The role of infections in autoimmune encephalitides.

Autoimmune encephalitides are autoimmune neurological disorders characterized by rapidly progressive central nervous system symptoms associated with specific auto-antibodies targeting neuronal cell-surface proteins. The clinical features of encephalitis are frequently preceded by symptoms suggesting an infectious process, and specific pathogens have been detected at the early phase of the disease in some patients, suggesting that it can be triggered by infections. Moreover, recent data have shown an association with specific HLA haplotypes, suggesting a genetic susceptibility to develop at least some subtypes of autoimmune encephalitis. Nonetheless, the immunological mechanisms leading from an adequate response to infection to autoimmunity against neuronal self-antigens remain highly hypothetical. Molecular mimicry, inborn errors of the host immune system, as well as epitope spreading and chronic activation of innate immunity actors, may be involved. Importantly, the frequency of prodromal infectious symptoms and association with HLA haplotypes differ among autoimmune encephalitides, suggesting that depending on the subtype distinct immunopathogenic mechanisms are involved. A direct link between infection and autoimmune encephalitis was recently provided by the demonstration that most of the so-called relapsing neurological symptoms post-herpes simplex virus encephalitis corresponded to viral-induced autoimmune encephalitis with antibodies against NMDA receptors or other, yet unknown, neuronal surface antigens. Although this association has also been demonstrated experimentally in mice, the underlying immunological mechanisms remain unknown. Overall, a body of clinical, epidemiological and experimental data suggests infections are involved in the pathogenesis of autoimmune encephalitides. Further studies, focusing on the interplays between pathogens, genetic determinants of the host immune response, and brain inflammation, are needed to clarify the immunological mechanisms that lead to autoimmune encephalitis after infection.

Syndrome and outcome of antibody-negative limbic encephalitis.

BACKGROUND AND PURPOSE: The aim was to report the clinical characteristics of 12 patients with limbic encephalitis (LE) who were antibody-negative after a comprehensive immunological study. METHODS: The clinical records of 163 patients with LE were reviewed. Immunohistochemistry on rat brain, cultured neurons and cell-based assays were used to identify neuronal autoantibodies. Patients were included if (i) there was adequate clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging information to classify the syndrome as LE, (ii) magnetic resonance images were accessible for central review and (iii) serum and CSF were available and were confirmed negative for neuronal antibodies. RESULTS: Twelve (7%) of 163 LE patients [median age 62 years; range 40-79; 9 (75%) male] without neuronal autoantibodies were identified. The most frequent initial complaints were deficits in short-term memory leading to hospital admission in a few weeks (median time 2 weeks; range 0.5-12). In four patients the short-term memory dysfunction remained as an isolated symptom during the entire course of the disease. Seizures, drowsiness and psychiatric problems were unusual. Four patients had solid tumors (one lung, one esophagus, two metastatic cervical adenopathies of unknown primary tumor) and one chronic lymphocytic leukemia. CSF showed pleocytosis in seven (58%) with a median of 13 white blood cells/mm3 (range 9-25). Immunotherapy included corticosteroids, intravenous immunoglobulins and combinations of both drugs or with rituximab. Clinical improvement occurred in six (54%) of 11 assessable patients. CONCLUSIONS: Despite the discovery of new antibodies, 7% of LE patients remain seronegative. Antibody-negative LE is more frequent in older males and usually develops with predominant or isolated short-term memory loss. Despite the absence of antibodies, patients may have an underlying cancer and respond to immunotherapy.

How strict is galactose restriction in adults with galactosaemia? International practice.

Dietary management of 418 adult patients with galactosaemia (from 39 centres/12 countries) was compared. All centres advised lactose restriction, 6 restricted galactose from galactosides ± fruits and vegetables and 12 offal. 38% (n=15) relaxed diet by: 1) allowing traces of lactose in manufactured foods (n=13) or 2) giving fruits, vegetables and galactosides (n=2). Only 15% (n=6) calculated dietary galactose. 32% of patients were lost to dietetic follow-up. In adult galactosaemia, there is limited diet relaxation.

Practices in prescribing protein substitutes for PKU in Europe: No uniformity of approach.

BACKGROUND: There appears little consensus concerning protein requirements in phenylketonuria (PKU). METHODS: A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute [PS]) by age, administration frequency and method, monitoring, and type of protein substitute. Data were analysed by European region using descriptive statistics. RESULTS: The amount of total protein (from PS and natural/intact protein) varied according to the European region. Higher median amounts of total protein were prescribed in infants and children in Northern Europe (n=24 centres) (infants <1 year, >2-3g/kg/day; 1-3 years of age, >2-3 g/kg/day; 4-10 years of age, >1.5-2.5 g/kg/day) and Southern Europe (n=10 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, 2 g/kg/day; 4-10 years of age, 1.5-2 g/kg/day), than by Eastern Europe (n=4 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, >2-2.5 g/kg/day; 4-10 years of age, >1.5-2 g/kg/day) and with Western Europe (n=25 centres) giving the least (infants <1 year, >2-2.5 g/kg/day, 1-3 years of age, 1.5-2 g/kg/day; 4-10 years of age, 1-1.5 g/kg/day). Total protein prescription was similar in patients aged >10 years (1-1.5 g/kg/day) and maternal patients (1-1.5 g/kg/day). CONCLUSIONS: The amounts of total protein prescribed varied between European countries and appeared to be influenced by geographical region. In PKU, all gave higher than the recommended 2007 WHO/FAO/UNU safe levels of protein intake for the general population.

The expanding field of IgG4-mediated neurological autoimmune disorders.

At least 13 different disease entities affecting the central nervous system, peripheral nervous system and connective tissue of the skin or kidneys are associated with immunoglobulin G4 (IgG4) immune reactivity. IgG4 has always been considered a benign, non-inflammatory subclass of IgG, in contrast to the well-known complement-activating pro-inflammatory IgG1 subclass. A comprehensive review of these IgG4 autoimmune disorders reveals striking similarities in epitope binding and human leukocyte antigen (HLA) associations. Mechanical interference of extracellular ligand-receptor interactions by the associated IgG4 antibodies seems to be the common/converging disease mechanism in these disorders.

Clinical spectrum and diagnostic value of antibodies against the potassium channel related protein complex.

INTRODUCTION: Antibodies against a protein complex that includes voltage-gated potassium channels (VGKC) have been reported in patients with limbic encephalitis, peripheral nerve hyperexcitability, Morvan's syndrome, and a large variety of neurological syndromes. REVIEW SUMMARY: In this article, a review is presented of the syndromes associated with antibodies against VGKC-related proteins and the main antigens of this protein complex, the proteins LGI1 (leucine rich glioma inactivated protein 1) and Caspr2 (contactin-associated protein-like 2). The conceptual problems and clinical implications of the description of antibodies against VGKC-related proteins other than LGI1 and Caspr2 are also discussed. Although initial studies indicated the occurrence of antibodies against VGKC, recent investigations have shown that the main antigens are a neuronal secreted protein known as LGI1 which modulates synaptic excitability, and a protein called Caspr2 located on the cell surface and processes of neurons of different brain regions, and at the juxtaparanodal region of myelinated axons. While antibodies against LGI1 preferentially associate with classical limbic encephalitis, antibodies against Caspr2 associate with a wider spectrum of symptoms, including Morvan's syndrome, peripheral nerve hyperexcitability or neuromyotonia, and limbic or more extensive encephalitis. In addition there are reports of patients with antibodies against VGKC-related proteins that are different from LGI1 or Caspr2. In these cases, the identity and location of the antigens are unknown, the syndrome association is not specific, and the response to treatment uncertain. CONCLUSIONS: The discovery of antigens such as LGI1 and Caspr2 has resulted in a clinical and molecular definition of the broad group of diseases previously attributed to antibodies against VGKC. Considering the literature that describes the presence of antibodies against VGKC other than LGI1 and Caspr2 proteins, we propose a practical algorithm for the diagnosis and treatment of these patients.

Screening for tumours in paraneoplastic syndromes: report of an EFNS task force.

BACKGROUND: paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible. OBJECTIVES: an overview of the screening of tumours related to classical PNS is given. Small cell lung cancer, thymoma, breast cancer, ovarian carcinoma and teratoma and testicular tumours are described in relation to paraneoplastic limbic encephalitis, subacute sensory neuronopathy, subacute autonomic neuropathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis and paraneoplastic peripheral nerve hyperexcitability. METHODS: many studies with class IV evidence were available; one study reached level III evidence. No evidence-based recommendations grade A-C were possible, but good practice points were agreed by consensus. RECOMMENDATIONS: the nature of antibody, and to a lesser extent the clinical syndrome, determines the risk and type of an underlying malignancy. For screening of the thoracic region, a CT-thorax is recommended, which if negative is followed by fluorodeoxyglucose-positron emission tomography (FDG-PET). Breast cancer is screened for by mammography, followed by MRI. For the pelvic region, ultrasound (US) is the investigation of first choice followed by CT. Dermatomyositis patients should have CT-thorax/abdomen, US of the pelvic region and mammography in women, US of testes in men under 50 years and colonoscopy in men and women over 50. If primary screening is negative, repeat screening after 3-6 months and screen every 6 months up till 4 years. In LEMS, screening for 2 years is sufficient. In syndromes where only a subgroup of patients have a malignancy, tumour markers have additional value to predict a probable malignancy.

Use of Bevacizumab for neurological complications during initial treatment of malignant gliomas.

INTRODUCTION: High grade gliomas are the most common primary malignant brain tumours. Treatment with chemoradiation and adjuvant chemotherapy with Temozolomide may prolong survival but some patients develop complications during or soon after therapy due to radiation necrosis, oedema or tumour progression. PATIENTS: We report the use of Bevacizumab in four patients with newly diagnosed high grade gliomas who developed cerebral oedema due to tumour progression or radiation necrosis that did not respond to corticosteroids, and who were not candidates for surgical debulking. OUTCOMES: All four patients had a rapid response to treatment with bevacizumab, tolerating a decrease of the dose of corticosteroids, and were able to continue their standard therapy. CONCLUSIONS: Bevacizumab is effective in controlling some of the neurological complications from oedema, radiation necrosis, or rapid tumour progression during the initial treatment of malignant gliomas.

[Anti-NMDA-receptor encephalitis. An interdisciplinary clinical picture]. / Anti-NMDA-Rezeptor-Enzephalitis. Ein interdisziplinäres Krankheitsbild.

Anti-NMDA-receptor encephalitis is a severe and considerably underdiagnosed form of encephalitis with characteristic clinical features including psychiatric symptoms, decreased levels of consciousness, hypoventilation, epileptic seizures, autonomic dysfunction and dyskinesias. Most patients are primarily seen by psychiatrists, often on the assumption of a drug-induced psychosis. Anti-NMDA-receptor encephalitis had initially been described in young women with ovarian teratoma, but is also common in women without tumour, in men and in children. The diagnosis is based on the characteristic clinical picture, supporting findings of brain MRI, electroencephalogram and cerebrospinal fluid (CSF), and the presence of highly specific autoantibodies directed against the NR1 subunit of NMDA-type glutamate receptors in the serum or CSF. In particular, anti-NMDA-receptor encephalitis must be excluded in patients with 'encephalitis of unknown cause'. In principle, the prognosis is favourable and recovery from symptoms can be expected even after prolonged intensive care treatment and mechanical ventilation. However, improvement correlates with prompt identification of the disorder, early immunotherapy and - in the case of a malignancy - with complete tumour removal. Patient care requires an interdisciplinary approach including neurologists, psychiatrists, paediatricians, oncologists and gynaecologists.

[Initial evaluation, diagnosis, staging, treatment, and follow-up of patients with primary cutaneous malignant melanoma. Consensus statement of the Network of Catalan and Balearic Melanoma Centers]. / Valoración inicial, diagnóstico, estadificación, tratamiento y seguimiento de los pacientes con melanoma maligno primario de la piel. Documento de consenso de la "Xarxa de Centres de Melanoma de Catalunya i Balears"

The consensus statement on the management of primary cutaneous melanoma that we present here was based on selection, discussion, review, and comparison of recent literature (including national and international guidelines). The protocols for the diagnosis, treatment, and follow-up used in the hospital centers throughout Catalonia and the Balearic Isles belonging to the Network of Catalan and Balearic Melanoma Centers were also considered. The main objective of this statement was to present the overall management of melanoma patients typically used in our region at the present time. As such, the statement was not designed to be an obligatory protocol for health professionals caring for this group of patients, and neither can it nor should it be used for this purpose. Professionals reading the statement should not therefore consider it binding on their practice, and in no case can this text be used to guarantee or seek responsibility for a given medical opinion. The group of dermatologists who have signed this statement was created 3 years ago with the aim of making our authorities aware of the importance of this complex tumor, which, in comparison with other types of cancer, we believe does not receive sufficient attention in Spain. In addition, the regular meetings of the group have produced interesting proposals for collaboration in various epidemiological, clinical, and basic applied research projects on the subject of malignant melanoma in our society.

A brainstem paraneoplastic syndrome associated with prostate cancer.

BACKGROUND: Paraneoplastic syndromes are seldom observed with prostate cancer. A rare paraneoplastic brainstem syndrome associated with prostate cancer is described, and the presence of antineuronal antibodies with this syndrome is demonstrated for the first time. SETTING: Tertiary referral centre for neurological disorders. PATIENT: This 59-year-old man developed ophthalmoplegia, dysarthria, dysphagia, pruritus, ataxia, corticobulbar and corticospinal signs in association with prostate cancer. The disorder was unaffected by treatment of the underlying malignancy, but responded initially to high-dose corticosteroid administration and intravenous immunoglobulins. RESULTS: Antibody to intracellular neuronal antigens was demonstrated in both the serum and the cerebrospinal fluid. CONCLUSIONS: This unique paraneoplastic syndrome chiefly affecting the brainstem may be a diagnostic clue to the presence of unsuspected prostate adenocarcinoma. Further studies will be required to determine the precise antigenic target.

Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis.

The California Encephalitis Project (CEP), established in 1998 to explore encephalitic etiologies, has identified patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, the likely etiology of their encephalitis. This study compares the presentation of such patients to those with viral encephalitis, so that infectious disease clinicians may identify individuals with this treatable disorder. Patients were physician-referred, and standardized forms were used to gather demographic, clinical, and laboratory data. Features of anti-NMDAR+ patients were compared with the viral encephalitides of enteroviral (EV), rabies, and herpes simplex-1 (HSV-1) origins. Sixteen cases with confirmed viral etiologies were all negative on NMDAR antibody testing. Ten anti-NMDAR+ patients were profiled with a median age of 18.5 years (range 11-31 years). None were Caucasian. They had a characteristic progression with prominent psychiatric symptoms, autonomic instability, significant neurologic abnormalities, and seizures. Two had a teratoma, and, of the remaining eight, four had serologic evidence of acute Mycoplasma infection. The clinical and imaging features of anti-NMDAR+ patients served to differentiate this autoimmune disorder from HSV-1, EV, and rabies. Unlike classic paraneoplastic encephalitis, anti-NMDAR encephalitis affects younger patients and is often treatable. The association of NMDAR antibodies in patients with possible Mycoplasma pneumoniae infection warrants further study.

Immune-mediated encephalitis and virilization in association with a mature cystic ovarian teratoma in an adolescent girl.

BACKGROUND: Mature cystic teratomas are the most common form of ovarian tumor in children and adolescents. These tumors are mostly benign and non-secreting. Virilization from an ovarian teratoma is exceptionally rare in pediatrics. Equally rare is the association of ovarian teratomas with auto-immune encephalitis. METHODS: We describe the case of a 15-year-old girl with menstrual abnormalities and virilization, who had a past medical history of encephalitis of an unknown etiology 16 months prior to presentation. RESULTS: Endocrine evaluation revealed an elevated serum testosterone and 17-hydroxy progesterone. A large left ovarian tumor was seen on a CT scan. Surgical excision revealed a mature cystic teratoma containing 6 liters of clear fluid with high androgen levels. Antibodies to the N-methyl-D-aspartate receptor of the hippocampus were detected in pre-operatively archived serum, but undetectable 6 months postoperatively. Immunohistochemistry studies on the tumor sections revealed that the antibodies in the patient's serum reacted with areas of the tumor expressing the N-methyl-D-aspartate receptor. Postoperatively, the patient's menstrual cycles became regular and her behavioral problems resolved. Her testosterone levels fell precipitously as well. CONCLUSION: Both virilizing mature cystic teratomas and teratoma-associated encephalitis are extremely rare in the pediatric population. We report on the first instance of these 2 rare entities occurring in the same patient.

Neurological response to early removal of ovarian teratoma in anti-NMDAR encephalitis.

We report an 18-year-old woman with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, who developed psychiatric symptoms, progressive unresponsiveness, dyskinesias, hypoventilation, hypersalivation and seizures. Early removal of an ovarian teratoma followed by plasma exchange and corticosteroids resulted in a prompt neurological response and eventual full recovery. Serial analysis of antibodies to NR1/NR2B heteromers of the NMDAR showed an early decrease of serum titres, although the cerebrospinal fluid titres correlated better with clinical outcome. The patients' antibodies reacted with areas of the tumour that contained NMDAR-expressing tissue. Search for and removal of a teratoma should be promptly considered after the diagnosis of anti-NMDAR encephalitis.

[Autoimmune encephalitis]. / Encefalitis autoinmunes.

Autoimmune encephalitis are a new category of inflammatory diseases of the central nervous system mediated by antibodies that attack neurotransmitter or protein receptors on the surface of neurons. The clinical syndromes are complex and are associated with manifestations that vary according to the type of antibody that is associated. The autoimmune response can start due to the presence of a tumour or viral infection, but in many case the cause remains unknown. In paediatrics, the most frequent autoimmune encephalitis is that associated with NMDA glutamate receptor antibodies (or anti-NMDA encephalitis). In children and teenagers, the initial symptoms are usually different from those of adults and the disease is rarely associated with tumours. In this article, in addition to anti-NMDA encephalitis, the general aspects of autoimmune encephalitis are reviewed and the most common questions asked about treatment of these diseases are addressed.

TITLE: Encefalitis autoinmunes.Las encefalitis autoinmunes constituyen una nueva categoria de enfermedades inflamatorias del sistema nervioso central mediadas por anticuerpos contra receptores de neurotransmisores o proteinas de la superficie neuronal. Los sindromes clinicos son complejos y se asocian a manifestaciones que varian en funcion del tipo de anticuerpo asociado. La respuesta autoinmune puede iniciarse por la presencia de un tumor o infeccion virica, pero en muchos casos se desconoce la causa. En pediatria, la encefalitis autoinmune mas frecuente es la que se asocia a anticuerpos contra el receptor de glutamato NMDA (o encefalitis anti-NMDAR). En niños y adolescentes, los sintomas iniciales suelen ser diferentes a los de los adultos y la enfermedad raramente se asocia a tumores. En este articulo, ademas de la encefalitis anti-NMDAR, se revisan los aspectos generales de las encefalitis autoinmunes y se abordan las preguntas mas frecuentes que suscita el tratamiento de estas enfermedades.

Paraneoplastic syndromes.

Paraneoplastic syndromes (i.e. organ/tissue disorders associated with cancer) affecting the nervous system are thought to be the result of an autoimmune response triggered by specific cancer antigens. Several of these antigens have recently been identified and include the Hu, Yo and Ri proteins, with the Hu antigens being the best studied. Immunization of animals with HuD has been shown to retard the growth of HuD-positive neuroblastomas. In addition, the presence of anti-HuD antibody in humans with small-cell lung cancer predicts the slow growth of the tumor. The associated neurological disorders, however, limit the use of these and other antigens with similar characteristics in cancer vaccines.

Autoimmune limbic encephalitis in 39 patients: immunophenotypes and outcomes.

BACKGROUND: About 40% of patients with limbic encephalitis do not have detectable CNS antibodies. Some of these patients have immune-mediated limbic encephalitis, but their frequency is unknown. AIMS: (1) To determine the spectrum of limbic encephalitis identified on clinical grounds in a single institution, and compare it with that in patients referred for antibody analysis. (2) To correlate clinical outcomes with the cellular location of the autoantigens. METHODS: Prospective clinical case studies. Immunohistochemistry with rat brain, live hippocampal neurones, HeLa cells expressing Kv potassium channels and immunoblot. RESULTS: In 4 years, 17 patients were identified in the Hospital of the University of Pennsylvania, Philadelphia, USA, and the serum or CSF samples of 22 patients diagnosed elsewhere were also studied. 9 of our 17 (53%) patients had antibodies to known neuronal antigens (paraneoplastic or voltage gated potassium channels (VGKCs)) and 5 (29%) to novel cell-membrane antigens (nCMAg) typically expressed in the hippocampus and sometimes in the cerebellum. Considering the entire series, 19 of 39 (49%) patients had antibodies to known antigens, and 17 (44%) to nCMAg. Follow-up (2-48 months, median 19 months) was available for 35 patients. When compared with patients with antibodies to intraneuronal antigens, a significant association with response to treatment was found in those with antibodies to cell-membrane antigens in general (VGKC or nCMAg, p = 0.003) or to nCMAg (p = 0.006). CONCLUSIONS: (1) 82% of patients with limbic encephalitis prospectively identified on clinical grounds had CNS antibodies; (2) responsiveness to treatment is not limited to patients with VGKC antibodies; (3) in many patients (29% from a single institution), the autoantigens were unknown but were found to be highly enriched in neuronal cell membranes of the hippocampus; and (4) these antibodies are associated with a favourable outcome.