prolonged illness [61].

Brain MRI that is often normal or shows transient fluid-attenuated inversion recovery (FLAIR) or contrast-enhancing abnormalities in cortical (brain, cerebellum) or subcortical (hippocampus, basal ganglia, white matter) regions [46,62]. While not routinely performed, positron emission tomography (PET) reportedly shows a characteristic increase in the frontal-occipital gradient of cerebral glucose metabolism, which correlates with disease severity [63].

The diagnosis of anti-NMDA receptor encephalitis is confirmed by the detection of IgG antibodies to the GluN1 (also known as NR1) subunit of the NMDA receptor in CSF (serum is less reliable) (table 2) [64]. However, results of antibody testing can be delayed. A set of criteria based on the clinical examination and commonly available diagnostic tests (eg, MRI, EEG, and routine CSF studies) has been proposed to support the diagnosis of probable anti-NMDA encephalitis [65]. Patients meeting these criteria should initiate treatment. The diagnosis and treatment approach can then be reevaluated when antibody testing results are available. A critical caveat to the use of these criteria is that they are not applicable to patients in the very early stages of the disease when they may have few symptoms or an isolated symptom (eg, only seizures), as the differential diagnosis is too broad.

CSF IgG antibody testing is highly sensitive and specific for anti-NMDA receptor encephalitis; false-positive and -negative results may occur when testing only serum [66]. IgM and IgA antibodies against the NMDA receptor, which have been described in some patients with chronic schizophrenia or other chronic neurologic disorders, are nonspecific, do not alter NMDA receptors in vivo, and have no additional value in the diagnosis of NMDA receptor encephalitis [67,68].

CSF antibodies are always present at the time of presentation; most patients have intrathecal synthesis of antibodies [69]. After treatment or in advanced stages of the disease, the CSF antibodies usually remain elevated if there is no clinical improvement, while serum antibodies may be substantially decreased by treatments [62,70,71]. The titer of CSF antibodies appears to correlate more closely with the clinical outcome than serum titers [46,62,66,70].

The differential diagnosis includes primary psychiatric disorders (acute psychosis or schizophrenia), malignant catatonia, neuroleptic malignant syndrome [72], viral encephalitis [73], and encephalitis lethargica [74], among others [75]. There have been several case reports of anti-NMDA receptor encephalitis in patients with current or recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [76-78]; the pathogenic link between both diseases is unclear. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Other acute neurologic manifestations'.)

Association with ovarian teratoma and other tumors — The detection of an ovarian teratoma is age dependent; approximately 50 percent of female patients older than 18 years have uni- or bilateral ovarian teratomas, while less than 9 percent of girls younger than 14 years have a teratoma [49]. A review of 400 cases showed that African-American patients have a mild predominance to have ovarian teratomas compared with patients from other ethnic groups [48]. Ovarian teratomas are often revealed by MRI and computed tomography (CT) of the abdomen and pelvis, along with abdominal or transvaginal ultrasound (table 3) [62]. (See "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis", section on 'Teratomas'.)

In male patients, the detection of a tumor is rare. Cases with associated tumors other than ovarian teratoma include testicular germ cell tumor [79], teratoma of the mediastinum, small cell lung cancer (SCLC) [46], Hodgkin lymphoma [80], ovarian cystadenofibroma [81], and neuroblastoma [82]. The frequency of underlying tumors in older patients (>45 years) is low, and when present, tumors are more often carcinomas instead of teratomas [60]. Cases have been described in patients with metastatic cancer being treated with checkpoint inhibitor immunotherapy [83]. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

Association with HSVE — Although preceding infections have been suspected to play a role in triggering autoimmune encephalitis, to date this has only been demonstrated for herpes simplex viral encephalitis (HSVE). Studies have shown that approximately 20 to 30 percent of patients who are NMDA receptor antibody-negative in serum and CSF at the time of HSVE infection seroconvert to positive NMDA receptor antibodies (or less commonly other antineuronal antibodies) in the setting of relapsing symptoms not attributable to HSVE relapse [84-87]. A smaller proportion develop NMDA receptor or other antibodies in the absence of clinical symptoms [87].

Symptoms of anti-NMDA receptor encephalitis in these cases begin at a median of four to six weeks after initial viral infection and may occur in contiguity with or after recovery from the HSVE [85,87-91]. In a series of 58 patients with antibody-confirmed autoimmune encephalitis after HSVE (74 percent with NMDA antibodies), the most common symptoms were change of behavior (93 percent), decreased level of consciousness (57 percent), choreoathetosis (47 percent, all in children four years of age or younger), seizures (38 percent), and dysautonomia (27 percent) [87]. In most pediatric cases, symptoms have included choreoathetosis and/or orofacial dyskinesias [85]; teenagers and young adults are more likely to develop behavioral and psychiatric symptoms [86]. Prompt diagnosis and treatment with immunotherapy improve symptoms and outcome despite persistence of deficits from the HSVE, especially in older children and adults [85,87].

In addition to NMDA receptor antibodies, antibodies to gamma-aminobutyric acid A (GABA-A), dopamine 2 receptor, and unknown neuronal cell-surface antigens have been reported in patients with autoimmune encephalitis after HSVE [86,87].

Treatment and prognosis — Treatment consists of immunosuppression and tumor resection when indicated [49,62,70,92]. Progressive neurologic deterioration and death can occur without treatment. However, spontaneous recovery has also been described in a few patients after several months of severe symptoms [93].

In the absence of prospective and randomized data, treatment decisions should be individualized and take into consideration patient age, the presence or absence of a tumor, and symptom severity. Based on observational studies reviewed below and clinical experience, we suggest initial treatment with intravenous methylprednisolone (eg, 1 gram daily for five days in an adult) and either intravenous immunoglobulin G (IVIG; eg, 400 mg/kg per day for five days) or plasma exchange in most patients, in addition to tumor removal when appropriate [94]. It is unknown whether IVIG and plasma exchange have similar efficacy; some clinicians may find IVIG easier to administer in patients with anti-NMDA receptor encephalitis, who may be very young and have severe dyskinesias, agitation, and autonomic instability.

If there is no evidence of clinical improvement with initial therapies, we proceed with second-line therapies including rituximab (either 375 mg/m2 weekly for four weeks, or 1 g twice two weeks apart), cyclophosphamide (750 mg/m2 monthly for four to six months depending on results), or both. A similar escalation approach is being used in children by many experts; however, in children the dose of medications is less clear and often has been adapted from the use of the same medications in other autoimmune conditions (eg, cyclophosphamide in pediatric systemic lupus erythematosus). (See "Systemic lupus erythematosus (SLE) in children: Treatment, complications, and prognosis", section on 'Severe SLE'.)

An alternative approach to stepwise escalation of immunotherapy is to use rituximab in combination with steroids and IVIG or plasma exchange as initial therapy. We increasingly favor this approach in severely affected patients, based on personal experience and accumulating data supporting the effectiveness of rituximab in reducing relapses when used in the second-line setting [94].

The largest single study on treatment and outcomes in anti-NMDA receptor encephalitis is a retrospective study of 577 patients that included 501 patients for whom treatment effects and outcome were assessable [49]. Nearly all patients (94 percent) were treated with tumor removal and first-line immunotherapy, including steroids, IVIG, and/or plasma exchange.

Half of patients improved within the first four weeks of first-line therapy. Of these, 97 percent had a good outcome at 24-month follow-up.

Of the 221 patients who did not improve within the first four weeks of first-line therapy, 125 (57 percent) received rituximab, cyclophosphamide, or both. Patients who received second-line therapy had a higher likelihood of a good outcome (modified Rankin Scale [mRS] 0 to 2) than those who did not (odds ratio [OR] 2.7, 95% CI 1.2-5.8). Response rates were similar in adults and children.

By 24 months, approximately 80 percent of patients achieved a good outcome (mRS 0 to 2) and 30 patients had died. Outcomes continued to improve for up to 18 months after symptom onset.

Twelve percent of patients relapsed within the first two years of the initial episode. Patients without a tumor and those who did not receive second-line immunotherapy were at increased risk for relapse.

The utility and safety of rituximab was examined in another retrospective study of 144 children with inflammatory or autoimmune encephalitis, including 39 with anti-NMDA receptor encephalitis [95]. All children in the series received rituximab at a median of six months from diagnosis. Early use of rituximab was associated with greater likelihood of good outcome. Infectious adverse events occurred in 8 percent of patients, including serious or fatal infection in four patients.

These and other smaller series support a treatment approach based on escalation of immunotherapy that results in substantial improvement in 75 to 80 percent of patients by 24 months [49,95-97]. Most studies show that predictors of good outcome are early treatment and low severity of disease (eg, no need for admission to an intensive care unit) [49,97]. For patients who do not appear to respond to first- and second-line therapies, other agents such as bortezomib [98-101] and tocilizumab [102,103] have been reported to provide some benefit. However, in these reports, the patients had received or were receiving standard therapies, and it is difficult to ascertain the contribution of bortezomib or tocilizumab to the response. A small series demonstrated no effect of bortezomib [104].

Patients may require intensive care support for several weeks or months, and afterwards a multidisciplinary team including physical rehabilitation and psychiatric management of protracted behavioral symptoms [46,93]. Symptoms of frontal lobe dysfunction (poor attention and planning, impulsivity, hyperphagia, behavioral disinhibition, memory deficits) and hypersomnia typically improve gradually over months but can persist long term in some patients [52,105]. Substantive persistent cognitive impairments are more common and more severe when there is a delay to diagnosis and treatment [106]. Most patients have resolution of seizures with a combination of antiseizure medications and immunotherapy, and the risk of long-term epilepsy in the absence of encephalitis relapse appears to be low [107].

The strongest risk factors for poor one-year functional outcomes are lack of clinical improvement within the first four weeks of treatment and requirement for intensive care unit admission [108]. Additional risk factors include extremes of age (≤2 or ≥65 years of age), extreme delta brush pattern on EEG, and lack of immunotherapy within the first 30 days of disease onset [94]. In children, an abnormal brain MRI and sensorimotor deficits at presentation have also been associated with worse outcomes [109].

As noted above, patients with anti-NMDA receptor encephalitis are at risk for relapse. Relapse occurs in 15 to 24 percent of patients, sometimes after several years [46,62,110]. Relapse may occur in the absence of a tumor or in association with an occult or recurrent teratoma. In several series, relapses were more common among those who did not receive immunotherapy with the initial presentation [49,110]. Adolescent presentation has also been associated with increased risk for relapse [94]. Relapses are typically treated similarly to the approach in newly diagnosed patients, with a lower threshold to initiate second-line therapies early in the course of the relapse.

Pregnancy and fetal effects — Transplacental transfer of IgG anti-NMDA receptor antibodies has been documented in serum of babies born to mothers with anti-NMDA receptor encephalitis. However, newborn outcomes appear to be good in most cases.

In a review of 21 previously published cases and 11 new cases of women who either developed anti-NMDA receptor encephalitis while pregnant or became pregnant while recovering from the encephalitis, the majority of newborns were healthy and had no evidence of neurodevelopment delay with follow-up ranging from 6 to 36 months [111-117]. Transient respiratory distress or neuromuscular deficits at delivery rarely occurred. Such complications spontaneously recovered and were considered secondary to antiseizure and sedative medications given to the mothers. Adverse outcomes included one infant with cortical dysplasia, developmental disorder, and seizures who was the result of a complicated pregnancy with uteroplacental insufficiency [112]. There was one neonatal death reported [111]. In this case, the mother had recovered from anti-NMDA receptor encephalitis 18 months before delivery and presented with eclampsia without prior knowledge of the pregnancy or prenatal care.

Obstetric complications were reported in approximately one-third of the women who developed anti-NMDA receptor encephalitis during pregnancy, mostly due to pathologic pregnancy or spontaneous miscarriage, supporting close monitoring in intensive care units focused on high-risk pregnancies [117].

Anti-LGI1 encephalitis — Patients with anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis develop memory disturbances, confusion, and seizures [118-121]. Memory and cognitive deficits may be preceded by short faciobrachial dystonic seizures that can be mistaken for myoclonus or dystonia and are often poorly responsive to antiseizure medication therapy. Patients may develop hyponatremia and rapid eye movement (REM) sleep behavior disorder.

MRI usually shows findings typical of limbic encephalitis (eg, medial temporal lobe hyperintensity) [122], while CSF is often normal or only shows oligoclonal bands [123]. Only 5 to 10 percent of cases are associated with cancer; the most common associated tumor is thymoma. The association with other tumors may be coincidental [124].

The associated antibodies target the LGI1 protein, a secreted neuronal protein that functions as a ligand for two epilepsy-related proteins, ADAM22 and ADAM23 [125]. The binding of the antibodies to LGI1 disrupts pre- and postsynaptic LGI1 signaling, resulting in neuronal hyperexcitability [126].

Treatment with glucocorticoids, IVIG, mycophenolate mofetil, and/or plasma exchange results in significant clinical improvement in 70 to 80 percent of patients [118,127-129]. Supportive evidence includes a small randomized trial of 17 patients with anti-LGI1 (n = 14) or anti-Caspr2 encephalitis and frequent seizures (two or more per week), which suggested that treatment with IVIG was superior to placebo [130]. Other observational data suggest that early initiation of immunotherapy in patients with faciobrachial dystonic seizures may prevent the development of cognitive impairment and improve long-term outcomes [120].

Experience with rituximab as an add-on therapy in patients with anti-LGI1 encephalitis is limited [131]. In our experience, complicating severe hyponatremia and nonconvulsive status epilepticus can be life threatening and should be aggressively treated. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis".)

Relapses occur in up to one-third of patients, often but not exclusively during the first six months of the disease, and are associated with worse outcome. In one study, the median time to relapse after initial presentation was 35 months [132]. Despite substantial recovery, cognitive deficits and disability persist in many patients, along with evidence of hippocampal atrophy on MRI [124,133]. The risk of long-term epilepsy appears to be low in the absence of disease relapse [107,134].

Anti-Caspr2 associated encephalitis — Anti-contactin-associated protein-like 2 (Caspr2)-associated encephalitis can manifest as limbic encephalitis, as Morvan syndrome (neuromyotonia, memory loss and confusion, sleep disturbances, autonomic instability), and in a small number of patients with isolated neuromyotonia [123,135-137]. The target antigen is Caspr2, which plays a role in maintaining the normal function of voltage-gated potassium channels (VGKC) [135]. Caspr2 autoantibodies inhibit cell adhesion interactions between Caspr2 and contactin-2, reduce levels of Caspr2 and related proteins, and cause reversible memory impairment in mice [138,139].

This disorder predominantly affects older men with a median age of 65 years, although rare pediatric cases have been described in children as young as two years old [121,137,140,141]. The presentation and disease course are slower than those of other autoimmune encephalitis syndromes. In one study, the median time to disease nadir was four months, but in 30 percent of cases it was >12 months.

Although the clinical syndrome is varied, almost 80 percent of patients develop three or more of the following core symptoms: cognitive changes, cerebellar symptoms, peripheral nerve hyperexcitability, autonomic dysfunction, insomnia, neuropathic pain, and weight loss [140]. Seizures occur in approximately one-third of patients, mostly focal nonmotor seizures with impaired awareness [142]. The disorder is usually not associated with cancer. Patients with a tumor (usually thymoma) are more likely to develop Morvan syndrome than isolated central or peripheral symptoms. Most patients have responses to immunotherapy, and approximately 25 percent will have relapses.

Anti-AMPA receptor encephalitis — Encephalitis associated with antibodies against the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor affects predominantly females, with a median age of onset of 50 to 60 years [143-147]. In a case series of 22 patients with anti-AMPA receptor antibodies, limbic encephalitis with or without seizures was the most common clinical presentation (55 percent); other presentations included limbic dysfunction along with multifocal or diffuse encephalopathy (36 percent), motor deficits followed by limbic encephalitis (one patient), and psychosis with bipolar features (one patient) [146].

An underlying neoplasm is identified in approximately two-thirds of the patients, most commonly lung, thymus, or breast [143,146,148]. A lymphocytic pleocytosis in the CSF has been reported in 50 to 90 percent of patients (range 5 to 164 cells) [143,146]. MRI is usually abnormal, with FLAIR signal abnormality in the medial temporal lobes.

In one series, 9 of 10 patients responded to treatment of the underlying neoplasm and/or immunotherapy, but subsequent relapses occurred in five (in the absence of tumor recurrence) and were associated with an incomplete treatment response and death from status epilepticus in one patient [143]. In another series, 15 of 21 patients had a full or partial response to treatment of the underlying neoplasm and/or immunotherapy [146].

Anti-GABA-A receptor encephalitis — Patients with encephalitis due to antibodies against the GABA-A receptor develop a rapidly progressive encephalitis with refractory seizures, status epilepticus, and/or epilepsia partialis continua [149]. Nearly half of reported cases are in children [150]. In these patients, the development of dyskinesias can suggest the diagnosis of anti-NMDA receptor encephalitis.

The CSF often shows lymphocytic pleocytosis with increased protein concentration. Unlike other causes of autoimmune encephalitis, in which the MRI is normal or shows abnormalities limited to the limbic system, the MRI in anti-GABA-A receptor encephalitis often shows multifocal cortical/subcortical and widespread FLAIR and T2 signal abnormalities [150]. Tumors (mostly thymoma) occur in 40 percent of patients, almost all adults; isolated cases with other tumors have been reported [149,150]. In children, anti-GABA-A receptor encephalitis may develop as a postviral encephalitis and coexist with NMDA receptor antibodies. (See 'Association with HSVE' above.)

Patients respond to immunotherapy but often require pharmacologic-induced coma for prolonged seizures.

Anti-GABA-B receptor encephalitis — Encephalitis due to antibodies against the B1 subunit of the gamma-aminobutyric acid B (GABA-B) receptor has been described primarily in adults presenting with limbic encephalitis, although presentations may vary and include limbic encephalitis with seizures, rapidly progressive dementia, status epilepticus, ataxia, or opsoclonus-myoclonus [151,152]. In one report, anti-GABA-B antibodies were the most common antibodies found in limbic encephalitis syndromes associated with SCLC that were previously considered seronegative [153]. One pediatric case was characterized by encephalopathy, refractory seizures, and a mixed movement disorder (opsoclonus, ataxia, and chorea) [154].

Approximately 50 percent of cases are paraneoplastic and almost always associated with SCLC [151,155]. Co-occurring antibodies against potassium channel tetramerization domain-containing 16 (KCTD16) increase the likelihood of a paraneoplastic etiology [152]. MRI shows FLAIR and T2 signal abnormalities consistent with limbic encephalitis in approximately one-half of patients and over one-half of patients have CSF pleocytosis and/or elevated protein levels [151].

Most patients have substantial improvement with treatment (ie, immunotherapy and tumor treatment when indicated).

Anti-IgLON5 disease — Patients with antibodies against IgLON family member 5 (IgLON5), a neuronal cell adhesion protein, manifest a neurologic disease with shared features of autoimmunity and neurodegeneration. Although REM and non-REM sleep parasomnias were highlighted in early case descriptions, subsequent studies have shown that abnormal movements and gait and balance problems are usually present, in addition to sleep problems [156-160].

In a series of 72 patients with anti-IgLON5 disease, the median age at symptom onset was 62 years (range 42 to 91 years) [160]. In approximately three-quarters of patients, symptoms progressed over months to years leading up to diagnosis. In the remaining quarter, the presentation was more rapid, with progression over weeks to a few months.

Four main clinical syndromes have been described at diagnosis: a movement disorder, which in some cases resembles progressive supranuclear palsy (PSP); a sleep disorder with parasomnias and sleep-disordered breathing; a bulbar syndrome including dysphagia, sialorrhea, stridor, or acute respiratory insufficiency; and cognitive decline with or without chorea [159,160]. Almost all patients eventually develop both abnormal movements and sleep problems, such as parasomnias, sleep apnea, insomnia, or excessive daytime sleepiness.

Video-polysomnography is essential to define the complex sleep disorder and identify characteristic features of the disorder [161] (see "Polysomnography in the evaluation of parasomnias and epilepsy"). CSF and imaging studies tend to be normal aside from the presence of anti-IgLON5 antibodies in CSF and serum. There appears to be a strong association with the human leucocyte antigen (HLA) DRB1*10:01 allele [159]. Prognosis is poor, with few patients responding to immunotherapy and a high mortality rate [159,160].

Neuropathologic evaluation of two patients at autopsy revealed neuronal loss and extensive deposits of hyperphosphorylated tau, mainly involving the brainstem tegmentum and hypothalamus. Neuropathologic criteria of anti-IgLON5-related tauopathy have been proposed [162].

Anti-DPPX encephalitis — Patients with antibodies against dipeptidyl-peptidase-like protein-6 (DPPX) develop severe prodromal symptoms of loss of weight, diarrhea, or other gastrointestinal symptoms followed within a few months (average four months) by the development of encephalitis with central hyperexcitability such as hyperekplexia, agitation, myoclonus, tremor, and seizures [163,164]. Some patients have symptoms suggestive of progressive encephalomyelitis with rigidity and myoclonus (PERM) [164,165]. Most patients have a protracted course, although subacute presentations have been reported [163,166]. Tumors are rare, and when they do occur, most are B cell neoplasms [166].

Other common features included CSF lymphocytic pleocytosis, but studies may be normal; the MRI is usually not specific. Patients usually have an initial benefit from immunotherapy, but often relapse when immunotherapy is tapered.

Anti-GlyR encephalopathy — Antibodies to the α-1 subunit of the glycine receptor (GlyR) have been associated with a syndrome of PERM, acquired hyperekplexia, and stiff-person syndrome in some patients without glutamic acid decarboxylase (GAD) antibodies [167-170]. A few patients have been reported with limbic or other encephalopathy without brainstem or spinal cord features. In a series of 45 patients, 5 had a past history and successful treatment of a tumor, and in 4 patients, the tumor diagnosis was concurrent with the neurologic disease [171]. Most patients have responses to immunotherapy. Antibodies to α-1 GlyR have also been reported in serum (and at low titers) of some patients with isolated optic neuritis, multiple sclerosis, or cerebellar ataxia without stiff-person syndrome or PERM [38,172].

Anti-mGluR5 encephalitis — Antibodies against the metabotropic glutamate receptor (mGluR) 5 have been associated with a limbic encephalitis, often including movement disorders, sleep dysfunction, and seizures [173-176]. The clinical spectrum includes prominent neuropsychiatric features (eg, progressive mood and personality changes, anterograde amnesia, disorientation), prosopagnosia, headaches, involuntary movements, and seizures. The CSF often shows pleocytosis, and in approximately half of the cases, the MRI shows FLAIR abnormalities in limbic or extralimbic regions [176].

The disorder is highly responsive to immunotherapy and treatment of the tumor, but relapses can occur. The syndrome is most commonly associated with Hodgkin lymphoma (Ophelia syndrome) or SCLC but can also occur in the absence of a tumor.

Anti-mGluR1 encephalitis — Patients with antibodies against the mGluR1 develop cerebellar ataxia that remains isolated in less than 15 percent of patients [177]. In the majority, the ataxia is accompanied by cognitive changes, seizures, or psychiatric symptoms [177-179]. Both sexes are affected, with a slight predominance of men and a median age of 55 years [177].

The CSF is abnormal is approximately 75 percent of patients, including pleocytosis, oligoclonal bands, or increased IgG index. Brain MRI is normal in most patients but can show cerebellar T2 hyperintensities or, less frequently, leptomeningeal enhancement. Cerebellar atrophy may develop over time.

The disorder is usually not cancer associated, although a few patients have had a history of a hematologic malignancy and one patient had a concurrent cutaneous T cell lymphoma. The disorder can improve with early immunotherapy. Relapses can occur, usually in the context of immunotherapy discontinuation.

Anti-neurexin-3 alpha encephalitis — Antibodies to neurexin-3 alpha have been described in a series of five patients who developed a severe encephalitis with rapid decline in consciousness, orofacial dyskinesias, and central hypoventilation that in some patients resembled anti-NMDA receptor encephalitis [180]; however, NMDA receptor antibodies were absent in all cases. Patients were relatively young (median age 44 years) and all had prodromal symptoms before the rapid decline. The CSF was abnormal in all (four with pleocytosis and one with elevated IgG index); brain MRI was normal in four and showed FLAIR abnormalities in the temporal lobes in one. All five patients received immunotherapy and three had partial recovery. One patient died from the disease and the other from sepsis. Four of the patients had evidence of systemic autoimmunity but none had a cancer history. A more complete clinical spectrum of this syndrome remains to be described.

Encephalopathy with antibodies against GFAP — Antibodies against glial fibrillary acidic protein (GFAP) have been described as a marker for a relapsing autoimmune meningoencephalitis or encephalitis, with or without myelitis [181,182]. Although these antibodies do not target a neuronal protein, they are included in this section because many of the reported patients had other relevant autoimmune responses (eg, anti-NMDA receptor antibodies, anti-GAD antibodies, and aquaporin-4 [AQP4] antibodies, among others) that may have driven the clinical syndrome. The patients had a range of clinical symptoms including headache, optic disc edema and optic papillitis, progressive encephalopathy, autonomic instability, myelopathy, tremor, and psychiatric disturbances [181-183]. Approximately one-third of the patients had a past or current systemic tumor. The CSF often showed a leukocytic pleocytosis. A variety of MRI features have been described including diffuse T2 abnormalities in periventricular white matter, leptomeningeal or perivascular enhancement (sometimes in a radial distribution), and longitudinally extensive T2 hyperintensity in the spine [184]. Most of the patients responded to glucocorticoids [181,182].

Others

Anti-mGluR2 encephalitis – Antibodies against mGluR2 were described in two patients with paraneoplastic cerebellar ataxia [185]. One patient was 78 years of age with SCLC who had a relapsing-remitting course and the other was three years old with an alveolar rhabdomyosarcoma who improved with corticosteroids. In both cases, the tumor was shown to express mGluR2.

Anti-SEZ6L2 encephalitis – Antibodies against seizure-related 6 homolog like 2 (SEZ6L2) were initially described in two patients who developed subacute cerebellar ataxia with retinopathy [186]. In a study of four additional patients, median age was 62 years, half were women, and the cerebellar syndrome was associated with extrapyramidal symptoms in three [187]. None of the reported patients had cancer.

Anti-AK5 encephalitis – Antibodies to adenylate kinase 5 (AK5) were initially described in two patients with the subacute onset of a severe limbic encephalitis refractory to therapy [188], and additional patients have been encountered [189-191]. In a review of 26 patients, the median age of onset was 66 years and 77 percent of patients were male [191]. Predominant symptoms were severe episodic amnesia, depression, anorexia, and weight loss. MRI demonstrated bilateral medial temporal T2-weighted signal abnormalities in most patients, which evolved to severe atrophy. The pathogenesis appears to involve T cell-mediated cytotoxicity and aggressive neuronal loss, and response to immunotherapy is generally poor.

DIAGNOSTIC APPROACH — In the appropriate clinical context, detection of specific autoantibodies establishes a definitive diagnosis of autoimmune or paraneoplastic encephalitis. However, not all patients with paraneoplastic encephalitis have antibodies. For these patients, the suspicion for a paraneoplastic etiology is based on the presence of a subacute, progressive neurologic syndrome conforming to the clinical features reviewed above, clinical history, including cancer risk factors, and supportive laboratory and radiologic findings.

In all patients, consideration of alternative etiologies for the encephalitis syndrome is critical (table 4), as treatment decisions should be made before confirmatory antibody test results are available, and infectious etiologies in particular should be excluded before embarking on immunosuppressive therapies.

Differential diagnosis — The differential diagnosis of autoimmune or paraneoplastic encephalitis includes a variety of alternative causes of encephalitis and encephalopathy. Broad categories include infection, toxic and metabolic disturbances, vascular disorders, neoplastic disorders, demyelinating and inflammatory disorders, psychiatric disease, neurodegenerative dementias, and rare heritable or metabolic disorders (table 4).

Some clinical syndromes, such as limbic encephalitis, may initially have a wide differential diagnosis. For example, metastatic disease affecting the brain or leptomeninges, viral encephalitis, Creutzfeldt-Jakob disease, ischemic and hemorrhagic cerebrovascular disease, Whipple disease, psychiatric disease, toxic-metabolic encephalopathy, Wernicke encephalopathy, and primary degenerative dementia have all been reported to cause a clinical syndrome for which the diagnosis of paraneoplastic or autoimmune limbic encephalitis was considered [1,64,75,192-194].

The differential diagnosis in patients with predominant brainstem encephalitis includes multiple sclerosis, Behçet syndrome, Listeria infection, enterovirus, and tuberculosis infection [11].

Some of the autoimmune encephalitides have early and prominent psychiatric manifestations, leading many of these patients to be admitted to psychiatry units, thought to be malingering, or to have a substance use disorder. Careful examination may reveal subtle neurologic deficits at this stage, findings that should lead to the consideration of autoimmune encephalitis. Most patients develop additional features of the syndrome within days or a few weeks [49,195].

Clinical evaluation and imaging — Patients with suspected autoimmune or paraneoplastic encephalitis (table 5) should have neuroimaging, EEG, lumbar puncture, and serologic testing for appropriate biomarkers to confirm the diagnosis and exclude alternative etiologies.

A brain MRI is helpful in this clinical setting to exclude a cerebrovascular event or metastatic disease, among others. Characteristic MRI findings in patients with paraneoplastic or autoimmune encephalitis include signal hyperintensities on fluid-attenuated inversion recovery (FLAIR) or T2-weighted images in affected brain regions (eg, medial temporal lobes and/or brainstem); subcortical regions and the cerebellum are sometimes affected as well. Contrast enhancement is variable. Although MRI findings are neither sensitive nor specific for these disorders, in the appropriate clinical setting they can be highly suggestive of specific syndromes (eg, multifocal FLAIR and T2 signal abnormalities in gamma-aminobutyric acid A [GABA-A] receptor encephalitis) [149]. (See 'Anti-GABA-A receptor encephalitis' above.)

An EEG should be performed in most cases to exclude nonconvulsive seizures. In patients with paraneoplastic and autoimmune encephalitis, nonspecific EEG abnormalities are common and include focal or generalized slowing, epileptiform activity, and periodic lateralized epileptiform discharges (PLEDs) [2]. Approximately one-third of patients with N-methyl-D-aspartate (NMDA) receptor encephalitis have an EEG pattern called extreme delta brush that is considered characteristic for the disorder [61].

Cerebrospinal fluid (CSF) examination should be performed and should include cell count, protein, and glucose; inflammatory markers (IgG index, oligoclonal bands); paraneoplastic and autoimmune encephalitis antibody panel testing; broad viral studies including herpes simplex virus (HSV) 1/2 and varicella zoster virus (VZV) polymerase chain reaction (PCR), and bacterial and fungal cultures when appropriate (see "Viral encephalitis in adults", section on 'Diagnosis'); and cytology to exclude leptomeningeal metastasis [196]. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors", section on 'Diagnostic evaluation'.)

Patients with paraneoplastic and autoimmune encephalitis may have normal or abnormal CSF findings. Abnormalities include modest elevation of protein (<100 mg/dL), mild to moderate lymphocytic pleocytosis, elevated IgG index, and/or the presence of oligoclonal bands [2,197]. However, these findings are variable, and some syndromes, such as anti-leucine rich glioma inactivated 1 (LGI1) encephalitis, often have only mildly abnormal or normal CSF studies [198]. A lack of inflammatory findings on CSF and MRI may be particularly common in older adults [199].

Metabolic and toxic encephalopathies should also be considered and excluded. (See "Acute toxic-metabolic encephalopathy in adults", section on 'Diagnosis'.)

If the patient does not have a known cancer diagnosis, evaluation for occult malignancy should also ensue, with the syndrome often providing a clue as to the tumor location (table 1 and table 3). For example, as small cell lung cancer (SCLC) comprises the majority of underlying neoplasms in older patients with limbic encephalitis, chest imaging should have a high priority in patients with this syndrome, whereas young women with anti-NMDA receptor encephalitis should be thoroughly investigated for an ovarian teratoma. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Search for occult malignancy'.)

Antibody testing — Paraneoplastic and autoimmune antibody testing should be performed on both serum and CSF (table 1) [64]. Not all biomarkers have commercially available testing, and some antigens remain to be characterized. Thus, negative results do not exclude a paraneoplastic or autoimmune disorder [197]. A sample of patient's CSF and serum can be sent to a research laboratory for examination in these cases. Other caveats regarding antibody testing are discussed separately. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Antibody screening'.)

General principles to follow when assessing and interpreting antibody testing in a patient with symptoms suggesting autoimmune encephalitis include the following:

Test for antibodies in serum and CSF. The approach of first testing serum and then, if negative, testing CSF is not recommended, as it delays diagnosis and may lead to false-positive results.

If serum antibody testing is positive but the CSF is negative, consider that the serum result is a false-positive diagnosis. Contact the laboratory and request retesting of the samples.

If the clinical picture does not fit with the antibody identified, the antibody may be a false-positive result [200], particularly if only serum has been examined, or it the antibodies were only identified in serum. In this case, contact the clinical laboratory for retesting or a research laboratory for guidance.

Clinical decisions should be based on clinical assessment rather than on antibody titers. Although the antibody titers may correlate with the clinical course, this correlation is imperfect, and antibody titers often remain detectable even after recovery.

Diagnostic criteria — Criteria for diagnosing paraneoplastic disorders and a clinical approach to the diagnosis of the autoimmune encephalitis have been developed by expert panels [65,201]. Because autoantibody test results (table 1) and response to antitumor and immunosuppressive therapy are not available at disease onset, these criteria rely on neurologic assessment and conventional neuroimaging and CSF testing reviewed above [65].

As an example, diagnostic criteria for definite autoimmune limbic encephalitis require all four of the following criteria (table 6):

Subacute onset (rapid progression of <3 months) of working memory deficits (short-term memory loss), seizures, or psychiatric symptoms suggesting involvement of the limbic system

Bilateral brain abnormalities on T2-weighted FLAIR MRI highly restricted to the medial temporal lobes

At least one of the following:

CSF pleocytosis (>5 white blood cells per mm3)

EEG with epileptic or slow-wave activity involving the temporal lobes

Reasonable exclusion of alternative causes

In the presence of antibodies against neuronal cell-surface/synaptic antigens or onconeural proteins, a definite diagnosis of autoimmune limbic encephalitis can be made when at least two of the first three criteria are met and alternative causes have been excluded [65]. In addition to limbic encephalitis, specific criteria for probable and definite anti-NMDA receptor encephalitis are also available (table 2). (See 'Anti-NMDA receptor encephalitis' above.)

Diagnostic criteria for paraneoplastic neurologic syndromes are reviewed separately [201]. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Diagnostic criteria'.)

TREATMENT APPROACH — The use of immunosuppressive therapy should not await the cancer diagnosis or antibody characterization in patients with a classical paraneoplastic syndrome or a highly characteristic autoimmune encephalitis syndrome (eg, anti-N-methyl-D-aspartate [NMDA] receptor encephalitis), provided an underlying infectious etiology has been ruled out [202] and there are no other contraindications. The results of antibody testing can then be used to refine or alter the treatment strategy [65,196].

There are no controlled studies of any form of immunotherapy in patients with paraneoplastic or autoimmune encephalitis. For the classical paraneoplastic encephalitis syndromes, the neuronal damage is T cell mediated, occurs rapidly, and is largely irreversible. Thus, these patients often have limited to no neurologic recovery even with maximal treatment. The best chance for symptom stabilization or improvement appears to be early identification and treatment of the tumor [203-205] and the use of immunotherapy (glucocorticoids, intravenous immune globulin [IVIG], plasma exchange, cyclophosphamide, or rituximab) in various combinations [196,203]. Exceptions include Ma2 encephalitis, in which approximately one-third of patients will improve with immunotherapy and tumor treatment, and some cases of paraneoplastic limbic encephalitis.

In contrast with paraneoplastic encephalitis, the autoimmune encephalitis syndromes are often treatment responsive, as the associated antibodies are pathogenic and reversibly affect the target antigens. Thus, treatments are aimed at antibody depletion and immunosuppression (see 'Anti-NMDA receptor encephalitis' above). Recovery can be slow (eg, up to two years in anti-NMDA receptor encephalitis). Patient response to treatment should be based on clinical evaluation, as antibody titers often do not correlate with disease activity [66].

Seizures should be treated aggressively with antiseizure medications during the acute illness (see "Initial treatment of epilepsy in adults"). Most patients will not require long-term antiseizure medication therapy [48].

The overall prognosis in patients with autoimmune encephalitis is highly variable, depending on the underlying tumor and its stage as well as the severity of the neurologic syndrome. Some patients make a complete recovery, while others die or have permanent neurologic sequelae of varying severity. Delay to diagnosis and treatment has been associated with a worse prognosis and increased relapse [49].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Paraneoplastic neurologic disorders".)

SUMMARY AND RECOMMENDATIONS

Terminology – Immune-mediated encephalitis includes the classic paraneoplastic encephalitis syndromes (table 1) and the encephalitis syndromes associated with antibodies against neuronal cell surface/synaptic proteins, referred to as "autoimmune encephalitis." (See 'Introduction' above.)

Paraneoplastic encephalitis syndromes – Paraneoplastic encephalitis can involve the limbic system (limbic encephalitis), brainstem (brainstem encephalitis), spinal cord (myelitis), or the entire neuraxis (encephalomyelitis). In most cases, symptoms have an acute to subacute onset and are accompanied by evidence of inflammation in the cerebrospinal fluid (CSF). (See 'Paraneoplastic encephalitis' above.)

Examples of classic antibody-mediated paraneoplastic encephalitis syndromes include anti-Hu encephalomyelitis, often associated with small cell lung cancer (SCLC), Ma2-associated encephalitis related to testicular cancer, and anti-collapsin-responsive mediator protein 5 (CRMP5) encephalomyelitis related to SCLC or thymoma (table 1). (See 'Specific antibody-associated syndromes' above.)

Autoimmune encephalitis syndromes – The autoimmune encephalitis syndromes have a wide clinical spectrum that ranges from typical limbic encephalitis to syndromes with complex neuropsychiatric symptoms such as deficits of memory, cognition, psychosis, seizures, abnormal movements, or coma (table 1). These disorders are associated with antibodies to neuronal cell surface/synaptic proteins and may occur in the presence or absence of cancer. The most common of these syndromes is anti-N-methyl-D-aspartate (NMDA) receptor encephalitis (table 2). (See 'Autoimmune encephalitis' above.)

Diagnostic approach – Patients with suspected paraneoplastic or autoimmune encephalitis (table 5) should have neuroimaging, EEG, lumbar puncture, and antibody testing on serum and CSF (table 1). Although antibody studies can confirm the diagnosis, initiation of treatment should not be delayed while waiting for antibody results. A provisional diagnosis should be based on the medical history and clinical features, laboratory and radiologic evidence of central nervous system (CNS) inflammation, and exclusion of infection and other alternative etiologies. (See 'Diagnostic approach' above.)

Differential diagnosis – The differential diagnosis includes a variety of alternative causes of encephalitis and encephalopathy. Broad categories include infection, toxic and metabolic disturbances, vascular disorders, neoplastic disorders, demyelinating and inflammatory disorders, psychiatric disease, neurodegenerative dementias, and rare heritable or metabolic disorders (table 4). (See 'Differential diagnosis' above.)

Treatment approach – For paraneoplastic neurologic disorders in general, there is evidence that prompt identification and treatment of the tumor (table 3) and early initiation of immunotherapy while the neurologic syndrome is still progressing offers the best opportunity to stabilize or slow the progression of the neurologic symptoms, although even in these cases, responses are rare. (See 'Treatment approach' above.)

For the autoimmune encephalitis syndromes such as anti-NMDA receptor encephalitis, early treatment (including that of the tumor, if present) is recommended, as this has been shown in some syndromes to improve outcome, speed recovery, and reduce the risk of relapses. (See 'Treatment and prognosis' above.)

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Topic 15759 Version 72.0

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