*Las características clínicas y del líquido cefalorraquídeo permiten la diferenciación temprana entre encefalitis infecciosas y no infecciosas

Encephalitis is defined as a disease process that involves cerebral inflammation causing neurological dysfunction of any degree1. Over a hundred different microorganisms can cause infectious encephalitis, including viruses, bacteria, fungi, and even parasites2. It should be highlighted that the prevalence of infectious encephalitis of certain etiologies varies from one geographical region to the next. Therefore, the knowledge both of regional epidemiology and recent patient travel history can contribute to diagnosis. Interestingly, even using state of the art diagnostic methods, the etiology of a significant number of cases remains undetermined3.

In noninfectious encephalitis, significant advances in the characterization of autoimmune causes have allowed the identification of new autoantibodies and their antigens4. This subtype of encephalitis may show identical clinical presentation to infectious forms, but treatment differs radically, and a favorable response can be observed with immunosuppressive therapy, underscoring the need for a swift and correct identification of the etiology.

The aim of the present study was to provide a detailed description of causes, clinical presentations, demographic characteristics, diagnostic approximation and prognosis of encephalitis, in a neurological center in Buenos Aires, Argentina. In addition, we aimed to assess whether any particular aspect of the initial clinical presentation, or of the general approach to patient management, helped to predict etiology and/or case prognosis.

Materials and methods

Medical records of all patients 18 years or older with presumptive diagnosis of encephalitis admitted between July 1, 2006 and July 1, 2013 were reviewed. The terms “encephalitis” and/or “meningoencephalitis” were identified in admission forms and case files of adult inpatient charts during the above mentioned period. In addition, symptoms that could be associated with encephalitis (such as seizures, sensory impairment and focal neurological deficit) were subjected to double cross-referencing on every admission record corresponding to this time period, in order to avoid selection bias.

Encephalitis was defined following the diagnostic criteria proposed in the “Consensus Statement of the International Encephalitis Consortium” in 2013, as altered mental status (altered level of consciousness or personality change) lasting more than 24 hours, with no identified alternative cause; associated with 3 or more of the following: fever, seizures, focal neurological signs, cerebrospinal fluid (CSF) white blood cell (WBC) count > 5/μl and suggestive magnetic resonance imaging (MRI) or electroencephalogram (EEG) findings. When meningeal signs were present, it was regarded as meningoencephalitis.

Data extracted from medical records belonging to 19 635 patients admitted in the study period were reviewed (Fig. 1). The initial search was made to include every patient 18 years of age or older admitted to the Neurology Department with probable diagnosis of encephalitis or meningoencephalitis, defined clinically as described above.

Eight hundred and fifty patients presenting neurological deficit not due to cerebrovascular disease, demyelinating disease, tumors or seizures, were included and their medical histories reviewed. Patients with meningitis and no CNS compromise were excluded. Only those with definitive diagnosis of encephalitis or meningoencephalitis were analyzed. This information was compared to results from an electronic search in our institute’s database of every discharge form in which the terms “encephalitis” or “meningoencephalitis” were reported as definitive diagnosis. Finally, one hundred and five patients met our inclusion criteria.

Abnormal CSF was defined using our laboratory reference ranges as follows: CSF white blood cell counts greater than 10 cells/μl, glucose concentration less than 50% of serum level, and/or protein concentration over 50 mg/dl. An alternative definition of abnormal CSF was used for comparison purposes: white blood cell counts greater than 5 cells/μl, glucose concentration less than 40% of serum level, and/or protein concentration over 60 mg/dl. There were no significant changes in the classification of abnormal CSF or in the comparison between infectious and noninfectious encephalitis when the alternative cutoff was used (data not shown).

Brain MRIs were reviewed, considering hyper intense lesions on T2 and FLAIR sequence images, associated (or not) with areas of bleeding and perilesional edema, as compatible pathological changes5. It is worthy of note that certain etiologies presented characteristic distribution of lesions (temporal lobe in herpetic encephalitis or mesial temporal lobes in limbic encephalitis). In addition, contrast-enhanced images were considered to be compatible with encephalitis after ruling out other potential causes such as demyelinating diseases or brain tumors.

On EEG analysis, not only were electroencephalographic seizures considered pathological, but also paroxysmal or focal alterations (epileptogenic waves), or presence of considerable disturbances in baseline recordings (non-epileptogenic waves).

The diagnosis of pathogen-specific infectious encephalitis was made using all available resources including PCR, culture and or antibody determination. All diagnostic procedures for infectious encephalitis are listed in the Supplementary Table.

For prognostic evaluation, we selected the modified Rankin Scale (mRS), used in cerebrovascular disease. Patients with no sequelae were scored 0-1, with increasing scores assigned as degree of disability progressed, for a maximum of 6 points.

Differences between etiologies as well as in clinical, radiological and demographic variables were investigated using Fisher´s exact test and Kruskal Wallis test followed by Dunn’s multiple comparison test. Factors associated with infectious or noninfectious origin were addressed using multivariable logistic regression. Every variable with a p < 0.25 in the univariate analysis was included, stepwise, in a final model, calculating odds ratio (OR) and 95% confidence interval (CI).

The present research protocol was submitted to and approved by the institutional Ethics Committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Results

One hundred and five patients met inclusion criteria, 64 (61%) men, median age of 48 years, with no significant differences between genders regarding age-related distribution. Demographic, clinical, radiological and electroencephalographic features are summarized in Table 1.

We identified 82 patients with infectious encephalitis (78% of total cases); 53 (65%) were men and the mean age was 47.8 years. In this subcategory, 64/82 cases (78%) were of suspected or confirmed viral origin, 12/82 (14%) had bacterial etiology, 3/82 (3.6%) had fungal disease and 1/82 (1.2%) had parasitic disease. The remaining two cases remained of undetermined origin. The clinical presentation was dominated by fever and headache, and only 10% had normal CSF values (Table 1).

CSF samples were submitted for viral, bacterial and fungal PCR or culture, and positive results were obtained in 47/82 (57%) patients. The identified etiologies were: Herpes Simplex Virus 1 (HSV-1), Varicella Zoster Virus (VZV), Herpes Simplex Virus 2 (HSV-2), Epstein Barr Virus (EBV), Mycoplasma pneumoniae, Cryptococcus neoformans, Mycobacterium tuberculosis, enterovirus,

Neiseria meningitidis, JC virus, Herpes Simplex Virus (HSV-6) and leptospiras, in descending order of frequency. Age distribution showed that EBV and HSV-1 were more common in young patients (Fig. 2).

In 35/82 (43%) of the infectious cases, a specific causal agent could not be determined (negative PCR, cultures and/or serology). Patients with unknown etiology within this group were considered to have an infectious origin as a result of the analysis of the clinical presentation, workup (CSF, Serum, MRI and EEG) and outcome after receiving antiviral or antibiotic treatment. The percentage of patients in whom the etiology could not be determined remained constant throughout the study period (data not shown).

Regarding treatment, 63 out of 82 (77%) patients received treatment with acyclovir, of which 41/63 (65%) were discharged without sequelae (mRS 0-1), while 13 patients had minimum sequelae (mRS = 2). Only 6 patients required further rehabilitation. Nineteen out of eighty two (23%) patients received antibiotics and 13/19 (68%) were discharged with no sequelae (mRS 0-1), while 4/19 (21%) presented minimal alterations (mRS 2) on discharge. No patient required rehabilitation.

Twenty-three patients (23/105, 22% of the series) had noninfectious encephalitis; the mean age was 50 years and 11 (48%) were males. In this subcategory, 4/23 (17%) patients required admission to the intensive care unit (ICU). A total of 20 cases corresponded to probable autoimmune origin, while the remaining 3 were paraneoplastic.

Clinical presentation of this subgroup was dominated by seizures, behavioral changes and altered state of awareness (see Table 1). During workup, only 5/15 (33%) presented abnormalities in the EEG, while 10/22 (45%) presented typical brain MRI changes and 14/23 (61%) had normal CSF biochemistry.

All patients with noninfectious encephalitis had negative results on viral and bacterial PCR in CSF samples, as well as negative CSF bacterial, fungal and mycobacterial cultures. Immunologic tests were performed (both in serum and CSF), obtaining positive results in 3/23 cases (13%): 2 patients with potassium channel autoantibodies in both serum and CSF, and one patient with anti Ma-2 antibodies in serum only. Multislice computerize tomography (CT) imaging of the neck, chest, abdomen and pelvis was also performed (with both oral and IV contrast), and positive findings were found in 2 cases (lung cancer and teratoma).

In 18/23 (78%) of cases of noninfectious encephalitis, no causal agent could be identified, a proportion that has remained unchanged throughout the study period (data