Article Type : Case Report
Authors : Weimer LE, Cattari G, Binelli A ,Fanales -Belasio E, Piras S and Sensi F
Keywords : Sars-Cov 2; Severe Pneumonia; Autoinmune Encephalitis; chronic alcoholism
The novel coronavirus disease (COVID-19) caused by the acute
and atypical respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared
a global pandemic by the World Health Organization (WHO) on the 11th of March.
At 8th July 2021, globally infections are crossing 185 million and there are
over 4.000.000 fatalities. Concerning central nervous system involvement, a
wide spectrum of non- bacterial encephalitis secondary to a direct viral damage
hyper inflammation syndrome have been described. Conversely, only few cases of
encephalitis due to an antibody-mediated mechanism have been reported and even
fewer of autoimmune limbic encephalitis. These cases have been mostly described
within case series involving other types of encephalitis or encephalopathies,
without receiving a specific attention. It is known that neurons and glia
express the putative SARS-CoV-2 receptor angiotensin converting enzyme 2, and
that the related coronavirus SARS-CoV (responsible for the 2003 SARS outbreak)
can inoculate the mouse olfactory bulb [5]. If SARS-CoV-2 can enter the central
nervous system (CNS) directly or through haematogenous spread, cerebrospinal
fluid (CSF) changes, including viral RNA, IgM, or cytokine levels, might
support CNS infection as a cause for neurologic symptoms. We present an Italian
patient with Severe Case of SARS-CoV-2 disease, chronic alcoholism with
evidence of autoimmune encephalitis.
The novel coronavirus
disease (COVID-19) caused by the acute and atypical respiratory syndrome
coronavirus 2 (SARS-CoV-2) has been declared a global pandemic by the World
Health Organization (WHO) on the 11th of March. At 8th July 2021, globally
infections are crossing 185 million and there are over 4.000.000 fatalities
[1]. Concerning central nervous system involvement, a wide spectrum of non-
bacterial encephalitis secondary to a direct viral damage hyper inflammation
syndrome have been described [2]. Conversely, only few cases of encephalitis
due to an antibody-mediated mechanism have been reported and even fewer of
autoimmune limbic encephalitis [3]. These cases have been mostly described
within case series involving other types of encephalitis or encephalopathies,
without receiving a specific attention. It is known that neurons and glia
express the putative SARS-CoV-2 receptor angiotensin converting enzyme 2, and
that the related coronavirus SARS-CoV (responsible for the 2003 SARS outbreak)
can inoculate the mouse olfactory bulb [4,5]. If SARS-CoV-2 can enter the
central nervous system (CNS) directly or through haematogenous spread,
cerebrospinal fluid (CSF) changes, including viral RNA, IgM, or cytokine
levels, might support CNS infection as a cause for neurologic symptoms. We present an Italian
patient with Severe Case of SARS-CoV-2 disease, chronic alcoholism with
evidence of autoimmune encephalitis.
Our Italian patient 66-year-old, male, developed fever up to 38.9 degrees C, asthenia, myalgia, dyspnea, poorly cough, seizure, headache, visual disturbances and confusional state on 4 April 2021. In the Hospital of Alghero, Sardigna, Italy he was admitted immediately after computed tomography scan (CT scan) imaging of his chest showed multiple and bilateral ground-glass opacities located in both subpleural and apico-basal spaces (especially on the left) and extensive left spontaneous pneumothorax with subtotal lung collapse. Nasopharyngeal swab specimens were collected to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid. The swab specimens were tested by real-time reverse transcriptase–polymerase chain reaction; a positive result was received 8 hours later on 4 April 2021. Our patient was diagnosed with COVID-19. He received 100 mg Remdesivir (Veklury) tablets orally, 3 times daily, Tocilizumab was given I.V.400 mg single dose for “cytokine storn”, O2 Therapy; Proton Pump Inhibitors (pantoprazole 40 mg , 2 times daily), steroid (dexamethasone 6 mg for 10 days), Meropenem 2 g tid, Acyclovir 750 mg tid, Midazolam 15 mg 3 f in 500 cc of SF in continuous infusion, chlorpromazine 50 mg bid, flecainide 100 mg bid, sotalol 80 mg/die, allopurinol 300 mg/die, rehydration therapy. Concomitant pathologies: arterial hypertension, dyslipidaemia, functional monorene, gouty arthropathy, prostatic hypertrophy, spinal canal stenosis (recent decompression and stabilization of L5-S1).
Figure 1: Arterial Haemogasanalysis.
One week after
admission, on 15 April, 2021 our patient show an important confusional state
and psychomotor agitation that resulted in bed restraint and sedation under
continuous infusion with midazolam, as per Neurological Consultation for
suspect of encephalitis. Control Computerized tomography scan performed:
uncooperative patient, examination significantly hampered by movement
artifacts. Not evident images referable to encephalic lesions of hemorrhagic
nature or gross encephalic lesions of ischemic nature. The patient showed a
severe agitation syndrome associated with mutism; he was uncooperative and
unable to carry out even simple orders if not stimulated. Positive palmomental
and glabella reflexes with moderate nuchal rigidity were detected, with no focal
signs at the neurological examination. Hematochemical examinations:
neutrophilic leukocytosis, increase of: C - reactive protein, procalcitonin,
fibrinogen, ferritin, urea, LDH, GT, blood glucose, cholinesterase, increased
D-dimer (968ng/ml) but normal concentrations of C-reactive protein. Emogasanalysis
and clinical course: (Figure 1).
07/04 FiO2 21% pH 7.44, pO2 62 mmHg, pCO2
37 mmHg P/F 295
08/04 Ventimask FiO2 31% pH 7.45, pO2 76 mmHg, pCO2
36 mmHg P/F 245
09/04 Ventimask FiO2 31% pH 7.38, pO2 71 mmHg, pCO2
35 mmHg P/F 229
10/04 Ventimask FiO2 31% pH 7.43, pO2 89 mmHg, pCO2
36 mmHg P/F 287
12/04 Ventimask FiO2 31% pH 7.33, pO2 85 mmHg, pCO2
39 mmHg P/F 274
10/04 Ventimask FiO2 31% pH 7.43, pO2 89 mmHg, pCO2
36 mmHg P/F 287
14/04 Ventimask FiO2 28% pH 7.49, pO2 66 mmHg, pCO2
36 mmHg P/F 236
16/04 Ventimask FiO2 28% pH 7.48, pO2 77 mmHg, pCO2
34 mmHg P/F 275
18/04 Ventimask FiO2 28% pH 7.45, pO2 92 mmHg, pCO2
37 mmHg P/F 329
25/04 Ventimask FiO2 40% pH 7.42, pO2 75.2 mmHg,
pCO2 26.5 mmHg, Lac 10 mg/dl P/F 307 Lumbar puncture:
Cerebrospinal fluid: cytochemical examination: Glucose 68 mg/dl [40-70];
Absent cells,Clear appearance:Colorless color,Chlorine 130,Protein 50 mg/dl
[12-40].
Molecular test FilmArray Meningitidis/Encephalitis panel (bacteria,
viruses, yeasts) NEGATIVE EBV-DNA negative; HSV2-DNA negative; HSV1-DNA
negative; CMV-DNA negative; Negative Sars-CoV-2.
Cerebrospinal fluid culture test negative. On 26 April 2021 Magnetic
Resonance Image and electroencephalogram not performed: death of the patient.
We are still learning about all the neurological complications of
COVID-19. Encephalitis appears to occur in multiple ways. There have been case
reports of SARS-CoV-2 detection within the spinal fluid and patients presenting
with an inflammatory syndrome of the brain. COVID-19 is associated with a high
state of inflammation throughout the body. This also adversely affects the brain.
There is speculation that the blood vessels that supply blood to the brain
become inflamed and result in brain injury in terms of stroke and secondary
tissue dysfunction. There also may be inflammation that causes secondary damage
to the brain as the immune system fights the virus and there is
cross-reactivity to the brain itself. Our case is characterized by evidence of
autoimmune encephalitis in the context of severe COVID-19 pneumonia and Chronic
Alcoholism. Clinically, the patient presented with various neuropsychiatric
symptoms, which were reported before in other COVID-19 patients with
encephalopathy [5]. Neither SARS-CoV-2 itself nor antibodies against the virus
were found positive in the CSF, precluding direct viral CNS infection.
Comprehensive laboratory tests ruled out antineuronal antibodies as well as
common infectious causes of encephalitis, altogether supporting the diagnosis
of parainfectious autoimmune encephalitis. In addition, the diagnostic criteria
for possible autoimmune encephalitis as proposed. Were met [6]. The use of
technology called next-generation sequencing of metagenomics has allowed the
identification of infectious causes of encephalitis that were not previously
considered. A new form of autoimmune encephalitis that was previously
unrecognized is also being recognized. Being able to reliably distinguish
between infectious and autoimmune encephalitis even a decade ago was extremely
difficult; this is important because treatment will differ greatly between the
two. One requires the use of antimicrobial drugs while the other relies on
immunomodulatory drugs. With the ability to more accurately diagnose the cause
of encephalitis, patients receive the appropriate treatment and have a better
chance of recovery [7]. Some of the diagnostic tests may take time to
accurately diagnose encephalitis. There is a saying in the stroke world that
time is brain; the same is true for encephalitis. The longer the diagnosis is
delayed, the more vulnerable the brain is to further injury. It would serve to
have timely diagnostics at the point of care that can quickly provide
physicians and patients with the cause of encephalitis and also to benefit from
more targeted treatments. For some forms of viral encephalitis, we can only
provide supportive care because we do not have a drug that can actively reduce
viral replication. There are still a number of unmet needs [8]. We need
prospective studies of treatment options and additional patient characteristics
to further understand the variables associated with COVID-19-associated death
in patients with Autoinmune Encephalopathy.
Although a very limited number of autoimmune have been described until
now, it is important to consider the possibility of an autoimmune process also
in the setting of COVID-19 infection, in particular if neurological impairment
appears late, when respiratory symptoms are resolving. In these cases, managing
an early diagnostic set-up with Cerebrospinal fluid analysis,
electroencephalogram (EEG), and brain imaging, represents the best diagnostic
strategy, in order to avoid unnecessary delays and promptly start the
appropriate treatments. Future studies oriented towards biomarkers
identification may help to correctly identify the pathophysiological mechanisms
underlying the wide spectrum of encephalitis and better clarify the
pathological process of LE encephalitis in the setting of COVID-19.