Coronavirus Disease (COVID-19) has spread as a world pandemic in the last few months. Since this epidemic is sustained by a new strain of coronavirus (Severe Acute Respiratory Syndrome Coronavirus-2: SARS-CoV-2), new aspects of this disease are emerging.
The first clinical descriptions of the disease point to lung disease often leading to pulmonary failure  . However, neurotropic properties have been shown for coronavirus and SARS-Cov-2  and neurological manifestations such as loss of smell have been described .
2. Clinical Case
Among atypical presentations of COVID-19, we describe here for the first time a neurological presentation with encephalitis and syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
The patient, Ms. P.A., female, 79 years old, was admitted on March 7th, 2020 to the University Hospital of Varese, during the epidemic phase of SARS-CoV-2 in Lombardy Region, Italy.
At admission in the emergency department, she presented with neurological symptoms suggesting encephalitis (confusion, somnolence, psychomotor retardation, cephalea). Five to 7 days before admission to the hospital the patient reported gastrointestinal symptoms, with vomit and diarrhea, followed by constipation. In her medical history, the patient referred rheumatoid arthritis treated with hydroxychloroquine sulfate (200 mg/day) and low dose steroid treatment (prednisone 5 mg/day).
At the clinical evaluation, no fever, no dyspnea and no cought were reported. Laboratory tests revealed severe hyponatremia (118 mEq/L; normal range: 136 - 150 mEq/L) and normal values of C reactive Protein (1.6 mg/L; normal range: 0.0 - 5.0 mg/L) and lactate dehydrogenase (235 U/L; normal range: 130 - 240 U/L), and no lymphopenia.
After submitting the patient to brain CT scan (Figure 1: non-specific diffuse cerebral atrophy), the neurologist suggested the execution of a lumbar puncture. Cerebrospinal fluid (CSF) analysis showed normal findings: glucose 49 mg/dL, proteins 61 mg/dL; <15 cells /field, negative search for cells and bacteria at microscopy. A search for polymerase chain reaction for Herpes Simplex Virus (HSV) 1 and HSV-2 was conducted on the CSF sample. At electroencephalography triphasic waves were interpreted as non-specific findings and in relation to dysmetabolic changes. At supine chest X Ray there were no signs of lung parenchymal disease (Figure 2(a)).
The patient was then transferred on March 10th to the Internal Medicine ward dedicated to non-COVID patients. She progressively continued the correction of hyponatremia, and SIADH was diagnosed  based on decreased effective osmolality of the extracellular fluid (Posm: 265 mOsmol/Kg H2O), inappropriate urinary concentration (Uosm: 377 mOsmol/KgH2O), and elevated urinary Na excretion (189 mmol/24h). A total body CT scan was prescribed for the clinical suspect of a malignant-associated SIADH. The patient was started on acyclovir therapy while waiting for the HSV-DNA result. To further investigate whether a sub-occluding fecaloma was the cause of the mild abdominal pain and constipation reported the days before admission, a rectal exploration was conducted with the finding of malodorous, curry-colored feces.
On March 11th and 12th, hyponatremia was almost completely corrected (130 mEq/L) with a progressive, slow improvement of neurological symptoms, but recovery was incomplete and she was still partially inappropriately confused (to be noted that the patient was fully active and was able of caring the whole family before hospital admission).
Figure 1. Brain CT scan. (a) and (b) show non-specific diffuse cortical atrophy at brain CT scan.
Figure 2. Chest X Rays at admission and during pneumonia. (a) shows a normal chest X Ray at admission to the hospital (patient in supine position), in the presence of only neurological symptoms and (b) (patient in sitting position) shows mild lung peripheral parenchymal infiltrate, in the presence of mild classical COVID-related symptoms adding to the neurological manifestations.
The total body CT scan was performed on March, 13th and showed normal findings; in particular no malignancies, no pneumonia or lung diseases. Testing for HSV was negative and acyclovir treatment was stopped.
On March 14th she presented fever (temperature 38˚ Celsius) and light cough and, therefore, she performed a nasopharyngeal swab for SARS-CoV-2 which resulted positive (for methods see supplemental material). The CSF obtained 7 days prior to the occurrence of fever in the suspect of neurological disturbances other than COVID-19, was then tested for SARS-CoV-2 with negative results (for methods see supplemental material).
The patient was then moved to a dedicated COVID department where she developed mild signs of COVID-19-related pneumonia (mild dyspnea and O2 desaturation at pulse oximeter; at chest X Ray (Figure 2(b)): mild peripheral parenchymal infiltrate), and was treated with lopinavir/ritonavir, hydroxychloroquine sulfate (200 mg twice/day), antibiotics (piperacillin/tazobactam) and mild non-invasive O2 therapy (2 L/min). In 15 days she recovered completely from COVID-19 and from the neurological symptoms which caused the admission to hospital. No fluid restriction was needed and no problems about hydro-electrolytic balance persisted during recovery and she was dismissed after performing 2 negative nasopharyngeal swabs.
Informed consent was obtained from the patient to report the case.
The unusual case of COVID-19 described here showed an initial clinical presentation with exclusive neurological symptoms and an infectious-related SIADH, followed by fever and dyspnea after few days. The oddity of this case is increased by the fact that the patient was already treated (because of rheumatoid arthritis) with drugs used for COVID-19 treatment (hydroxychloroquine and steroids) before admission and before developing more classical symptoms and signs of the SARS-CoV-2-related pneumonia. Possibly, this treatment may have masked for a few days the developing of a COVID-19-related typical lung disease and may have interfered with the finding of SARS-CoV-2 in the cerebrospinal fluid.
Ye et al. showed encephalitis as an additional manifestation of COVID-19 coming with the classical symptoms  and Poyiadji et al. reported images of acute hemorrhagic necrotizing encephalopathy associated with COVID-19 . Our report adds to the one from Moriguchi et al.  who described a meningitis/encephalitis associated with SARS-CoV-2 in a case of convulsion accompanied by unconsciousness as presenting symptoms.
Preventive measures against pandemics are based on a prompt recognition of cases that can lead to patient’s isolation, the only measure to contrast the propagation of infection. The attempt to make an early diagnose of COVID-19 is a crucial step to avoid contaminations of non-COVID medical departments. The unusual occurrence of early neurological symptoms as first manifestation of SARS-CoV-2 infection suggests that health professionals should be advised to consider COVID-19 in patients showing unclear clinical presentations of complex neurological symptoms.
METHODS: Evaluation of SARS-CoV-2 in biological specimens
After virus inactivation for 1 minute at 90˚C, RNA extraction from the nasopharyngeal swab is performed with Abbott mSample Preparation System (Promega corporation) and an automated extraction system (Extraction m2000SP, Abbott Molecular). Obtained RNA is amplified with GeneFinder COVID-19 plus RealAmp PCR kit (ELITechGroup), one step Reverse Transcription Real-Time PCR system targeting RdRp, E, and N genes.
Cerebrospinal fluid was subjected to RNA extraction by QIAmp Viral RNA mini kit (Qiagen) and eluted in 60 μl. One step rRT-PCR was performed using Luna Universal qPCR Master Mix (New England BioLab) with primers targeting the 5’UTR region of SARS-CoV-2. A nested PCR, after retrotranscription with Superscript IV Reverse Transcriptase (Thermo Fisher Scientific) was used to amplify ORF1ab, S, E, and N regions. All tested regions gave a negative result.
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