Critical illness polyneuropathy, myopathy and neuronal biomarkers in COVID-19 patients: A prospective study

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

Biomarkers for CNS injury in CSF are elevated in COVID-19 and associated with neurological symptoms and disease severity

BACKGROUND: Neurological symptoms have been frequently reported in hospitalized patients with coronavirus disease 2019 (COVID-19) and biomarkers of CNS injury are reported to be increased in plasma but not extensively studied in CSF. This study examines 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 protein (NfL) glial fibrillary acidic protein (GFAp) and total tau) was performed and related to neurological features and disease severity. RESULTS: Neurological symptoms included altered mental status (42%), headache (42%), 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, GFAp and total-tau protein were seen in 63%, 37%, and 16% of patients, respectively. Increased NfL correlated with disease severity, time in intensive care and level of consciousness. NfL in CSF was higher in patients with central neurological symptoms. CONCLUSION: Although limited by small sample size, our data suggest that levels of NfL, 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 work-up where pathological findings are scarce. NfL in particular, is associated with central neurological symptoms and disease severity

The extent of neuroradiological findings in COVID-19 shows correlation with blood biomarkers, Glasgow coma scale score and days in intensive care

Background and purpose: A 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 methods: Patients 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 conclusions: The 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

Anti-SARS-CoV2 antibody responses in serum and cerebrospinal fluid of COVID-19 patients with neurological symptoms

Antibody responses to SARS-CoV-2 in serum and CSF from 16 COVID-19 patients with neurological symptoms were assessed using two independent methods. IgG specific for the virus spike protein was found in 81% of cases in serum and in 56% in CSF. SARS-CoV-2 IgG in CSF was observed in two cases with negative serology. Levels of IgG in both serum and CSF were associated with disease severity (p<0.05). All patients with elevated markers of CNS damage in CSF also had CSF antibodies (p=0.002), and CSF antibodies had the highest predictive value for neuronal damage markers of all tested clinical variables

Idiopathic Normal Pressure Hydrocephalus : Cerebrospinal Fluid Tap Test and Magnetic Resonance Imaging as Preoperative Prognostic Investigations

Idiopathic normal pressure hydrocephalus (iNPH) is a condition with dilated cerebral ventricles but intracranial pressure within normal limits. The symptoms of gait impairment, cognitive decline and urinary incontinence develop gradually. Treatment with shunt insertion results in improvement in eight out of ten patients. The cerebrospinal fluid tap test (CSF TT) and preoperative magnetic resonance imaging (MRI) are methods used to select patients who may benefit from shunt surgery, but they are performed and interpreted differently in different centers throughout the world. The aim of this thesis was to evaluate the performance of the CSF TT and the underlying mechanisms of improvement in gait function after CSF removal, and to investigate the prognostic value of preoperative MRI scans. Improvement in gait and changes in cerebral blood flow (CBF) after a CSF TT were investigated in two prospective studies that included 39 and 20 patients, respectively. Gait assessment and perfusion MRI were done before and several times during the first 24 hours after a CSF TT. Perfusion was investigated with pseudo-continuous arterial spin labeling. At the group level, gait function was significantly improved at all investigation times, but only one-third of individual CSF TT responders were improved at all investigation times. In patients with increased CBF in lateral and frontal white matter after the CSF TT, gait function improved more than it did in patients with decreased CBF in these regions. However, in the whole sample, there was no significant increase in CBF after CSF removal. Preoperative MRI scans were retrospectively evaluated in 109 patients with iNPH who had undergone shunt surgery. The callosal angle was smaller in shunt responders compared with non-responders. The following findings showed the highest association with a positive outcome after shunting: a small callosal angle, wide temporal horns, and occurrence of disproportionally enlarged subarachnoid space hydrocephalus. In conclusion, CBF in white matter close to the lateral ventricles may play a role in the reversibility of symptoms after CSF removal in patients with iNPH. The CSF TT should be reevaluated if the patient does not initially improve, and preoperative MRI investigations can add prognostic information regarding the selection of shunt candidates

Idiopathic Normal Pressure Hydrocephalus : Cerebrospinal Fluid Tap Test and Magnetic Resonance Imaging as Preoperative Prognostic Investigations

Idiopathic normal pressure hydrocephalus (iNPH) is a condition with dilated cerebral ventricles but intracranial pressure within normal limits. The symptoms of gait impairment, cognitive decline and urinary incontinence develop gradually. Treatment with shunt insertion results in improvement in eight out of ten patients. The cerebrospinal fluid tap test (CSF TT) and preoperative magnetic resonance imaging (MRI) are methods used to select patients who may benefit from shunt surgery, but they are performed and interpreted differently in different centers throughout the world. The aim of this thesis was to evaluate the performance of the CSF TT and the underlying mechanisms of improvement in gait function after CSF removal, and to investigate the prognostic value of preoperative MRI scans. Improvement in gait and changes in cerebral blood flow (CBF) after a CSF TT were investigated in two prospective studies that included 39 and 20 patients, respectively. Gait assessment and perfusion MRI were done before and several times during the first 24 hours after a CSF TT. Perfusion was investigated with pseudo-continuous arterial spin labeling. At the group level, gait function was significantly improved at all investigation times, but only one-third of individual CSF TT responders were improved at all investigation times. In patients with increased CBF in lateral and frontal white matter after the CSF TT, gait function improved more than it did in patients with decreased CBF in these regions. However, in the whole sample, there was no significant increase in CBF after CSF removal. Preoperative MRI scans were retrospectively evaluated in 109 patients with iNPH who had undergone shunt surgery. The callosal angle was smaller in shunt responders compared with non-responders. The following findings showed the highest association with a positive outcome after shunting: a small callosal angle, wide temporal horns, and occurrence of disproportionally enlarged subarachnoid space hydrocephalus. In conclusion, CBF in white matter close to the lateral ventricles may play a role in the reversibility of symptoms after CSF removal in patients with iNPH. The CSF TT should be reevaluated if the patient does not initially improve, and preoperative MRI investigations can add prognostic information regarding the selection of shunt candidates

Levodopa-carbidopa enteral suspension in advanced Parkinson’s disease: clinical evidence and experience

The duration of action of oral levodopa becomes shorter as Parkinson’s disease (PD) progresses. Patients with advanced PD may develop potentially disabling motor fluctuations and abnormal involuntary movement (dyskinesia), which cannot be managed with optimized oral or transdermal PD medications. The progressively worsening symptoms can have a substantial impact on the patient quality of life (QoL). Levodopa–carbidopa intestinal gel (LCIG) is delivered continuously via a percutaneous endoscopic gastrostomy with a jejunal extension (PEG-J). LCIG is licensed for the treatment of levodopa-responsive advanced PD in individuals experiencing severe motor fluctuations and dyskinesia when available combinations of antiparkinsonian medications have not given satisfactory results. Initial evidence for the efficacy and tolerability of LCIG came from a number of small-scale studies, but recently, three prospective studies have provided higher quality evidence. A 12-week double-blind comparison of LCIG with standard levodopa therapy, a 52-week open-label study extension of the double-blind study, and a 54-week open-label safety study, demonstrated significant improvements in ‘off’ time and ‘on’ time without troublesome dyskinesia, and QoL measures that were maintained in the longer term. There are also observations that LCIG may be effective treatment for nonmotor symptoms (NMS) although the evidence is limited. There is a need for further research on the efficacy of LCIG in reducing NMS, dyskinesia and improving QoL. This review surveys the clinical evidence for the effectiveness and tolerability of LCIG in the management of advanced PD and highlights some practical considerations to help optimize treatment