- Email: [email protected]
Encephalitis associated with anti-NMDA antibodies
Med Clin (Barc). 2015;145(11):504–506
www.elsevier.es/medicinaclinica
Scientific letters Encephalitis associated with anti-NMDA antibodies夽 Encefalitis asociada a anticuerpos contra el receptor de NMDA Dear Editor, Anti-N-methyl-d-aspartate receptor (anti-NMDAR ab) encephalitis is an immune encephalitis mediated by the presence of surface antibodies against the NMDA receptor. 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. 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. 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.1 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%).2 The differential diagnosis should
夽 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. ˜ S.L.U. All rights reserved. 2387-0206/© 2015 Elsevier Espana,
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),3 and immunological disorders. Among the antibodymediated encephalitis there are those directed against surface antigens of the neuronal membrane, intracellular directed against onconeuronal antigens and intracellular against synaptic antigens (Table 1).4,5 Although the presentation varies between children and adults, most patients show a similar syndrome after a month of progression.2 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.4 The findings are variable (increased temporal-level signal, meningeal enhancement, punctiform demyelinating lesions, signs of intracranial hypertension).6 PET scan can show frontotemporal hypermetabolism associated with occipital hypometabolism. This gradient correlates with the severity of the disease, and its normalization, with recovery.5 The EEG shows abnormalities by pathology in up to 90% of cases, although the findings are often nonspecific. 30% showed an extreme brush delta pattern which is associated with poor prognosis.7 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,5 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.2 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,2 mainly from respiratory, heart and infectious causes.
Scientific letters / Med Clin (Barc). 2015;145(11):504–506
505
Table 1 Antibody mediated encephalitis.
Antigen Age Association with tumour Response to treatment Relapses
Intracellular, onconeuronal antigen
Intracellular, synaptic antigen
Cell surface or synaptic receptor
Hu, CRMP5, Ri, Yo, Ma2 Predominant in older age Yes 10–30% Uncommon
GAD, anfisina Adults Varies with the antigen Partial improvement 60% Uncommon
NMDAR, AMPAR, GABA (B) R, Caspr2 All ages, although more in children Varies with the antigen and age Partial or complete improvement 75–80% Varies with the antigen (10–25%)
References 1. Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011;77:179–88. 2. Titulaer MJ, McCrackern L, Gabilondo I, Armangué T, Glaser C, Lizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with antiNMDA receptor encephalitis: an observational cohort study. Lancet. 2013;12: 157–65. 3. González-Valcárcel J, Rosenfeld MR, Dalmau J. Diagnóstico diferencial en la encefalitis por anticuerpos contra el receptor NMDA. Neurologia. 2010;25:409–13. 4. Lancaster E, Dalmau J. Neuronal autoantigens. Pathogenesis, associated disorders and antibody testing. Nat Rev Neurol. 2012;8:380–90. 5. Rosenfeld MR, Titulaer MJ, Dalmau J. Paraneoplastic syndromes and autoimmune encephalitis: five new things. Neurol Clin Pract. 2012;2:215–23. 6. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74.
Fever induced by hydroxycarbamide夽 Fiebre por hidroxiurea Dear Editor, Drug-induced fever is a rare clinical problem, although its actual incidence is unknown because it is probably underdiagnosed.1,2 The list of drugs involved is extensive, although beta-lactam antibiotics seem to stand out due to their frequency.3 We present a case of fever induced by hydroxyurea (HU) without any other accompanying clinical manifestations. It is a 66-year-old male with no history of interest except hypertension, dyslipidaemia and depressive syndrome, under treatment with aspirin, simvastatin, clomipramine, olmesartan medoxomil, amlodipine and hydrochlorothiazide. Diagnosed with essential thrombocythemia 7 years before, carrier of the V617F mutation in the JAK2 gene, without treatment during 3 weeks before admission, when HU administration started with a dose of 1000 mg/day. Admitted due to a 10-day long condition of malaise, myalgia and fever without any focal clinical evidence. Examination revealed a temperature of 39 ◦ C and a systolic murmur. No skin lesions were observed. The blood count was normal, without eosinophilia. Biochemical studies showed values of 69 U/L AST, 55 U/L ALT and 24.4 mg/dL C-reactive protein, with no other abnormalities. Blood culture, urine culture, Legionella and pneumococcus antigen detection in urine and cytomegalovirus, Epstein–Barr virus, HIV, syphilis, Brucella, Mycoplasma, Coxiella burnetii and Chlamydia serology were all negative. The chest radiograph was normal and abdominal ultrasonography showed a hyperechogenic liver relative to fatty infiltration and increased prostate size. HU was discontinued at admission, with fever remission in 36 h. Its controlled administration was resumed two weeks later with a single dose of 500 mg, showing recurrence of fever after 8 h.
夽 Please cite this article as: Lizarralde Palacios E, Gutiérrez Macías A, Rámiz Martínez M, Escalante Boleas M. Fiebre por hidroxiurea. Med Clin (Barc). 2015;145:505–506.
7. Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79:1094–100.
Rosa Escudero Sánchez a,∗ , María Teresa Montojo Villasanta b , María Isabel González Anglada a a
Servicio Medicina Interna, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain b Servicio Neurología, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain ∗ Corresponding
author. E-mail address: [email protected] (R. Escudero Sánchez).
It has been estimated that drug-induced fever accounts for 0.01–5% of adverse drug reactions in hospitalized patients.1–3 It is defined as a febrile reaction related to drug administration, which disappears as soon as the drug is interrupted and in the absence of other causes that may explain it.3,4 The most common mechanism for fever is a hypersensitivity reaction1 ; although in these cases the fever is usually accompanied by skin lesions, eosinophilia or other manifestations, in the context of a delayed hypersensitivity syndrome or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome.5 In the definition of drug-induced fever, patients in whom the fever is accompanied by skin lesions are specifically excluded.2,3 In the case of antineoplastic agents, the pharmacological action itself, which leads to cell necrosis and release of potential pyrogens, could contribute to the onset of fever.1 Early recognition of drug-induced fever is vital to avoid prolonged hospitalizations, unnecessary diagnostic procedures or treatments as well as new exposures to the inducing drug. Our case meets the criteria of causality established in the algorithm Karch and Lasagna,6 which classifies the adverse effect as clearly defined; however, compliance with these criteria requires rechallenge, which is not without risk and should not be done in severe cases.1 The HU or hydroxyurea is an anticancer drug whose mechanism of action is the blocking of DNA synthesis mediated by the inhibition of the ribonucleotide reductase enzyme. It is used in the treatment of myeloproliferative diseases with negative Philadelphia chromosome and sickle cell anaemia. It is usually well tolerated; the most common side effects are myelosuppression with occurrence of peripheral cytopenias, digestive intolerance and skin lesions associated with its use, among which hyperpigmentation, alopecia and painful skin and mucous ulcers stand out. Pulmonary complications such as pneumonitis or bronchiolitis and drug-induced fever are less frequent.7 In a large series of 3411 patients treated with HU, drug-induced fever was observed in 0.5%.8 38 cases have been reported in the literature, including those reported in the series just mentioned and reviewed by Doutrelon et al.,9 no cases have been published in Spanish literature [Spanish Medical Index; search strategy of “hidroxiurea” (hydroxyurea) or “hidroxicarbamida” (hydroxycarbamide)
www.elsevier.es/medicinaclinica
Scientific letters Encephalitis associated with anti-NMDA antibodies夽 Encefalitis asociada a anticuerpos contra el receptor de NMDA Dear Editor, Anti-N-methyl-d-aspartate receptor (anti-NMDAR ab) encephalitis is an immune encephalitis mediated by the presence of surface antibodies against the NMDA receptor. 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. 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. 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.1 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%).2 The differential diagnosis should
夽 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. ˜ S.L.U. All rights reserved. 2387-0206/© 2015 Elsevier Espana,
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),3 and immunological disorders. Among the antibodymediated encephalitis there are those directed against surface antigens of the neuronal membrane, intracellular directed against onconeuronal antigens and intracellular against synaptic antigens (Table 1).4,5 Although the presentation varies between children and adults, most patients show a similar syndrome after a month of progression.2 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.4 The findings are variable (increased temporal-level signal, meningeal enhancement, punctiform demyelinating lesions, signs of intracranial hypertension).6 PET scan can show frontotemporal hypermetabolism associated with occipital hypometabolism. This gradient correlates with the severity of the disease, and its normalization, with recovery.5 The EEG shows abnormalities by pathology in up to 90% of cases, although the findings are often nonspecific. 30% showed an extreme brush delta pattern which is associated with poor prognosis.7 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,5 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.2 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,2 mainly from respiratory, heart and infectious causes.
Scientific letters / Med Clin (Barc). 2015;145(11):504–506
505
Table 1 Antibody mediated encephalitis.
Antigen Age Association with tumour Response to treatment Relapses
Intracellular, onconeuronal antigen
Intracellular, synaptic antigen
Cell surface or synaptic receptor
Hu, CRMP5, Ri, Yo, Ma2 Predominant in older age Yes 10–30% Uncommon
GAD, anfisina Adults Varies with the antigen Partial improvement 60% Uncommon
NMDAR, AMPAR, GABA (B) R, Caspr2 All ages, although more in children Varies with the antigen and age Partial or complete improvement 75–80% Varies with the antigen (10–25%)
References 1. Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011;77:179–88. 2. Titulaer MJ, McCrackern L, Gabilondo I, Armangué T, Glaser C, Lizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with antiNMDA receptor encephalitis: an observational cohort study. Lancet. 2013;12: 157–65. 3. González-Valcárcel J, Rosenfeld MR, Dalmau J. Diagnóstico diferencial en la encefalitis por anticuerpos contra el receptor NMDA. Neurologia. 2010;25:409–13. 4. Lancaster E, Dalmau J. Neuronal autoantigens. Pathogenesis, associated disorders and antibody testing. Nat Rev Neurol. 2012;8:380–90. 5. Rosenfeld MR, Titulaer MJ, Dalmau J. Paraneoplastic syndromes and autoimmune encephalitis: five new things. Neurol Clin Pract. 2012;2:215–23. 6. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74.
Fever induced by hydroxycarbamide夽 Fiebre por hidroxiurea Dear Editor, Drug-induced fever is a rare clinical problem, although its actual incidence is unknown because it is probably underdiagnosed.1,2 The list of drugs involved is extensive, although beta-lactam antibiotics seem to stand out due to their frequency.3 We present a case of fever induced by hydroxyurea (HU) without any other accompanying clinical manifestations. It is a 66-year-old male with no history of interest except hypertension, dyslipidaemia and depressive syndrome, under treatment with aspirin, simvastatin, clomipramine, olmesartan medoxomil, amlodipine and hydrochlorothiazide. Diagnosed with essential thrombocythemia 7 years before, carrier of the V617F mutation in the JAK2 gene, without treatment during 3 weeks before admission, when HU administration started with a dose of 1000 mg/day. Admitted due to a 10-day long condition of malaise, myalgia and fever without any focal clinical evidence. Examination revealed a temperature of 39 ◦ C and a systolic murmur. No skin lesions were observed. The blood count was normal, without eosinophilia. Biochemical studies showed values of 69 U/L AST, 55 U/L ALT and 24.4 mg/dL C-reactive protein, with no other abnormalities. Blood culture, urine culture, Legionella and pneumococcus antigen detection in urine and cytomegalovirus, Epstein–Barr virus, HIV, syphilis, Brucella, Mycoplasma, Coxiella burnetii and Chlamydia serology were all negative. The chest radiograph was normal and abdominal ultrasonography showed a hyperechogenic liver relative to fatty infiltration and increased prostate size. HU was discontinued at admission, with fever remission in 36 h. Its controlled administration was resumed two weeks later with a single dose of 500 mg, showing recurrence of fever after 8 h.
夽 Please cite this article as: Lizarralde Palacios E, Gutiérrez Macías A, Rámiz Martínez M, Escalante Boleas M. Fiebre por hidroxiurea. Med Clin (Barc). 2015;145:505–506.
7. Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79:1094–100.
Rosa Escudero Sánchez a,∗ , María Teresa Montojo Villasanta b , María Isabel González Anglada a a
Servicio Medicina Interna, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain b Servicio Neurología, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain ∗ Corresponding
author. E-mail address: [email protected] (R. Escudero Sánchez).
It has been estimated that drug-induced fever accounts for 0.01–5% of adverse drug reactions in hospitalized patients.1–3 It is defined as a febrile reaction related to drug administration, which disappears as soon as the drug is interrupted and in the absence of other causes that may explain it.3,4 The most common mechanism for fever is a hypersensitivity reaction1 ; although in these cases the fever is usually accompanied by skin lesions, eosinophilia or other manifestations, in the context of a delayed hypersensitivity syndrome or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome.5 In the definition of drug-induced fever, patients in whom the fever is accompanied by skin lesions are specifically excluded.2,3 In the case of antineoplastic agents, the pharmacological action itself, which leads to cell necrosis and release of potential pyrogens, could contribute to the onset of fever.1 Early recognition of drug-induced fever is vital to avoid prolonged hospitalizations, unnecessary diagnostic procedures or treatments as well as new exposures to the inducing drug. Our case meets the criteria of causality established in the algorithm Karch and Lasagna,6 which classifies the adverse effect as clearly defined; however, compliance with these criteria requires rechallenge, which is not without risk and should not be done in severe cases.1 The HU or hydroxyurea is an anticancer drug whose mechanism of action is the blocking of DNA synthesis mediated by the inhibition of the ribonucleotide reductase enzyme. It is used in the treatment of myeloproliferative diseases with negative Philadelphia chromosome and sickle cell anaemia. It is usually well tolerated; the most common side effects are myelosuppression with occurrence of peripheral cytopenias, digestive intolerance and skin lesions associated with its use, among which hyperpigmentation, alopecia and painful skin and mucous ulcers stand out. Pulmonary complications such as pneumonitis or bronchiolitis and drug-induced fever are less frequent.7 In a large series of 3411 patients treated with HU, drug-induced fever was observed in 0.5%.8 38 cases have been reported in the literature, including those reported in the series just mentioned and reviewed by Doutrelon et al.,9 no cases have been published in Spanish literature [Spanish Medical Index; search strategy of “hidroxiurea” (hydroxyurea) or “hidroxicarbamida” (hydroxycarbamide)