Matthew S. Kayser, MD, PhD

While a biological basis for numerous psychiatric illnesses has become increasingly appreciated, few mechanistic hypotheses have gripped psychiatric researchers as strongly as an autoimmune basis for behavioral abnormalities. Perhaps the most extreme example of autoimmune phenomena that result in psychiatric changes can be found in antibody-mediated limbic encephalitis. In these syndromes, autoantibodies interfere either directly or indirectly with neuronal function, the outcome of which is striking cognitive and behavioral changes often accompanied by severe neurological symptoms (

In this article, we explore the psychiatric features of autoimmune encephalopathies, and discuss their diagnosis and management.

Paraneoplastic disorders are caused by autoimmune activity triggered by neuronal antigens expressed by tumors located outside the CNS that impinge on the nervous system in a manner independent from the cancer itself.

 These disorders may cause symptoms that range from sensory neuropathies to severe psychiatric disturbances and involve the peripheral or central nervous system.

Early recognition of paraneoplastic disorders is essential given the potential for treatment with immunotherapy (intravenous immunoglobulin, plasmapheresis, corticosteroids, among others) and the improved outcomes of many cancers.

 Not all patients with paraneoplastic disorders harbor known antibodies, but characterization of many paraneoplastic antibodies has provided a method for screening as well as early detection of cancers.

 The prevalence of paraneoplastic disorders is variable and depends on the type of cancer: rates are highest in small-cell lung cancer (3% to 5%) and thymomas (20%).

Many paraneoplastic disorders with neuropsychiatric manifestations occur in association with autoantibodies directed against intracellular neuronal antigens, including Hu, Ma2, and CV2/CRMP5 (

). The pathogenic activity in these disorders may be mediated by cytotoxic T-cell immunity, as opposed to a direct effect of the antibodies themselves.

 These disorders may present as classic limbic encephalitis, in which symptoms evolve over days to weeks and may include psychiatric changes (irritability, depression, hallucinations, personality disturbances) and cognitive changes (short-term memory loss, sleep disturbances, seizures, confusion). Brain MRI can show medial temporal lobe hyperintensities, and cerebrospinal fluid (CSF) shows mild lymphocytic pleocytosis.

Anti-Hu encephalitis usually occurs in association with small-cell lung cancer and manifests with a wide spectrum of additional neurological abnormalities, such as sensory neuropathy, motor neuron abnormalities, and cerebellar ataxia.

 Patients present in their 50s or 60s with a history of smoking and new-onset confusion or amnesia with peripheral neuropathies

; hallucinations and depressed mood have also been reported in this patient population.

 Overall, patients with small-cell lung cancer and limbic encephalitis do not fare well, with median survival of about 1 year.

 Tumor treatment with chemotherapy and radiation therapy along with immunotherapy to mitigate the T-cell response can result in symptom stabilization.

A 76-year-old male smoker presented to an inpatient psychiatric unit with sudden-onset amnesia and confusion. He described depressive symptoms and was experiencing sleep disturbances and agitation that did not respond well to treatment. Subsequently, he became delirious and deteriorated neurologically and was unable to stand without assistance. Four months following onset of memory dysfunction, the patient died with a diagnosis of small-cell lung cancer.

In contrast to anti-Hu paraneoplastic disorders, anti-Ma2 antibodies are usually associated with testicular cancer and occur in young men who may present with severe short-term memory deficits. There are few reports of confusion at onset.

 Other neurological deficits, such as visual abnormalities, gait disturbances, and hypokinesis, often occur concurrently.

 An association between anti-Ma2 antibodies and sleep disorders has also been demonstrated.

 One case study describes a man in his late 60s with a 3-month history of worsening hypersomnia, memory loss, double vision, ataxia, apathy, and short episodes of fear.

 Ultimately, rapid eye movement sleep behavior disorder was characterized along with the presence of anti-Ma2 antibodies. 

Paraneoplastic disorders may cause symptoms that range from sensory neuropathies to severe psychiatric disturbances and involve the peripheral or central nervous system.

One group of autoimmune-mediated disorders results in limbic encephalitis but is not usually associated with underlying neoplasm. The syndrome is caused by antibodies against voltage-gated potassium channels that are thought to directly result in symptoms by disrupting normal synaptic transmission.

Psychiatric disturbances with Hashimoto encephalopathy are extremely frequent and include disorganized behavior with poor self-care, psychosis (often with visual hallucinations), changes in mood or personality, and sleep dysfunction.

? Patients with an autoantibody syndrome that involves the 

-methyl-D-aspartate–type glutamate receptor are most often young women or children who present with symptoms such as delusional/paranoid thought disorder, agitation, bizarre behavior, changes in speech, and hallucinations.

Patients with isolated anti-Ma2 antibodies respond relatively well to treatment of the tumor and immunotherapy. Improvement is seen in one-third of cases, symptom stabilization in about 20% to 40%, and deterioration in 30% to 50% (death rate about 15%).

 Remarkably, in a man younger than 50 years with anti-Ma2 antibodies, orchiectomy or testicular irradiation should be considered given the significant association with testicular cancer even if a tumor cannot be found.

CRMP5 and CV2 antibodies are most commonly found in patients with small-cell lung cancer or thymoma and are associated with various cognitive deficits and limbic encephalitis.

 Subacute dementia is the most frequent presentation, but personality change, depression, and other psychiatric symptoms have also been reported.

One case study describes a 69-year-old woman with irrational and obsessive-compulsive–like behaviors, followed by chorea, ataxia, and neurological deterioration; CV2 antibodies were discovered after death.

 Response to treatment is not as well described in anti-CV2/CRMP5 patients as in patients with other paraneoplastic disorders, but therapy is still geared toward tumor treatment and immunotherapy.

Another group of autoimmune-mediated disorders results in limbic encephalitis but is not usually associated with an underlying neoplasm. One such syndrome is caused by antibodies against voltage-gated potassium channels that are thought to directly result in symptoms by disrupting normal synaptic transmission.

 The typical presentation of voltage-gated potassium channel limbic encephalitis is a middle-aged patient with memory deficits and confusion

; seizures are also common, but CSF pleocytosis is rare.

 Behavioral changes often include apathy and irritability that occur with autonomic abnormalities, such as sweating and salivation.

Voltage-gated potassium channel limbic encephalitis is far more responsive to immunomodulation than are T-cell–mediated counterparts: about 80% of patients improve following immunotherapy, although the majority of patients still continue to experience short-term memory deficits, and relapses are frequent.

 In some patients, the clinical fea-tures and MRI findings may resemble a prion-related rapidly progressive dementia.

Hashimoto encephalopathy is an autoimmune limbic encephalitis characterized by high levels of antithyroid antibodies in serum, although usually without clinically relevant thyroid dysfunction. Patients are women in their 40s to 50s who present with waxing and waning cognitive impairment, such as memory dysfunction and speech abnormalities.

 Psychiatric disturbances are extremely frequent as well and include disorganized behavior with poor self-care, psychosis (often with visual hallucinations), changes in mood or personality, and sleep dysfunction.

Seizures are often associated with Hashimoto encephalopathy, but unique to this syndrome are fluctuating stroke-like episodes that span multiple different vascular territories.

 Other neurological symptoms such as myoclonus, tremor, ataxia, and headache have been reported in one-third of cases.

Thyroid peroxidase antibodies assist in the diagnosis of Hashimoto encephalopathy. This finding is reported in nearly all cases.

 However, a well-defined pathogenic role for these antibodies has not been established, and the antibodies are highly prevalent in the general population, which complicates diagnosis based on antibodies alone.

 Results of brain MRI scans are normal 50% of the time, and changes are nonspecific, even when abnormal.

Finally, another critical feature that supports the diagnosis of this disorder is the response to treatment: Hashimoto encephalopathy is almost uniformly responsive to a prolonged course of high-dose corticosteroids.

 On average, treatment continues 4 to 6 weeks before clinical recovery starts and corticosteroid taper is initiated.

 Multiple studies have described relapse of symptoms with early cessation of therapy, which highlights the need to continue therapy beyond simply the appearance of improvement.

Anti-NMDA receptor encephalitis and syndromes that involve other glutamate receptors

While many of the disorders described in this review result in mixed neurological and psychiatric disturbances, an autoantibody syndrome that involves the 

-methyl-D-aspartate (NMDA)-type glutamate receptor presents first to psychiatrists nearly 75% of the time.

 NMDA receptors are ionotropic glutamate receptors with fundamental roles in synaptic transmission, neuronal plasticity, and neuropsychiatric disease.

 Patients are most often young women (nearly half are younger than 18 years) or children who present with symptoms such as delusional/paranoid thought disorder, agitation, bizarre behavior, changes in speech, and hallucinations.

 It is therefore easy to see how this disorder is often misdiagnosed initially as acute psychosis, malingering, or drug abuse.

A viral prodrome often precedes psychiatric changes, and patients rapidly deteriorate after inpatient hospitalization. Symptoms such as seizures, decreased consciousness, dyskinesias, autonomic instability, and hypoventilation necessitate ventilatory support.

 CSF analysis usually shows lymphocytic pleocytosis, although in the early stages of disease, it can be normal. Brain MRI results are less predictable: 50% show no changes, and only 15% show limbic encephalitis signs of medial temporal lobe hyperintensities.

Sample case reports of anti-NMDA receptor encephalitis illustrate the broad psychiatric disturbances that can occur, yet highlight the apparent pure psychiatric nature of the presentation. One case describes a 14-year-old girl who presented with hallucinations and extreme panic, followed by combative behavior and pressured speech.

 Another reported a 34-year-old wom-an first thought to have a psychotic breakdown after she presented feeling feverish and unsure of herself; this was followed by confusion and, the next day, visions of stabbing and killing her 3-year-old son.

 Both of these patients were found to have ovarian teratomas. Finally, Vitaliani and colleagues

 describe a 26-year-old woman who presented with inappropriate laughing, paranoid thoughts, and combative behavior, who subsequently deteriorated neurologically before an ovarian cyst was identified. With treatment, she returned to normal function over 6 months.

Although anti-NMDA receptor encephalitis was initially associated with ovarian teratomas, larger studies have revealed that nearly half of patients do not have an identifiable tumor.

 Patients usually fare well with intervention and treatment early in the course of the disease, including tumor resection if applicable; with immunotherapy, 75% of patients have full or substantial recovery.

 Most patients continue to have psychiatric abnormalities after neurological recovery, including attention deficits and behavioral disinhibition.

 Return to baseline behavioral status is usually slow, and often requires months for symptom resolution.

Another limbic encephalitis is associated with antibodies against subunits of a different glutamate receptor, the Î±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type receptor (

 This glutamate receptor plays a significant role in learning, memory, fear, and addiction.

 Patients with anti-AMPA receptor limbic encephalitis are almost always women aged 50 to 70 years who present with subacute memory loss and confusion.

Of the 14 confirmed cases, most had an associated tumor of breast, lung, or thymoma, for which they underwent appropriate cancer treatment.

 Nearly all patients also received immunotherapy that resulted in reduced symptom severity, although the majority experienced frequent relapses.

A few patients with anti-AMPA receptor limbic encephalitis also had symptoms of agitation and/or aggressive behavior.

 Remarkably, 2 of these patients presented with isolated rapidly progressive behavioral changes resembling atypical psychosis, without focal neurological deficits or deterioration. Both recovered with corticosteroid therapy.

 This finding illustrates the possibility of an auto-immune cause for certain forms of psychosis, even in the absence of classic limbic encephalitis.

Encephalitis associated with GABAergic signaling

In addition to syndromes that involve excitatory synaptic transmission, research has shown that limbic encephalitis can result from antibody-recognizing receptors that mediate inhibitory neurotransmission. Anti–Î³-aminobutyric acid (GABA) B receptor antibodies have been identified in association with small-cell lung cancer, seizures, confusion, and severe memory abnormalities.48 Affected patients were equally likely to be men or women, with median age in the 60s. More than half showed neurological improvement with immunotherapy and tumor treatment. Findings suggest that alterations in neuronal excitatory/inhibitory balance underlie diseases ranging from autism to schizophrenia.

Glutamic acid decarboxylase is an enzyme required for the production of the GABA neurotransmitter. Glutamic acid decarboxylase antibodies may occur in patients with limbic encephalitis, although these antibodies are more frequently found in nonparaneoplastic stiff man syndrome, cerebellar ataxia, refractory epilepsy, downbeat nystagmus, palatal tremor, and brain stem dysfunction.

 Although glutamic acid decarboxylase antibodies have been reported in a small number of patients with limbic encephalitis, other antibodies (AMPA or GABA

 receptor) are more likely the cause of symptoms.

 Nevertheless, there are patients with limbic dysfunction and glutamic acid decarboxylase antibodies in whom no other immune responses are identified; these patients usually have chronic and difficult-to-treat seizures.

An autoimmunological basis for psychiatric disturbances such as schizophrenia and depression has been theorized for decades.

 The characterization of multiple encephalopathies as autoimmune in nature provides a foothold for a greater under-standing of how antibody-mediated syndromes can manifest with behavioral changes. Paraneoplastic limbic encephalitis, nonparaneoplastic limbic encephalitis, and encephalitis that involves glutamate receptors represent a heterogeneous group of disorders with common pathogenic mechanisms.

The diverse cognitive and behavioral symptoms in these disorders emphasize the need for psychiatrists to consider such syndromes in their differential diagnosis for patients with atypical behavioral changes. Moreover, given the potential for a significant role in recognition of these neurologically complex disorders, psychiatrists should become familiar with diagnostic criteria and appropriate therapeutic options.

 Bakheit AM, Kennedy PG, Behan PO. Paraneoplastic limbic encephalitis: clinico-pathological correlations. 

 Bataller L, Dalmau J. Paraneoplastic disorders of the memory and cognition. In: Miller BL, Boeve BF, eds. 

New York: Cambridge University Press; 2009:377-394.


 Brierley JB, Corsellis JA, Hierons R, Nevin S. Subacute encephalitis of later adult life. Mainly affecting the limbic areas. 

 Corsellis JA, Goldberg GJ, Norton AR. “Limbic encephalitis” and its association with carcinoma. 

 Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. 

 TÃ¼zÃ¼n E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. 

 Alamowitch S, Graus F, Uchuya M, et al. Limbic encephalitis and small cell lung cancer. Clinical and immunological features. 

 Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. 

 Bernal F, Graus F, PifarrÃ© A, et al. Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis. 

 Voltz R, Dalmau J, Posner JB, Rosenfeld MR.T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis. 

 Lawn ND, Westmoreland BF, Kiely MJ, et al. Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis. 

 Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. 

 Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. 

 Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu–associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. 

 Graus F, Keime-Guibert F, ReÃ±e R, et al. Anti-Hu–associated paraneoplastic encephalomyelitis: analysis of 200 patients. 

 Sillevis Smitt P, Grefkens J, de Leeuw B, et al. Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. 

 Byrne T, Mason WP, Posner JB, Dalmau J. Spontaneous neurological improvement in anti-Hu associated encephalomyelitis. 

 Newman NJ, Bell IR, McKee AC. Paraneoplastic limbic encephalitis: neuropsychiatric presentation. 

 Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2–associated encephalitis. 

 Hoffmann LA, Jarius S, Pellkofer HL, et al. Anti-Ma and anti-Ta associated paraneoplastic neurological syndromes: 22 newly diagnosed patients and review of previous cases. 

 Mathew RM, Vandenberghe R, Garcia-Merino A, et al. Orchiectomy for suspected microscopic tumor in patients with anti-Ma2–associated encephalitis. 

 Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. 

 Voltz R, Gultekin SH, Rosenfeld MR, et al. A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. 

 Compta Y, Iranzo A, Santamaria J, et al. REM sleep behavior disorder and narcoleptic features in anti-Ma2–associated encephalitis. 

 Overeem S, Dalmau J, Bataller L, et al. Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. 

Articles

Given the potential for a significant role in recognition of neurologically complex disorders, psychiatrists should become familiar with diagnostic criteria and appropriate therapeutic option.

Matthew S. Kayser, MD, PhD

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Psychiatric Presentations of Autoimmune Encephalopathies