| 1. |
- Abdelhak, Ahmed, et al.
(author)
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Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis.
- 2023
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In: Journal of neurology. - : Springer. - 1432-1459 .- 0340-5354. ; 270:7, s. 3315-3328
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Journal article (peer-reviewed)abstract
- To investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19).We conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU)admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL.We identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2±15.0years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with ahigher likelihood of ICU admission, need ofMV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need ofMV and ICU admission, respectively.Blood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.
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| 2. |
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| 3. |
- Frithiof, Robert, et al.
(author)
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Critical illness polyneuropathy, myopathy and neuronal biomarkers in COVID-19 patients: A prospective study
- 2021
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In: Clinical Neurophysiology. - : Elsevier BV. - 1388-2457 .- 1872-8952. ; 132:7, s. 1733-1740
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Journal article (peer-reviewed)abstract
- Objective: The aim was to characterize the electrophysiological features and plasma biomarkers of critical illness polyneuropathy (CIN) and myopathy (CIM) in coronavirus disease 2019 (COVID-19) patients with intensive care unit acquired weakness (ICUAW). Methods: An observational ICU cohort study including adult patients admitted to the ICU at Uppsala University Hospital, Uppsala, Sweden, from March 13th to June 8th 2020. We compared the clinical, electrophysiological and plasma biomarker data between COVID-19 patients who developed CIN/CIM and those who did not. Electrophysiological characteristics were also compared between COVID-19 and non-COVID-19 ICU patients. Results: 111 COVID-19 patients were included, 11 of whom developed CIN/CIM. Patients with CIN/CIM had more severe illness; longer ICU stay, more thromboembolic events and were more frequently treated with invasive ventilation for longer than 2 weeks. In particular CIN was more frequent among COVID-19 patients with ICUAW (50%) compared with a non-COVID-19 cohort (0%, p = 0.008). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp) levels were higher in the CIN/CIM group compared with those that did not develop CIN/CIM (both p = 0.001) and correlated with nerve amplitudes. Conclusions: CIN/CIM was more prevalent among COVID-19 ICU patients with severe illness. Significance: COVID-19 patients who later developed CIN/CIM had significantly higher NfL and GFAp in the early phase of ICU care, suggesting their potential as predictive biomarkers for CIN/CIM. (c) 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 4. |
- Fällmar, David, et al.
(author)
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The extent of neuroradiological findings in COVID-19 shows correlation with blood biomarkers, Glasgow coma scale score and days in intensive care
- 2022
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In: Journal of neuroradiology. - : Elsevier. - 0150-9861 .- 1773-0406. ; 49:6, s. 421-427
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Journal article (peer-reviewed)abstract
- Background and purposeA wide range of neuroradiological findings has been reported in patients with coronavirus disease 2019 (COVID-19), ranging from subcortical white matter changes to infarcts, haemorrhages and focal contrast media enhancement. These have been descriptively but inconsistently reported and correlations with clinical findings and biomarkers have been difficult to extract from the literature. The purpose of this study was to quantify the extents of neuroradiological findings in a cohort of patients with COVID-19 and neurological symptoms, and to investigate correlations with clinical findings, duration of intensive care and biomarkers in blood.Material and methodsPatients with positive SARS-CoV-2 and at least one new-onset neurological symptom were included from April until July 2020. Nineteen patients were examined regarding clinical symptoms, biomarkers in blood and MRI of the brain. In order to quantify the MRI findings, a semi-quantitative neuroradiological severity scale was constructed a priori, and applied to the MR images by two specialists in neuroradiology.Results and conclusionsThe score from the severity scale correlated significantly with blood biomarkers of CNS injury (glial fibrillary acidic protein, total-tau, ubiquitin carboxyl-terminal hydrolase L1) and inflammation (C-reactive protein), Glasgow Coma Scale score, and the number of days spent in intensive care. The underlying radiological assessments had inter-rater agreements of 90.5%/86% (for assessments with 2/3 alternatives). Total intraclass correlation was 0.80.Previously reported neuroradiological findings in COVID-19 have been diverse and heterogenous. In this study, the extent of findings in MRI examination of the brain, quantified using a structured report, shows correlation with relevant biomarkers.
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| 5. |
- Mulder, Jan, et al.
(author)
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Autoimmune Encephalitis Presenting With Malignant Catatonia in a 40-Year-Old Male Patient With COVID-19
- 2021
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In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 178:6, s. 485-489
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Journal article (other academic/artistic)abstract
- A 40-year-old man who had previously had symptoms of and a positive test for COVID-19, but had no other previous medical or psychiatric conditions or medication, presented to the emergency unit with acute debut of agitation, grimacing, and repetitive speech and movements (verbigeration and stereotypies); his behavior was bizarre, disorganized, hyperkinetic, and uncooperative and met DSM-5 criteria for catatonia. Twenty-two days before admission, the patient had developed COVID-19-related respiratory symptoms and fatigue, which did not require hospital care. He had tested positive for SARS-CoV-2 RNA in a naso-pharyngeal swab using the Abbott RealTime SARSCoV-2 assay on the Abbott m2000 platform (day 14; Figure 1A). Anosmia and ageusia were not present. During the several days before admission, he had suffered from a headache. On admission (day 22), he no longer had respiratory symptoms but he did have a fever (38.4 degrees C). He made no eye contact, his reflexes were normal, and Babinski's sign was absent. Treatment with antibiotics and acyclovir was initiated until the tests excluded bacterial infection and herpes encephalitis. Brain CT, MRI, and blood tests were unremarkable. The patient was lightly sedated with midazolam, followed with dexmedetomidine. Neuroleptics were not used. Lumbar puncture showed a high red blood cell count (19,000 cellsx10(6)/L) secondary to traumatic lumbar puncture. CSF cell count indicated pleocytosis, with 23x10(6)/L mononuclear and 8x10(6)/L polymorphonuclear cells. Signs of blood-brain barrier disruption were present, with elevated albumin levels in CSF, at 838 mg/L (reference, <400 mg/L), and the CSF/serum albumin quotient was 15.6 (reference, <6.8). Interleukin-6 (IL-6) in CSF was elevated at 102.1 pg/mL ( reference, <5 pg/mL), but CSF levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and tau protein were normal. PCR tests for SARS- CoV-2 were repeatedly negative in CSF and nasopharyngeal swabs. Antineuronal antibodies against N-methyl-D-aspartate receptor (NMDAR), glutamic acid decarboxylase, contactin-associated protein-like 2, leucine-rich, glioma inactivated 1, and ganglioside antibodies in serum and CSF were negative (Euroimmune, Lubeck, Germany). Hours later, the patient's state deteriorated, and his temperature rose to 39 degrees C. He became mutistic and showed signs of autonomic instability, with recurrent episodes of fluctuating heart rate and arterial blood pressure and periods of oxygen desaturation (Figure 1B). The hypertension was difficult to treat, despite high doses of clonidine and labetalol. Plasma lactate levels varied between 0.6 and 8 mmol/L (reference, 0.8-2.0 mmol/L), but myoglobulin and creatine kinase myocardial band (CKMB) remained normal. The patient's pupil size, reaction to light, and oculocephalic reflex were normal. Slow, horizontal roving eye movements were noted. The patient displayed decorticate posturing and increased tonus; he resisted movement of arms and jaw but had normal tonus in the legs. Hyperreflexia was present, with bilateral foot clonus and Babinski's sign but no neck stiffness. Anesthesia was induced with propofol and clonidine to facilitate endotracheal intubation. D-Dimer was slightly elevated (1.2 mg/L; reference <0.5 mg/L), without signs of thromboembolic events. Respiration and cardiovascular function remained stable. Continuous EEG monitoring showed nonspecific slowing with left hemisphere predominance without epileptiformactivity. An episode of asystole with spontaneous recovery, episodes of bradycardia of 27 bpm and repeated P waves without QRS complexes were interpreted as third-degree atrioventricular block. Signs of autoimmune encephalitis were present, but this case did not meet the proposed criteria (1, 2). Standard radiological findings were normal, and the discrete pleocytosis and elevated protein in CSF was nonspecific. Although the diagnosis remained uncertain, parainfectious autoimmune encephalitis was still suspected. Plasmapheresis was initiated and repeated three times over 4 days. After two courses, the patient was extubated and was autonomically stable. Eye movement was normalized and hyperreflexia was less prominent, but bilateral Babinski's sign persisted. Treatment was initiated with 1 g methylprednisolone per day. On day 28, the patient showed a dramatic improvement. He was awake, oriented, and communicative but had no memories from the past several days. He was distracted by complex visual hallucinations of black and white figures (animals and famous people) appearing on his right side. He described them as being in a mirror (suspected polyopia). These figures were often stationary but could make gestures. He also described an experience of feeling that the world was different-strange and unreal, with brighter colors (suspected hyperchromatopsia and derealization). He had frequent episodes of failing to recognize his right hand and leg as his own and experienced their movement as unexpected (alien hand syndrome). He denied the presence of other perceptual disturbances. His understanding of Swedish, his second language, seemed intact, but his responses were mostly monosyllabic. He could name his children and give his personal identification number but was slow and made mistakes in naming the months. Mild visual object agnosia was present. Simultanagnosia was prominent, he showed deficits in isolating figures in a tangled pictorial array, and he could depict details but excluded the global features of complex pictures. He could recall one of three objects after a short delay and draw a correct clock but required three repetitions of the instructions. He had difficulty mirroring and performing fine movements. Finally, he showed no signs of visual neglect and could read text. The patient's EEG was normal. A second lumbar puncture showed pleocytosis, 10 mononuclear cells and 1 polymorphonuclear cell x10(6)/L, elevated IgG levels and IgG index, and two oligoclonal bands in CSF not represented in serum, indicating intrathecal production of antibodies. The IL-6 level in CSF was normalized. GFAP and tau remained normal, but NfL was increased to 1,030 ng/L (reference, <890 ng/L). A second MRI and a standard neurological examination on day 31 were normal. The hallucinations were less frequent. The patient described increased emotional lability and mental fatigue, with disturbed short-term memory and decision making. He also found it challenging to recognize the voices and faces of acquaintances. Serology on day 33 was strongly positive (index 8.88 S/CO [signal/cutoff]) for IgG against SARS- CoV-2 analyzed with the CE-labeled SARS- CoV-2 IgG kit with nucleoprotein-based antigen with the Abbott Architect i2000SR Analyzer at the Laboratory of Clinical Microbiology, Uppsala University Hospital, as previously described (3). [F-18]fluorodeoxyglucose ([F-18]FDG) PET scan on day 35 (after treatment) showed high bilateral uptake in the striatum (caudate nucleus and putamen) compared with the cortex (Figure 1C). Using immunohistochemistry in the research lab, we detected IgG autoantibodies against mouse brain neuronal proteins in serum and CSF collected at admission (Figure 2). Neuronal labeling intensity was strongest in the CA3 in the hippocampal formation, layer V in the somatosensory cortex, and the paraventricular and reticular nucleus in the thalamus. A subset of ependymal cells located in the ventricle wall and choroid plexus revealed strong immunoreactivity of the (peri)nuclear compartment and cytoplasm. Immunoreactivity of neuropil was most intense in the caudate putamen, revealing neuronal processes and spine-like structures. Posttreatment IgG immunoreactivity in the (peri)nuclear compartment and neuropil was notably reduced, reaching the levels of reference CSF and serum.
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| 6. |
- Shanks, J., et al.
(author)
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Aqueductal CSF Stroke Volume Is Increased in Patients with Idiopathic Normal Pressure Hydrocephalus and Decreases after Shunt Surgery
- 2019
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In: AJNR. American journal of neuroradiology. - : American Society of Neuroradiology. - 1936-959X .- 0195-6108. ; 40:3, s. 453-459
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE: Increased CSF stroke volume through the cerebral aqueduct has been proposed as a possible indicator of positive surgical outcome in patients with idiopathic normal pressure hydrocephalus; however, consensus is lacking. In this prospective study, we aimed to compare CSF flow parameters in patients with idiopathic normal pressure hydrocephalus with those in healthy controls and change after shunt surgery and to investigate whether any parameter could predict surgical outcome. MATERIALS AND METHODS: Twenty-one patients with idiopathic normal pressure hydrocephalus and 21 age- and sex-matched healthy controls were prospectively included and examined clinically and with MR imaging of the brain. Eighteen patients were treated with shunt implantation and were re-examined clinically and with MR imaging the day before the operation and 3 months postoperatively. All MR imaging scans included a phase-contrast sequence. RESULTS: The median aqueductal CSF stroke volume was significantly larger in patients compared with healthy controls (103.5 μL; interquartile range, 69.8-142.8 μL) compared with 62.5 μL (interquartile range, 58.3-73.8 μL; P < .01) and was significantly reduced 3 months after shunt surgery from 94.8 μL (interquartile range, 81-241 μL) to 88 μL (interquartile range, 51.8-173.3 μL; P < .05). Net flow in the caudocranial direction (retrograde) was present in 11/21 patients and in 10/21 controls. Peak flow and net flow did not differ between patients and controls. There were no correlations between any CSF flow parameters and surgical outcomes. CONCLUSIONS: Aqueductal CSF stroke volume was increased in patients with idiopathic normal pressure hydrocephalus and decreased after shunt surgery, whereas retrograde aqueductal net flow did not seem to be specific for patients with idiopathic normal pressure hydrocephalus. On the basis of the results, the usefulness of CSF flow parameters to predict outcome after shunt surgery seem to be limited.
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| 7. |
- Virhammar, Johan, et al.
(author)
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Biomarkers for central nervous system injury in cerebrospinal fluid are elevated in COVID-19 and associated with neurological symptoms and disease severity
- 2021
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In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 28:10, s. 3324-3331
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Journal article (peer-reviewed)abstract
- Background and purpose: Neurological symptoms have been frequently reported in hospitalized patients with coronavirus disease 2019 (COVID-19), and biomarkers of central nervous system (CNS) injury are reported to be increased in plasma but not extensively studied in cerebrospinal fluid (CSF). This study examined CSF for biomarkers of CNS injury and other pathology in relation to neurological symptoms and disease severity in patients with neurological manifestations of COVID-19. Methods: Nineteen patients with neurological symptoms and mild to critical COVID-19 were prospectively included. Extensive analysis of CSF, including measurement of biomarkers of CNS injury (neurofilament light chain [NfL] protein, glial fibrillary acidic protein [GFAp], and total tau), was performed and compared to neurological features and disease severity. Results: Neurological symptoms included altered mental status (42%), headache (42%), and central (21%) and peripheral weakness (32%). Two patients demonstrated minor pleocytosis, and four patients had increased immunoglobulin G levels in CSF. Neuronal autoantibody testing using commercial tests was negative in all patients. Increased CSF levels of NfL protein, total tau, and GFAp were seen in 63%, 37%, and 16% of patients, respectively. Increased NfL protein correlated with disease severity, time in intensive care, and level of consciousness. NfL protein in CSF was higher in patients with central neurological symptoms. Conclusions: Although limited by the small sample size, our data suggest that levels of NfL protein, GFAp, and total tau in CSF are commonly elevated in patients with COVID-19 with neurological symptoms. This is in contrast to the standard CSF workup where pathological findings are scarce. NfL protein, in particular, is associated with central neurological symptoms and disease severity.
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