Scientific letter
Encephalitis associated with anti-NMDA antibodies
Encefalitis asociada a anticuerpos contra el receptor de NMDA
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The clinical condition is characterized by heterogeneous neuropsychiatric symptoms, memory deficit, crisis, motion disorders and dysautonomic symptoms, often associated with ovarian teratoma. It is a rare disease in which there is often a delay in diagnosis and poor prognosis without treatment.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We report the case of a 34-year-old male with no history of interest who presented with time–space disorientation symptoms, incoherent speech and mnemonic gaps after a common cold episode. On examination, a significant tendency to sleep, inattention, persevering attitude with increased response latency, time–space disorientation and memory impairment for recent and remote events was observed. The lab and imaging tests were normal in the ER as well as the CSF biochemistry, with 144 cells, 85% lymphomononuclear. EEG showed activity in the low voltage, without epileptiform abnormalities. The immunological profile in blood, tumour markers, virus serology and rapid plasma reagin were negative. The anti-NMDAR Ab were determined in the CSF, which were positive, starting treatment with IVIG for 5 days. On the fourth day of treatment the patient presented low level of awareness with central hypoventilation which required transfer to the Intensive Care Unit (ICU), without the need of mechanical ventilation. The study was completed with thoracoabdominal CT and testicular ultrasound, all being normal. The clinical course was slowly favourable. Finally, he was discharged 10 weeks after admission without antipsychotics. A month after discharge, upon follow-up, clinical improvement was observed, although there were still minimal cognitive dysexecutive and extrapyramidal motor sequelae.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Anti-NMDAR Ab encephalitis is a neuroimmunological disorder, described in 2007, representing 4% of cases of encephalitis, and the second most frequent among immunological cases.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">1</span></a> Although knowledge of the pathogenesis of this entity is limited, the immune substrate seems demonstrated by the ability of these antibodies to cause a disorder and a reduction in the synaptic NMDAR levels. The frequent association with ovarian teratoma and/or prodromal flu-like symptoms could act as a trigger of the immune process. It occurs in all ages, but is most common in children and adolescents, with an average age of 21 years, being more prevalent in women (81%).<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">2</span></a> The differential diagnosis should include infections (such as VHS virus, HIV, enteroviruses and rabies, mycoplasma, tuberculosis, PANDA and syphilis), drugs (such as haloperidol neuroleptic malignant syndrome and NMDAR blockers), psychiatric disorders (schizophrenia, bipolar disorder and catatonia),<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">3</span></a> and immunological disorders. Among the antibody-mediated encephalitis there are those directed against surface antigens of the neuronal membrane, intracellular directed against onconeuronal antigens and intracellular against synaptic antigens (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">4,5</span></a> Although the presentation varies between children and adults, most patients show a similar syndrome after a month of progression.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">2</span></a> Often presents with a prodromal phase with flu-like symptoms, followed by psychiatric symptoms (psychosis, apathy, fear, depression), mainly in adults, and movement disorders (orofacial dyskinesias and choreoathetosis) in the case of children. It is frequently associated with epileptic seizures and varying degrees of cognitive impairment. The patient subsequently progresses into a catatonic state and autonomic instability (cardiac arrhythmias, hypo/hypertension, central hypoventilation and hypo/hyperthermia). In 60% of cases ICU support will be necessary. Diagnosis is based on clinical suspicion, supported by the antibody positivity in the CSF. NMR is pathological only in 50% of cases.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">4</span></a> The findings are variable (increased temporal-level signal, meningeal enhancement, punctiform demyelinating lesions, signs of intracranial hypertension).<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">6</span></a> PET scan can show frontotemporal hypermetabolism associated with occipital hypometabolism. This gradient correlates with the severity of the disease, and its normalization, with recovery.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">5</span></a> The EEG shows abnormalities by pathology in up to 90% of cases, although the findings are often nonspecific. 30% showed <span class="elsevierStyleItalic">an extreme brush delta</span> pattern which is associated with poor prognosis.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">7</span></a> CSF is abnormal in 80–90% of cases, showing lymphocytic pleocytosis with elevated protein concentration and detection of oligoclonal bands. The definitive diagnosis is made after detection of antibodies against the N1 subunit of the NMDA receptor in serum or CSF. Antibody titre may be useful in assessing the response to treatment, recurrence and chronic persistent disease. However, the interpretation should be cautious,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">5</span></a> so as to avoid being the only argument to guide treatment decisions. The association with ovarian teratoma is common in young women while coexistence with other malignancies is rare but more prevalent in males and old age. The start of treatment responds to a clinical indication. It is based on an immunomodulatory, symptomatic and etiologic (causal) approach, based on the neoplasm finding. Regarding the latter, the first-line treatment consists of corticosteroids, immunoglobulins or plasmapheresis, with a success rate of 53% during the first month, and 97% after 2 years, in some series.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">2</span></a> Immunomodulation therapy with rituximab, associated or not to cyclosporine, is indicated in patients who do not respond. The recurrence rate is around 12%, being more common in those patients who had no associated malignancy diagnosed and did not receive immunomodulation. If a tumour is not detected, it is necessary to do a follow-up according to the patient's age and sex. The estimated mortality rate is 7% after 2 years,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">2</span></a> mainly from respiratory, heart and infectious causes.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Escudero Sánchez R, Montojo Villasanta MT, González Anglada MI. Encefalitis asociada a anticuerpos contra el receptor de NMDA. Med Clin (Barc). 2015;145:504–505.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Intracellular, onconeuronal antigen \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Intracellular, synaptic antigen \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cell surface or synaptic receptor \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antigen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hu, CRMP5, Ri, Yo, Ma2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GAD, anfisina \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NMDAR, AMPAR, GABA (B) R, Caspr2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Predominant in older age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Adults \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">All ages, although more in children \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Association with tumour \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Varies with the antigen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Varies with the antigen and age \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Response to treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10–30% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Partial improvement 60% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Partial or complete improvement 75–80% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Relapses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Uncommon \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Uncommon \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Varies with the antigen (10–25%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1037627.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Antibody mediated encephalitis.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:7 [ 0 => array:3 [ "identificador" => "bib0040" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Encephalitis and antibodies to synaptic and neuronal cell surface proteins" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "E. 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