3.2. Study characteristics
Of the 14 articles included in this study, nine were case reports(15–23), three were retrospective studies(24–26), one was a letter to the editor reporting original data of a patient(27), and one follow up letter to the editor of the same latter patient(28),. All were published in 2020. The studies were conducted worldwide, including France, USA, Spain, Brazil, Japan, Turkey, Sweden, UAE, France, Germany and Iran (Table 1). From the 14 eligible studies identified, the total sample size was 733. Out of these, only 14 patients tested positive for SARS-CoV-2 in their CSF samples. As the scope of this review is to investigate only patients who tested positive for SARS-CoV-2 in their CSF according to the eligibility criteria, we only described these 14 patients
Table 1
Characteristics of included studies.
Study
|
Authors
|
Country
|
Research Design
|
Sample Size
|
Number of CSF-Positive Cases
|
Gender
|
Age
|
1
|
Grégory Destras, et al.
|
France
|
Retrospective Cohort Study
|
555
|
2
|
N/A
|
Adults
|
2
|
Y. H. Huang, et al.
|
USA
|
Case Report
|
1
|
1
|
F
|
40
|
3
|
J. Cebrián, et al.
|
Spain
|
Case Report
|
1
|
1
|
F
|
74
|
4
|
Renan Barros Domingues, et al.
|
Brazil
|
Case Report
|
1
|
1
|
F
|
42
|
5
|
T. Moriguchi, et al.
|
Japan
|
Case Report
|
1
|
1
|
M
|
24
|
6
|
N. Fadakar, et al.
|
Iran
|
Case Report
|
1
|
1
|
M
|
47
|
7
|
G. Demirci Otluoglu, et al.
|
Turkey
|
Case Report
|
1
|
1
|
M
|
48
|
8
|
J. Helms, et al.
|
French
|
Cohort Study
|
140
|
1
|
N/A
|
N/A
|
9
|
Elham Rostami, et al.
|
Sweden
|
Case Report
|
1
|
1
|
F
|
55
|
10
|
M. Al-olama, et al.
|
UAE
|
Case Report
|
1
|
1
|
M
|
36
|
11
|
M. Mardani, et al.
|
Iran
|
Case Report
|
1
|
1
|
F
|
64
|
12
|
S. Kremer, et al.
|
France
|
Retrospective Cohort
|
28
|
1
|
N/A
|
N/A
|
13
|
T. H. Westhoff, et al.
|
Germany
|
Case Report
|
1
|
1
|
M
|
69
|
CSF = Cerebrospinal fluid; N/A = Not Available; M = male; F = Female |
Clinical Course and Diagnosis
In 21.4% (3/14) of cases, nasopharyngeal (NP) swabs initially tested negative despite a positive CSF sample(15, 17, 18). 14.2% (2/14) of positive cases as per NP swab tested negative after supposed recovery, but progressed to neurological deterioration and positive CSF tests(20, 22). 10/14 patients had both positive nasopharyngeal sample and CSF sample(16, 19–25, 28) (in two of these cases CSF was not tested initially, but was found to be positive at post-mortem), however samples were not always positive on the first test; 3/14 cases demonstrated a positive nasopharyngeal test but an initially negative CSF test(20, 22, 28). Table 2 summarises the clinical and diagnostic findings.
Table 2
Summary of presentation and clinical course of all cases testing positive for SARS-CoV-2 in CSF samples.
Study
|
Author
|
NP Result
|
Positive CSF Result
|
General Signs
|
Neural Signs & Symptoms
|
Respiratory Symptoms
|
1
|
Grégory Destras, et al.
|
Positive
|
2/555
|
N/A
|
N/A
|
N/A
|
2
|
Y. H. Huang, et al.
|
Positive
|
1
|
Fever; Lethargy
|
Headache; Seizures; Photophobia; Impaired consciousness; Neck stiffness
|
None
|
3
|
J. Cebrián, et al.
|
Positive
|
1
|
Myalgia; Nausea;Vomiting
|
Headache; Photophobia; Visual disturbance (blurred binocular vision); Incoherent speech
|
None
|
4
|
Renan Barros Domingues, et al.
|
Negative
|
1
|
Diarrhoea
|
Paresthesia and hypoesthesia of the left upper limb; Left hemithorax and hemiface
|
Common cold; Nasal obstruction
|
5
|
T. Moriguchi, et al.
|
Negative
|
1
|
Fever; Fatigue
|
Headache; Seizures (transient generalised); Impaired consciousness
|
Sore throat
|
6
|
N. Fadakar, et al.
|
Positive
|
1
|
Myalgia; Fatigue
|
Headache; Visual disturbances (saccade eye movements, optokinetic and end gaze rotational nystagmus); Gait disturbances; Vertigo
|
Cough
|
7
|
G. Demirci Otluoglu, et al.
|
N/A
|
1
|
Myalgia; Fatigue
|
Headache; Neck stiffness; Anosmia
|
Cough
|
8
|
J. Helms, et al.
|
Positive
|
1/140
|
N/A
|
N/A
|
Acute respiratory distress syndrome
|
9
|
Elham Rostami, et al.
|
Positive
|
1
|
Fever; Myalgia
|
Impaired brain stem reflexes
|
None
|
10
|
M. Al-olama, et al.
|
Positive
|
1
|
Fever; Myalgia, Diarrhoea; Vomiting
|
Headache; Impaired consciousness
|
Cough; Pharyngitis
|
11
|
M. Mardani, et al.
|
Positive
|
1
|
Generalised weakness
|
Impaired consciousness
|
Acute progressive dyspnoea
|
12
|
S. Kremer, et al.
|
N/A
|
1/28
|
N/A
|
N/A
|
N/A
|
13
|
T. H. Westhoff, et al.
|
Positive
|
1
|
Fever; Diarrhoea
|
Seizures (convulsive); Left-sided neglect
|
Cough
|
N/A = Not Available; CSF = Cerebrospinal Fluid. |
Symptoms
Most commonly reported symptoms included: Headache (6/14)(15–17, 19, 21, 28), fever (5/14)(17, 20, 21, 23, 28), vomiting (4/14)(16, 21), cough (4/14)(15, 19, 21, 23), visual disturbances (4/14)(16, 19, 23, 28), diarrhea (3/14)(18, 21, 23), and seizure (3/14)(17, 23, 28)(Table.2). In two of the studies, the patients’ COVID status was identified as severe(25, 26) and in one of these cases the patient was noted to be suffering from acute respiratory distress syndrome(25). Neurological symptoms were cited as the reason CSF test was carried out in 6/14 of the studies(16–18, 20, 22, 28).
Lab findings
Studies of the positive patients’ CSF samples (Table 3) revealed leukocytosis in 2/14 patients(17, 22), elevated protein in 3/14(22, 23, 28), hypoglycorrhachia in 1/14(22), and an elevated RBC in 1/14 samples(28). D-dimers were elevated in 3/14 blood samples(16, 21, 22).
Table 3
Blood and cerebrospinal fluid lab findings of cases with SARS-CoV-2 positive CSF samples.
Study
|
Author
|
Laboratory Findings
|
CSF Sample
|
Blood Sample
|
RBC
|
WBC
|
Protein
|
Glu
|
WCC
|
Glu
|
CRP
|
1
|
Grégory Destras, et al.
|
Data could not be extracted
|
2
|
Y. H. Huang, et al.
|
↑
|
N/A
|
↑
|
*
|
↑
(100% lymphocytes)
|
*
|
N/A
|
3
|
J. Cebrián, et al.
|
N/A
|
N/A
|
N/A
|
N/A
|
↑
|
N/A
|
↔
|
4
|
Renan Barros Domingues, et al.
|
N/A
|
↔
|
↔
|
↔
|
N/A
|
N/A
|
↔
|
5
|
T. Moriguchi, et al.
|
↔
None
|
↑
(10MN**, 2PMN***)
|
N/A
|
N/A
|
↑
(Neutrophil Predominant)
|
N/A
|
↑
|
6
|
N. Fadakar, et al.
|
N/A
|
N/A
|
N/A
|
N/A
|
↔
(32% lymphocytes)
|
N/A
|
↔
|
7
|
G. Demirci Otluoglu, et al.
|
N/A
|
↔
|
↔
|
↑
|
↔
(24.4% lymphocytes, 62.8% Neutrophils)
|
↑
105mmol/L****
|
↔
|
8
|
J. Helms, et al.
|
Data could not be extracted.
|
9
|
Elham Rostami, et al.
|
N/A
|
N/A
|
N/A
|
N/A
|
↔ / ↑
|
N/A
|
↔/↑
|
10
|
M. Al-olama, et al.
|
N/A
|
N/A
|
N/A
|
N/A
|
↑
|
↑
|
↔
|
11
|
M. Mardani, et al.
|
N/A
|
↑
(90% polymorph)
|
↑
|
↓
|
↑
Polymorphs > lymphocytes
|
↑
|
N/A
|
12
|
S. Kremer, et al.
|
Data could not be extracted.
|
13
|
T. H. Westhoff, et al.
|
N/A
|
↔
(100% lymphocytes)
|
↑
|
↔
|
↓
Lymphopenia
|
N/A
|
↑
|
*Units Not Reported, **Polymorphonuclear, ***Mononuclear. ****Non-fasting blood glucose |
RBC = Red blood cells; WBC = White blood cells; Glu = Glucose; WCC = White cell count; CRP = C-reactive protein; N/A = Not available; ↑= elevated levels; ↓= decreased levels; ↔= normal levels |
Radiological findings
Radiological findings (CXR, chest CT, systemic CT, Brain MRI and head CT) were reported for 11/14 patients. However, we could NOT extract the data from one cohort study(26). Radiological findings were normal in 2/14 patients(18, 28). The most common findings on brain MRI FLAIR were hyperintense regions in different areas of the brain (6/14)(15, 17, 19–21, 23), and the commonest finding on chest CT was ground glass opacities in the lungs (5/14)(15, 17, 20, 22) (23)(Table 4).
Table 4
Radiological findings of cases with SARS-CoV-2 positive CSF samples.
Study
|
Authors
|
Chest findings
|
Brain MRI
|
Head CT
|
1
|
Grégory Destras, et al.
|
N/A
|
N/A
|
N/A
|
2
|
Y. H. Huang, et al.
|
Unremarkable.
|
N/A
|
Unremarkable.
|
3
|
J. Cebrián, et al.
|
Unremarkable.
|
Right parietal cortical-subcortical restricted diffusion
|
Unremarkable.
|
4
|
Renan Barros Domingues, et al.
|
Unremarkable.
|
Unremarkable.
|
Unremarkable.
|
5
|
T. Moriguchi, et al.
|
Ground glass opacities
|
Hyperintense lesions in the right mesial temporal lobe and hippocampus; Slight hippocampal atrophy.
|
Unremarkable.
|
6
|
N. Fadakar, et al.
|
N/A
|
Bilateral cerebellar hemispheres and vermis hyperintensities; Edema; Cortical-meningeal enhancement of cerebellum
|
N/A
|
7
|
G. Demirci Otluoglu, et al.
|
Ground glass opacities; Consolidation
|
Hyperintense lesions in the posterior medial cortical surface of the temporal lobe; Hyperintense lesions in the upper cervical spinal cord.
|
Unremarkable.
|
8
|
J. Helms, et al.
|
N/A
|
N/A
|
N/A
|
9
|
Elham Rostami, et al.
|
Ground Glass opacities/ consolidations.
|
1st Brain MRI: Acute necrotizing encephalitis.
2nd Brain MRI: Partial regression of the changes in the brainstem and medial temporal lobes; More pronounced hyperintensities in central thalami and subinsular regions.
|
Symmetrical hypodensities in the thalami; Low attenuation areas in the thalami and midbrain.
|
10
|
M. Al-olama, et al.
|
Unremarkable
|
Right frontal intracerebral hematoma; Subarachnoid hemorrhage in the ipsilateral sylvian fissure and frontal and temporal lobes; Acute subdural hematoma; Edema causing midline shift.
|
Hyperintensities in the bilateral supratentorial leptomeningeal area; Chronic right subdural hematoma; Re-reabsorbing intracerebral hematoma; Perilesional brain edema causing midline shift.
|
11
|
M. Mardani, et al.
|
Bilateral Pleural effusion; Collapse consolidation of basal segments; Patchy ground-glass opacities
|
N/A
|
N/A
|
12
|
S. Kremer, et al.
|
Data could not be extracted
|
13
|
T. H. Westhoff, et al.
|
Ground-glass opacities; Consolidation
|
Linear meningeal hyperintensities; White matter edema
|
N/A
|
EEG findings
EEG findings were reported in two studies(20, 28), two of which noted a similar generalised slowing of waves with no epileptic activity(20, 28). One of these patients was noted to have a previous seizure(28).
Management and Treatment
The management of 4 patients was not discussed in their respective studies(18, 24–26), while the management for the remaining patients varied. Invasive intervention was required in two patients: Surgery was performed on 1/14 patients to remove the chronic subdural haematoma(21) and endotracheal intubation and mechanical ventilation was required on another patient with impaired consciousness(17). The mainstay initial management in 4/14 patients was acyclovir(15, 20, 22, 28)/This was however discontinued in one patient following negative herpes simplex virus results(28). Levetiracetam was given in 3/14 patients(15, 23, 28) and hydroxychloroquine was administered to 5/14 patients(15, 16, 22, 23, 28). Table.5 shows the management and outcomes of the 14 SARS-CoV-2 CSF positive patients.
Table 5
The management and outcomes of SARS-CoV-2 CSF positive patients.
Study
|
Authors
|
Antivirals
|
Antibiotics
|
Antiepileptics
|
Other Medications
|
Outcomes
|
1
|
Grégory Destras, et al.
|
N/A
|
N/A
|
N/A
|
N/A
|
Death (2)
|
2
|
Y. H. Huang, et al.
|
Acyclovir
|
Ceftriaxone/Vancomycin
|
Levetiracetam
|
HCQ
|
Full Recovery
|
3
|
J. Cebrián, et al.
|
Lopinavir/ Ritonavir
|
Ceftriaxone
|
none
|
Pain drugs; Fluid replacement; Oxygen therapy; HCQ; Acetaminophen; Dexketoprofen; Acetylsalicylic acid
|
Discharged
|
4
|
Renan Barros Domingues, et al.
|
N/A
|
N/A
|
N/A
|
N/A
|
Full recovery
|
5
|
T. Moriguchi, et al.
|
Aciclovir; Favipiravir
|
Ceftriaxone; Vancomycin
|
Levetiraceta
|
Endotracheal intubation + Mechanical ventilation; Steroids
|
ICU
|
6
|
N. Fadakar, et al.
|
Lopinavir; Ritonavir
|
none
|
none
|
none
|
Discharged
|
7
|
G. Demirci Otluoglu, et al.
|
Favipiravir; Acyclovir
|
Piperacillin/Tazobactam
|
Levetiracetam
|
HCQ; Steroids
|
Stable under treatment
|
8
|
J. Helms, et al.
|
N/A
|
N/A
|
N/A
|
N/A
|
ICU
|
9
|
Elham Rostami, et al.
|
Acyclovir
|
none
|
none
|
IVIG; Immunotherapy with plasma exchange
|
Discharged; Rehabilitation
|
10
|
M. Al-olama, et al.
|
|
none
|
none
|
Burr hole
|
ICU
|
11
|
M. Mardani, et al.
|
Lopinavir/ Ritonavir; Acyclovir
|
Ceftriaxone; Clindamycin; Meropenem; Vancomycin; Ampicillin
|
none
|
HCQ; Steroids; Folinic acid; Fluorouracil; Irinotecan
|
N/A
|
12
|
S. Kremer, et al.
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
13
|
T. H. Westhoff, et al.
|
none
|
none
|
Levetiracetam
|
Steroids; Insulin; Oxygen supply; Tacrolimus; HCQ
|
ICU → full recovery
|
N/A = Not available; HCQ = Hydroxychloroquine; IVIG = intravenous immunoglobulin G; ICU = Intensive Care Unit. |
Clinical Outcomes
The outcomes at the end of the study periods varied in these 14 SARS-CoV-2 CSF positive patients (Table 5). 2/14 deaths(24) and 4/14 ICU admissions(17, 21, 25) were reported overall. Symptoms improved in 1/14 cases who remained admitted(15), while 6/14 cases were discharged/recovered(16, 18–20, 23, 28), and 1/14 was transferred to a rehabilitation centre(20). Outcomes were not stated for two of the 14 patients(22, 26).