Dear Sirs,
Recent evidence supports a neurotropic activity of SARS-CoV-2, causing encephalopathy
with various neurological symptoms. Apart from acute necrotizing encephalopathy (ANE),
imaging findings on brain MRI scans in COVID-19 encephalopathy were reported as being
unspecific and equivocal. Herein, we present a severe case of SARS-CoV-2 disease,
with evidence of parainfectious autoimmune encephalitis, causing a specific and previously
undescribed MRI pattern.
A 54-year-old male, Caucasian outpatient was diagnosed with COVID-19 by a positive
RT-PCR test for SARS-CoV-2 using a nasopharyngeal swab. Initial symptoms included
weakness, fever and unproductive cough. The patient was admitted to hospital on day
3 following clinical deterioration and presented with neuropsychiatric symptoms (aggressiveness,
disorientation, stupor) even before respiratory deterioration, suggestive for encephalitic
syndrome. There were no signs of epileptic activity or seizure-like symptoms. Medical
history revealed arterial hypertension, obesity (BMI 34 kg/m2) and obstructive sleep
apnea syndrome. Lung sounds and blood gas analysis were unremarkable ruling out hypoxemia.
Chest CT disclosed multilobular, bilateral lung infiltrates. Laboratory tests results
are presented in (Table 1) and included positive serum antibody indices for SARS-CoV-2.
On day 4, respiratory deterioration required endotracheal intubation and treatment
of bacterial superinfection was started according to antibiogram. Eight days later,
the patient could be extubated and PCR tests were negative for SARS-CoV-2. Yet, the
patient continued to show concentration difficulties and delirious behavior. Subsequent
MRI (Fig. 1a-c) revealed signal alterations within the claustrum/external capsule
region, showing reduced diffusion. Cerebrospinal fluid (CSF) analysis disclosed a
mild lymphocytic pleocytosis with negative test results for common neurotropic viruses.
Tests in serum and CSF were also negative for various antineuronal antibodies. The
patient recovered and was discharged with only mild cognitive impairment.
Table 1
Laboratory findings in blood and CSF (in the inpatient course)
Measure (blood)
Reference range
Result
White blood cell count (G/L)
4.40–11.30
6.7
Red blood cell count (T/L)
4.50–5.90
4.72
Lymphocytes (%)
10–50
13
LDH (U/L)
< 248
328
d-dimers (µg/l)
< 500
2001
Myoglobin (µg/l)
23.0–72.0
370.9
IL-6 (pg/ml)
< 8.0
90.2
CRP (mg/l)
< 5.0
93.3
SARS-CoV-2-IgA antibody (indices)
< 0.8–1.0
10.9
SARS-CoV-2-IgG antibody (indices)
< 0.8–1.0
13.2
Measure (CSF)
Reference range
Result
CSF aspect
Clear
Clear
White blood cell count (/µl)
< 5
9
Red blood cell count (/µl)
< 100
< 100
Monocytes (%)
12
Lymphocytes (%)
88
Total Proteins (mg/l)
180–430
396
Glucose (mg/dl)
< 75
57
Lactate (mmol/l)
1.70–2.60
1.65
Isoelectrofocusing
Normal
Normal
Advanced virus measures (CSF)
Reference range
Result
DNA-PCR of Herpes Simplex Virus, Varicella-Zoster Virus, Cytomegaly and Epstein Barr
Virus
Negative
Negative
RT-PCR for SARS-CoV-2 Virus
Negative
Negative
SARS-CoV-2-IgA antibody
Negative
Negative
SARS-CoV-2-IgG antibody
Negative
Negative
Measles IgG
< 1.4
1.1
Rubella IgG
< 1.4
1.3
Herpes Simplex Virus 1/2 IgG
< 1.4
1.1
Varicella Zoster Virus IgG
< 1.4
1.1
Advanced antineuronal antibody measures (serum and CSF)
GAD65, NMDA-, and GABA-B-receptor, IgLON5, AMPA-R subtype 2, DPPX, LGI1, CASPR2, Glycine-receptor,
mGluR5, mGluR1, Amphiphysin, CV2/CRMP5, Ma2/Ta, Hu, Ri, Yo, Zic4, Recoverin, Sox1,
Titin, DNER/Tr
Negative
Negative
Fig. 1
a-f MR scans 2 weeks (a–c) and 4 months (d–e) post symptom onset as well as CSF cytology
(f): On axial FLAIR (a), Diffusion-weighted images (b) and the corresponding ADC map
(c), bilateral signal alterations within the external capsule/claustrum regions are
depicted (arrows), indicative of reduced diffusion. On follow-up imaging (d–e), the
FLAIR-hyperintensities persist (d) whereas tissue diffusion has normalized (e). CSF-cytology
(f) showed a slightly elevated cell count (9/µl) with a lymphocytic predominance (88%
lymphocytes, 12% monocytes). A meaningful plasmacytic transformation was not observed,
the monocytes being only slightly activated
Follow-up has been carried out four months later showing a normalization in cell count
of CSF and improvement of MRI findings, although the claustrum lesions persisted.
Clinically, his neurological and cognitive status was normal.
Our case is characterized by evidence of parainfectious autoimmune encephalitis in
the context of severe COVID-19 pneumonia. Clinically, the patient presented with various
neuropsychiatric symptoms, which were reported before in other COVID-19 patients with
encephalopathy [1]. 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
by Gaus et al. were met [2].
While immunological markers remained unspecific and imaging findings of acute necrotizing
encephalitis were absent in our patient, brain MRI disclosed a unique pattern, a.k.a.
the claustrum sign. Previously, this sign has been coined in MRI studies of autoimmune
epilepsy, where an immune‐inflammatory‐mediated encephalopathy is suspected [3]. The
claustrum is known to play a crucial role in regulating consciousness [6] correlating
well to the clinical findings of impaired levels of consciousness in the presented
case.
In autoimmune epilepsy, the claustrum signals normalized in the majority but not in
all patients [4], suggesting a varying severity of claustrum damage. This is confirmed
by reduced diffusion in the first MRI scan of our patient, heralding irreversible
tissue damage (as proven by the 4-month MRI follow-up). At no point in time, there
was evidence for other causes of diffusion reduction, i.e., hypoxemia or status epilepticus.
Comparable claustrum lesions have also been reported in the context of autoimmune
encephalitis without epileptic or anoxic episodes, supporting inflammation as a decisive
factor [5].
A particular vulnerability of claustral neurons to hypoxic stress has been shown [7],
without relating to the inflammatory pathogenesis of our MRI findings. Yet, astrocyte
proliferations and microglia/macrophage infiltrations of the claustrum have been observed
in non-herpetic encephalitis [8]. To which extent other pathomechanisms, such as encephalitic
hypermetabolism as known from the striatum [9]. Additionally, compromise the claustrum
remains speculative.
Common MRI findings in a recent study of COVID-19 encephalopathy were cortical signal
abnormalities on FLAIR images (37%), accompanied by diffusion reduction, leptomeningeal
enhancement and cortical blooming artifacts in some cases. These imaging findings,
termed by the authors themselves as “rather unspecific”, did not allow differentiation
among various possible causes such as viral neurotropism, cytokine storm syndrome,
hypoxia, subclinical seizures or critical illness-related encephalopathy [10].
MRI findings in COVID-19 encephalitis, especially when suggesting autoimmune encephalopathy
may imply therapeutic interventions, such as immunosuppressive therapy. Recently,
progressive clinical improvement along with a reduction of inflammatory CSF parameters
has been observed in COVID-19 encephalitis, following high-dose steroid treatment
[11].
In summary, a previously undescribed imaging pattern in parainfectious COVID-19 encephalitis
is presented that bears a strong resemblance to MRI findings in autoimmune encephalitic
syndromes, such as known from epileptic or encephalitis caused by antineuronal antibodies.
This claustrum sign should be added to the still limited knowledge of encephalitic
imaging patterns in COVID-19, as it most probably represents an autoimmune phenomenon
that might progress from reversible signal changes to permanent tissue damage and
thus may trigger appropriate as well as timely therapy.