Neuropsychiatri synptoms in auto-immune encephalopathies - a clinician's guide

2013/2014 Fátima Vanessa Santos Carvalho Neuropsychiatric symptoms in auto‐immune encephalopathies ‐a clinician's guide março, 2014 Doutor Neuropsychiatric symptoms Trabalho organizado de acordo com as normas da revista International Journal Fátima Vanessa Santos Carvalho   Mestrado Integrado em Medicina Área: Neurociências clínicas e saúde mental Trabalho efetuado sob a Orientação de: Dr. João dos Santos Massano de Carvalho E sob a Coorientação de: Doutor Rui Manuel Bento de Almeida Coelho symptoms in auto  immune encephalopathies  a clinician's guide Trabalho organizado de acordo com as normas da revista : Journal of Clinical Neurosciences and Mental Health março, 2014 Title: Neuropsychiatric symptoms in autoimmune encephalopathies - a clinician’s guide Running head: Neuropsychiatric symptoms in autoimmune encephalitis Authors and affiliations: Fátima Carvalho 1 , João Massano 1,2 , Rui Coelho 1,3 1-Department of Clinical Neurosciences and Mental Health, Faculty of Medicine University of Porto, Porto, Portugal 2-Department of Neurology, Hospital Pedro Hispano/ULS Matosinhos, Matosinhos, Portugal 3-Department of Psychiatry, Centro Hospitalar São João, Porto, Portugal Corresponding author: Fátima Carvalho Department of Clinical Neurosciences and Mental Health, Faculty of Medicine University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal Telephone: +351-917922173 Email: v.s.carv[email protected] Keywords: Clinical medicine; Paraneoplastic Syndromes; Limbic encephalitis; Psychotic Disorders; Autoantibodies; Immunotherapy Abstract word count: 253 Body text word count: 4374 6 tables and 1 figure Abstract Background: The spectrum of central nervous system autoimmune disorders has recently expanded with the discovery of disorders associated with antibodies directed against the neuronal membrane surface. Although many of these disorders have an underlying malignancy and present with signs of dysfunction of the limbic system (paraneoplastic limbic encephalitis, PLE), a high proportion of cases is nonparaneoplastic. They may occur with milder symptoms, and present no abnormalities in the exams usually used in the investigation of PLE. A striking number of cases may be misdiagnosed as primary psychiatric or other neurological disorders. Objective: Review the current knowledge on this topic, and provide physicians with an updated text on the neuropsychiatric presentation, diagnostic approach and current management of autoimmune encephalopathies. Methods: We searched Pubmed for articles in English until December 2013, using the terms: "Autoimmune limbic encephalitis"; “Limbic encephalitis”; “Psychiatry”; “Psychotic Disorders”; “Anti-N-Methyl-D-Aspartate Receptor Encephalitis”; "Gamma-aminobutyric- acid receptor”; “Leucine-rich-glioma-inactivated 1”; "Voltage-gated-potassium channel”; "α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid receptor”; “Ri”; “Ma2”; and “Hu”. We restricted the search to human studies, and selected articles for further analysis. The Article reference lists were also reviewed and relevant articles retrieved for consultation. Results: 109 articles have been reviewed, and data summarized. The authors propose a diagnostic flowchart. Conclusions: Autoimmune encephalitis is not a rare disorder, often has a psychiatric presentation, and should be considered whenever a non-psychiatric etiology is considered. Diagnosis is often challenging, but certain clinical features should rise suspicion about an underlying autoimmune or paraneoplastic disorder, thus guiding the physician to structured investigations, including tumor screening, and adequate therapeutic interventions, namely immunotherapy. GLOSSARY AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANNA-1: antineuronal nuclear antibodies 1; ANNA-2: anti-neuronal nuclear antibodies 2; ANNA-3: antineuronal nuclear antibodies 3; Caspr2: contactin-associated-protein relates 2; CV2/CRMP5: crossveinless-2/collapsing response mediated protein 5; FDG-PET: fluorodeoxyglucose-positron emission tomography; FLAIR: fluid-attenuated inversion recovery; GABA B R: gamma-aminobutyric acid receptor B; GAD: glutamic acid decarboxylase ; LE: limbic encephalitis; LGI-1: leucine-rich glioma inactivated 1; NMDAR: N-methyl-D-aspartate receptor; VGKC: voltage-gated potassium channel. INTRODUCTION The association between antibodies and encephalopathies has been known for several decades, since paraneoplastic limbic encephalitis (PLE) was first described, back in the 1960’s. Since then, the clinical spectrum of central nervous system autoimmune disorders has expanded astonishingly. In the past decade, several new antibodies against proteins and receptors involved in synaptic transmission and neuronal plasticity have been discovered in patients presenting with encephalitis. When compared to PLE, they differ in their pathophysiology, cancer association, and clinical response, since not all cases are paraneoplastic, they occur frequently in young individuals and children, and can show an impressive response to immunotherapy.(1-6) Furthermore, while PLE is uncommon, recent data suggests a much higher prevalence of non-paraneoplastic autoimmune encephalitis (AE) than previously imagined. Autoimmune etiology was reported in 7% of patients in a sample of 203 individuals with encephalitis. This percentage might even be higher since in cases associated with unknown causes, only anti-VGKC and NMDAR antibodies were searched for. (7) Also, in the last few years, several case reports describing milder or atypical presentations have been published. These cases of encephalitis can present predominantly or solely with psychiatric symptoms, frequently mimicking schizophreniform or mood disorders. (8-30) Hence, this diagnostic entity can present as a clinical challenge to any physician, especially neurologists and psychiatrists, whom the majority of patients seek for help first. This paper aims to review the current knowledge on this topic, and to clarify physicians about the neuropsychiatric presentation of the most common autoimmune encephalopathies, their diagnostic approach and current management. CLINICAL PRESENTATION, WITH EMPHASIS ON NEUROPSYCHIATRIC FEATURES Antinuclear/cytoplasmatic autoimmune encephalitis Anti-nuclear antibodies usually occur in PLE. As the name suggests, symptoms related to limbic system involvement predominate, as individuals present with the classic triad of memory impairment, temporal lobe seizures and psychiatric symptoms. It occurs predominantly in the elderly and, like most paraneoplastic syndromes, a higher incidence is noted in women. (31) Seizures can be subtle, and even follow an unrecognized course. Cognitive impairment, such as confusion or short-term memory dysfunction, occurs within days to weeks, and progression to dementia may be noted over time. Overall, depression, psychosis, and behavioral changes are the most usual psychiatric spectrum manifestations, sometimes accompanied by delusions and hallucinations. Patients can also experience sleep disturbances and obsessive-compulsive behavior (OCB). (31, 32) Data suggest that classical onconeuronal antibodies have no pathological role, and that central nervous system (CNS) damage is mediated by T cells. Nevertheless, these antibodies underlie different tumor associations, disorder-predominant neuropsychiatric features, and response to treatment. (5, 33) PLE associated with anti-Hu, also called anti-neuronal nuclear antibodies 1 (ANNA-1), occurs in older patients usually with a long history of smoking, as 74% of patients with underlying malignancy have small cell lung carcinoma (SCLC). More frequently than limbic encephalitis (LE), individuals present with sensory neuropathy (54%), cerebellar ataxia (10%), or multisystem disease (11%). More commonly they have depression or hallucinations, but confusion, sleep disturbances, agitation, and anxiety can occur. These symptoms respond poorly to antipsychotics and sedatives, and are followed by the onset of seizures, ataxia, and depressed alertness. (34) On the contrary, anti-Ma2 is more often seen in younger men, and there is a strong association with testicular cancer. Besides LE, they can also develop diencephalic or brainstem encephalitis, or a disorder with mixed features. Individuals usually display severe short-term memory deficits, gait disturbances, and hypokinesia. Signs of hypothalamic dysfunction (i.e., diurnal hypersomnia, cataplexy, hyperphagia, hormonal deficits, hyperthermia, weight gain, or sexual dysfunction) occur in up to one third of patients. Signs of brainstem dysfunction include cranial neuropathy, nuclear or supranuclear ophtalmoparesis, dysarthria, dysphagia, and parkinsonism. Anxiety, OCB, and personality changes are the most frequently reported psychopathological manifestations. Contrarily to anti-Hu, mood disorders and hallucinations are rare. Anti- Ma1 antibodies can also be present and are associated with female gender, older patients, cerebellar dysfunction and malignancies other than testicular, thus predicting poorer prognosis. (35) Another common antibody in PLE is anti-crossveinless-2/collapsing response mediated protein 5 (anti-CV2/CRMP5). It has a strong association with thymoma and SCLC (in this particular case, it may co-exist with anti-Hu), but can also occur with other malignancies, such as uterine sarcoma. It associates with a wide range of neurological and psychiatric symptoms, being subacute dementia and peripheral neuropathy the most common. Ocular abnormalities (optic neuritis, posterior uveitis), olfactory or taste loss are more frequent than in other forms of PLE, and the presence of chorea, particularly facial, is highly suggestive. Patients may also display personality changes, depression, confusion, psychosis, manic mood, OCB, memory deficits, spatial and temporal disorientation. (36- 38) Anti-Ri antibody, also called ANNA-2, is a rare oncoantibody associated with breast, lung, or cervical cancer. It is more frequent in the female gender and has been associated with several neurological paraneoplastic syndromes, most frequently brainstem symptoms, but cerebellar syndrome, peripheral neuropathy, cranial neuropathy, Lambert-Eaton myasthenic syndrome (LEMS), and limbic encephalitis can also coexist. Patients can present with subacute behavioral and neuropsychiatric changes, (39, 40) although gait instability is the commonest symptom at presentation. Most individuals develop multifocal neurological impairment, including ataxia, opsoclonus, myoclonus, jaw-opening dystonia, visual blurring, laryngospasm, sphincter incontinence, cranial nerve impairment, peripheral neuropathy, or myelopathy. Neurological impairment can be severe, and 60% of the patients will require the use of a wheelchair. Contrarily to ANNA-1, gastrointestinal motility disorders are not common. Most patients show concomitant antibodies in serum (Hu, CRMP5, GAD65, but also thyroid peroxidase or thyroglobulin), suggesting predisposition to autoimmunity, and the majority will respond to immunotherapy. (40-42) Other oncoantibodies associated with paraneoplastic neurological syndromes include antiamphyphisin, anti-Yo/anti-Purkinje cell 1 (PCA-1), and, less commonly, anti-neuronal nuclear antibodies 3 (ANNA-3), anti-Purkinje cell 2 (PCA2), anti-Zic4, and anti-mGluR1, found in several syndromes, especially paraneoplastic cerebellar degeneration or stiffperson syndrome (SPS). (33) In most patients, PLE will present before cancer is diagnosed, so tumoral screening in the presence of onconeuronal antibodies is mandatory. Coexistence with anti-surface antibodies, most commonly anti-VGKC, can occur, as does the development of onconeural-antibodies-associated LE without an underlying malignancy, although less frequenty. (33, 34) More recently, anti-Glutamic Acid Decarboxylase (GAD), already associated with diabetes mellitus type 1, SPS, cerebellar ataxia, and epilepsy, has been associated with nonparaneoplastic LE. These patients are more frequently young adults (median age 23 years old), with female predominance. Seizures are universal at presentation and cognitive impairment or psychiatric disturbances are rare. This disorder usually responds to immunotherapy, but to a much less extent than anti-surface disorders, and patients rarely become seizure-free. (43) Another recent study also reported the presence of GAD antibodies in idiopathic limbic encephalitis in children. All had fever and acute clinical deterioration, followed by refractory seizures and a wide spectrum of neuropsychiatric disturbances, even after immunomodulatory therapy. (44) ANTI-NEURONAL SURFACE AUTOIMMUNE ENCEPHALITIS Anti-VGKC complex These antibodies are associated with a wide range of clinical manifestations such as LE, cramp fasciculation syndrome, Isaac’s syndrome, LEMS, or Morvan’s syndrome. Previously thought to be a disorder associated with antibodies to the voltage-gated potassium channels (VGKC), recent studies revealed that in fact, the targets are the associated proteins, rather than the channel itself. (45) Most cases are associated with antibodies against leucine-rich glioma inactivated 1 (LGI1) or contactin-associated protein relates 2 (Caspr2), but evidence suggest that other still unrecognized antibodies to VGKC- associated proteins might be involved, explaining such diversity. (46) Although cell-based assays can differentiate them, radioimmunoassay (RIA, still considered the diagnostic gold-standard exam), cannot, and they are still commonly called VGKC-complex antibodies. Anti-LGI1 is by far the most common and afflicts middle-aged to older patients. It is almost exclusive of patients exhibiting the classic LE clinical presentation triad. Tumor association is infrequent, occurring in 11% of the patients. (45) Concerning Caspr2, the spectrum of associated disturbances is wider (LE, Morvan’s syndrome, neuromyotonia, painful neuropathy) and has a stronger association with cancer, notably thymoma. (47, 48) Signs of autonomic dysfunction such as sialorrhea and hyperhydrosis are common features. Hyponatremia, often resistant to treatment, (49) and faciobrachial dystonic seizures (FBDS), are other peculiar symptoms. FBDS are almost exclusive of patients with anti-LGI1 antibodies and present as frequent, sudden, brief myoclonic-like movements, with facial grimacing accompanied by ipsilateral arm posturing, often preceding the onset of other symptoms. They are often resistant to antiepileptic drugs but show a good response to immunotherapy. Verbal and visual memory deficits may also be present. (50) Organ specific autoimmunity is seen in one third of these patients, often with a family history of autoimmune disorder. (51, 52) Common disturbances include behavioral changes, depression, hallucinations and delusions, as well as REM sleep disorders. (52) Seizures occur in the majority of patients, usually of the temporal lobe type but the frontal lobe can also be involved, without EEG abnormalities even during the seizure, thus can be mistaken for psychogenic non-epileptic seizures. (53) Anti-NMDAR This is probably the most common form of autoimmune encephalitis (AE). Since it was first reported in 2006, the number of cases dramatically increased, surpassing the 500 cases, with the California encephalitis project reporting an incidence nearly as high as viral encephalitis. (54) It is more common in young females (median age 21 years, but age range between 8 months and 85 years), and nearly half are paraneoplastic. Ovarian teratoma is by far the most frequent malignancy, particularly between 12 and 45 years old, especially in females of African or Asian descent. SCLC, neuroblastoma, breast carcinoma, thymoma, testicular cancer, and non-gonadal teratomas may also underlie this disorder, especially in older patients. (55-57) Unlike most AEs, symptoms are not mainly limited to the limbic system. Clinical manifestations can be subdivided into eight categories: behavior, cognition, memory deficits, seizures, movement disorders, impairment of alertness, autonomic dysfunction, and central hypoventilation. Although initially monosymptomatic, the majority of patients will exhibit symptoms in at least 4 categories within 4 weeks after presentation, with monosymptomatic disease occurring in only 5% of individuals. (56) The initial clinical presentation differs among age groups: while adults tend to manifest behavioral changes, movement disorders and seizures are more common in children, although psychopathological manifestations can also dominate the clinical picture (29, 58- 61), as well as developmental regression. (13) In older adults (> 45 years) predominant symptoms also diverge, as they are more prone to exhibit behavioral changes, and cognitive impairment, and less commonly movement disorders, decreased level of consciousness, or prodromal symptoms. (57) In the extremes of age, no gender preference is observed, with tumors or need for ventilatory support being less frequent. In young adults, this disorder evolves according to a pattern that often starts with a flu-like prodromal phase, characterized by fever, headache, gastrointestinal, or upper respiratory symptoms. Subsequently psychiatric symptoms arise, isolated or along with cognitive decline and/or seizures. 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Antibody Patient Features Associated malignancies Common psychiatric symptoms Other findings Hu Older patients Smoking history SCLC Depression Hallucinatory activity Sleep disturbances Anxiety disorders Seizures Ataxia Consciousness impairment Painful sensitive neuropathy Gastrointestinal motility disorders Ma2 Young males Older women Testicular germ cell tumor SCLC Sleep disturbances Anxiety disorders OCB Mood disturbances Supranuclear gaze palsy Cranial neuropathy Parkinsonism Hypothalamic dysfunction CV2/ CRMP5 SCLC Thymoma Uterine sarcoma OCB Personality changes Mood disturbances Psychosis Subacute dementia Chorea Ocular disturbances (uveitis, optic neuritis) Olfactory/ taste loss Cerebellar ataxia Peripheral neuropathy Hu-AB can coexist Ri Older women Smoking history Lung cancer Breast cancer Cervical cancer Bladder cancer Behavioral changes Ataxia Opsoclonus-myoclonus Laryngospam Jaw-opening dystonia Visual blurring TABLE 1- Clinical features of the different oncoantibody associated disorders. Abbreviations: AB: Antibodies; CV2/CRMP5: Crossveinless-2/collapsing response mediated protein 5; OCB: Obsessive-compulsive behavior; SCLC: Small cell lung cancer. Antibody Patient Features Associated malignancies Common psychiatric symptoms Other findings LGI1 Middle age to older patients males Personal/ familiar history of autoimmune disorders a Rare Behavioral changes Depression Delusions Hallucinations REM sleep disorders Hyponatremia FBDS Seizures Autonomic instability Neuromyotonia Ataxia Intestinal pseudoobstruction Caspr2 Older males Personal/ familiar history of autoimmune disorders a Thymoma SCLC Severe insomnia Hallucination Personality changes Delusion Autonomic dysfunction Weight loss Neuromyotonia Painful neuropathy Seizures NMDAR Younger patients and children Paraneoplasti c cases more common in non-caucasian females Ovarian teratoma SCLC Neuroblastoma Breast carcinoma Thymoma Delusion and hallucination Anxiety disorders Agression and agitation Bizarre behavior Mood disorders Prodromal flu-like Dissociative anesthesia Decreased conscience Seizures Autonomic instability Orofacial dyskinesia, facial grimacing, jaw opening distonia Opisthotonus, catatonic postures AMPAR Older females Breast cancer Lung carcinoma Thymoma Behavioral changes Sleep disorders Confabulation Hallucination Short-term memory impairment Seizures Confusion Relapsing disease GABA B Older men Younger nonparaneopl astic group SCLC Thymoma Psychosis Hallucination Sleep disturbances Paranoia Short-term memory impairment Seizures at presentation TABLE 2- Clinical features of the most common anti-surface autoimmune encephalitis. Abbreviations: AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; Caspr2: contactin-associated protein relates 2; FBDS: Fachiobraquial dystonic seizures; GABA B R: Gamma-aminobutyric acid receptor; LG1: Leucine-rich glioma inactivated 1; NMDAR: N-methyl-D-aspartate receptor;SCLC: Small cell lung cancer; VGKC: Voltagegated potassium channel. a Data relates to anti-VGKC-complex-associated encephalitis. Paraneoplastic encephalitis Non-paraneoplastic autoimmune encephalitis Viral encephalitis Dementia, including neurodegenerative diseases (e.g. Alzheimer disease, Frontotemporal dementia) Malignancy (glioma, lymphoma) Temporal lobe seizures Wilson’s Disease Huntington’s disease Endocrine dysfunction (Hypothyroidism) Toxic-metabolic encephalopathy (e.g. sepsis, liver failure) Vitamin deficiency (Wernicke-Korsakoff encephalopathy, B12 or folic acid deficiency) Autoimmune systemic disorder (Lupus erythematosus, Vasculitis, Sjögren’s syndrome) Neurosyphilis Creuzfeldt-Jakob disease Primary psychiatric disorder TABLE 3 - Differential diagnosis of suspected autoimmune encephalopathies. Recent flu-like syndrome No past psychiatric illness Rapid onset of psychosis and/or catatonia Seizures/neurological dysfunction Known history of malignancy, especially if SCLC, teratoma or thymus cancer Signs of autonomic dysfunction Worsening of symptoms after antipsychotic ministration Refractory hyponatremia Long history of smoking Personal/family history of auto-immune disease TABLE 4 - features that should raise the suspicion of autoimmune etiology in case of atypical psychiatric presentation, particularly in first episode psychosis or mania. Abbreviation: ECT: electroconvulsive therapy; SCLC: Small cell lung cancer. Antibody EEG changes MRI CSF abnormalities Prognosis Onco-AB Common, non specific Temporomesial hyperintensities Ma2: lesions outside the limbic system are common Common ymphocitic pleocytosis Mild elevation of protein levels Hu: Poor, median survival 12 months Ma2: 50-70% clinical stabilization/ improvement CV2/ CRMP5: poor, median survival 48 months; 18 months if anti-HU antibodies coexist Ri: good response to treatment; better than CV2 or Hu LGI1 Common, non specific Temporomesial hyperintensities Cortical atrophy Mesiotemporal and basal ganglia hypermetabolism Rare Slight increase in proteins level Seldom OCB Excellent response to immunotherapy Improvement: 80% Full recovery: 24% Mortality: 6% Caspr2 Common, non specific Same as LGI1 Same as LGI1 Poor prognosis, although good response to therapy NMDAR Common, non specific “Extreme delta brush” pattern Rare Abnormalities outside the medial temporal lobe Fronto-temporo- parietal grandient on PET Very common Mild pleocytosis Raised protein level Oligoclonal bands Good Full recovery: 70-80% Mortality: 10% AMPAR Common, non specific Temporomesial hyperintensities Lesions outside the limbic system (i.e.,anterior septal nuclei, cerebellum) Common Lymphocitic pleyocitosis Poor, although good response to therapy Relapses are common GABA B R Common, non specific Common Lymphocytic pleocytosis Abnormal in half of the cases Poor Full recovery: 18% Partial response: 36% Table 5 - Correlation between associated antibody frequency of findings in auxiliary exams and prognosis. Abbreviations: AMPAR: α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor; Caspr2: contactin-associated protein relates 2; CV2/CRMP5: crossveinless-2/collapsing response mediated protein 5; GABA B R: Gammaaminobutyric acid receptor; LG1: Leucine-rich glioma inactivated 1; NMDAR: N-methyl-D- aspartate receptor; PET: positron emission tomography; OCB: oligoclonal bands; VGKC: voltage-gated potassium channel Suspected malignancy Auxiliary exams SCLC Chest CT; if negative FDG-PET Non-SCLC Chest CT; if negative FDG-PET Thymoma Chest CT Testicular cancer Ultrasonography; if negative pelvic CT Teratoma Pelvic ultrasonography; if negative CT/MRI of pelvis/abdomen; if negative chest CT Breast cancer Mammography; if negative MRI; if negative FDG-PET TABLE 6 - Recommended auxiliary exams according suspected underlying malignancy. 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