In December, 2019, WHO was notified by clinicians in Wuhan, China, of a novel and severe respiratory virus, later called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19, the disease caused by SARS-CoV-2, was recognised as a substantial global public health emergency and SARS-CoV-2 was declared a pandemic on March 11, 2020. The neurological community were alerted to the high prevalence of anosmia and dysgeusia in early reports. Some of these early cohorts also featured non-specific neurological symptoms, such as dizziness and headache. However, severe neurological and neuropsychiatric presentations associated with COVID-19 have become increasingly apparent, including a patient with encephalitis in China in whom SARS-CoV-2 was identified in cerebrospinal fluid (CSF), a patient with acute necrotising encephalopathy in Japan, and cases of cerebrovascular disease.
During other pandemics of respiratory pathogens, including severe acute respiratory syndrome, Middle East respiratory syndrome, and H1N1 influenza, there were similar reports of patients with neurological complications, either during the acute phase, thought to reflect direct viral cytopathy or a para-infectious cytokine storm, or later as a post-infectious, probably cellular immune or antibody-mediated phenomenon, classically manifested as Guillain-Barré syndrome. Additionally, occasional neuropsychiatric and psychiatric presentations have been reported in severe coronavirus infections, although such presentations could reflect broader socioeconomic implications of the pandemic on mental health. These complications are relatively uncommon, but such patients are often the most severely affected, necessitating protracted intensive care admission and often resulting in poor outcomes.
Most published reports on the neurological complications of COVID-19 are limited to individual cases or small case series. A few studies showed the benefits of identifying patients with neurological complications across centres. However, these studies have largely been limited to two or three hospitals and are restricted by both geography and specialty, therefore not assessing the neurological and neuropsychiatric complications of COVID-19 across the clinical spectrum of neurology, stroke or acute medicine, psychiatry, and intensive care.
Consequently, many important questions remain for neurologists and psychiatrists. How common are neurological and psychiatric complications in patients with COVID-19? What proportion of neurological and psychiatric complications affect the CNS versus the peripheral nervous system, and are novel syndromes emerging? And who is most at risk?
The breadth of early clinical presentations has not been represented in the literature, at least in part because patients could be primarily managed by physicians with various clinical specialties, including neurologists, stroke or acute medical physicians, psychiatrists, or intensive care physicians. More comprehensive and integrated epidemiological characterisation is crucial to understanding the mechanisms that underlie these presentations, without which it will be impossible to rationally select, evaluate, and use appropriate therapies.
We aimed to collate data through a large-scale, national, dynamic, cross-specialty collaborative structure, to both inform best practice management guidelines and to direct research priorities.
During the exponential phase of the pandemic, we developed an online network of secure rapid-response case report notification portals (CoroNerve platforms) comprising the Association of British Neurologists (ABN) Rare Diseases Ascertainment and Recruitment (RaDAR), the British Association of Stroke Physicians (BASP), and the Royal College of Psychiatrists (RCPsych), in collaboration with the British Paediatric Neurology Association (BPNA), the Neuro Anaesthesia and Critical Care Society (who used the ABN portal), the Intensive Care Society, and key stakeholders. Reporting portals for fully anonymised details were hosted on the web platforms of these collaborating professional bodies and via a novel web portal. Members of these professional organisations were emailed weekly to remind them of the surveillance programmes and were invited to notify the central CoroNerve Group at CoroNerve.com of any cases of COVID-19 associated with any of the clinical case definitions that they had seen through these portals.
Because of the clinical demands of the pandemic, we identified minimum clinical datasets that could be completed in under 5 min to reflect the crucial data required to determine the confidence in the diagnosis of COVID-19, demography, geography, and the nature of the clinical syndrome. Physicians were encouraged to report cases prospectively and we also permitted recent cases to be notified retrospectively when assigned a confirmed date of admission or initial clinical assessment, allowing identification of cases that occurred before notification portals were available. Patients were not randomly assigned. Awareness of the study and notification portals was increased through social platforms during the peak of the pandemic, including professional webinars, recorded online presentations, and social media. The ABN portal was launched on April 2, 2020, the BASP portal on April 3, 2020, and the RCPsych portal on April 21, 2020. Data lock for this report was on April 26, 2020. Given the propensity for hospitalisation with COVID-19 for older demographic groups, older patients were defined as those aged 60 years or older and younger patients as those less than 60 years old.
Evidence of COVID-19
Evidence of SARS-CoV-2 infection was defined as confirmed COVID-19 if PCR of respiratory samples (eg, nasal or throat swab) or CSF was positive for viral RNA or if serology was positive for anti-SARS-CoV-2 IgM or IgG. Cases were defined as probable COVID-19 if a chest radiograph or chest CT was consistent with COVID-19 but PCR and serology were negative or not done. Cases were defined as possible COVID-19 if the disease was suspected on clinical grounds by the notifying clinician but PCR, serology, and chest imaging were negative or not done.
Clinical case definitions
Broad clinical syndromes associated with COVID-19 were classified as a cerebrovascular event (defined as an acute ischaemic, haemorrhagic, or thrombotic vascular event involving the brain parenchyma or subarachnoid space), altered mental status (defined as an acute alteration in personality, behaviour, cognition, or consciousness), peripheral neurology (defined as involving nerve roots, peripheral nerves, neuromuscular junction, or muscle), or other (with free text boxes for those not meeting these syndromic presentations). Data were collected on the specific clinical case definitions within these broad presentations, as follows: a cerebrovascular event (ischaemic stroke, intracerebral or subarachnoid haemorrhage, cerebral venous sinus thrombosis, or cerebral vasculitis); altered mental status (encephalopathy, encephalitis—defined as encephalopathy with evidence of inflammation in the CNS [CSF white cell count >5 cells per μL, protein >0·45 g/dL, or MRI consistent with inflammation], seizures [clinical or electroencephalographic evidence], and neuropsychiatric syndromes notified through psychiatrists or neuropsychiatrists [psychosis, neurocognitive dementia-like syndrome, personality change, catatonia, mania, anxiety or depression, chronic fatigue syndrome, and post-traumatic stress disorder]); and peripheral neurology (Guillain-Barré syndrome, Miller Fisher syndrome, brachial neuritis, myasthenia gravis, peripheral neuropathy, myopathy, myositis—defined as myopathy with evidence of inflammation [eg, by MRI or biopsy of muscle with elevated creatine kinase], and critical illness neuromyopathy).
When patients met more than one specific clinical case definition (eg, seizures and encephalitis), the underlying causal diagnosis was considered primary and complications of that diagnosis considered secondary features (eg, encephalitis would be considered primary and seizures secondary). Where there were discrepancies in classification, these were resolved through discussion with senior authors (BDM, IG, and RHT).
Additional data collection
By asking reporting physicians to submit their contact details at the time of notification (including a National Health Service email address), we established confirmation of the veracity of the data and created a log for subsequent sample collection and longitudinal follow-up studies, through linkage with existing platforms including co-recruitment into the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) Clinical Characterisation Protocol, which was also recorded. Data collected were compared with the geographical, demographic, and temporal presentation of overall cases of COVID-19 as reported by national government public health bodies representing each of the regions of the UK (Public Health England, Health Protection Scotland, Public Health Wales, and the Public Health Agency [Northern Ireland]).
The UK Health Research Authority formally confirmed this approach was compliant with regulations regarding anonymised surveillance of routine clinical practice in pandemic conditions, as initiated by the local attending clinician.
Role of the funding source
There was no funding source for this study. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
In the first 3 weeks of the submission portals accepting notifications (April 2–26, 2020), the CoroNerve study platforms received notification of 153 unique cases that met the clinical case definitions by clinicians in the UK. Patients were geographically dispersed across the UK, as were overall laboratory-confirmed cases of patients with COVID-19 reported by government public health bodies during the same time period Data from the admitting medical units were available for 152 (99%) of 153 patients. 26 (17%) of 152 patients were from tertiary care hospitals, 125 (82%) were from secondary care hospitals, and one (1%) was from primary care. Overall, 75 (49%) of 153 cases were notified through the BASP portal, 53 (35%) through ABN or CoroNerve.com, and 25 (16%) through the RCPsych portal. Cases were reported retrospectively for 24 (16%) of 153 patients and the remainder were reported prospectively. The BPNA surveillance network was not available for notifications, as the portal was not live during the study period. Data on reporting physician specialty were available for 150 patients: 61 (41%) were stroke physicians, 39 (26%) were neurologists, 26 (17%) were psychiatrists or neuropsychiatrists, 23 (15%) were acute medicine or other physicians, and one (1%) was a general practitioner.
Complete clinical datasets were available for 125 (82%) of 153 patients. Dates of admission or initial clinical assessment were available for 112 (90%) of 125 patients and correlated with the national case identification data of all laboratory-confirmed patients with COVID-19 reported by government public health bodies over the same time period, reflecting the exponential phase of infection.
Data on the sex and age of notified patients are reported in the table. Overall, the median age of 71 years (range 23–94; IQR 58–79) was similar to national data collected through UK Government public health bodies over the same time period, although for some centiles an older population could be overrepresented within the study cohort (figure 2). Data were available for sex for 117 (76%) of 153 patients as this question was not included in the original ABN RaDAR web portal, representing 28 (19%) cases, and this question was not answered in the other portals in eight (5%) cases. Therefore, data regarding sex were available for 117 (94%) of 125 patients for whom these data were requested.
114 (92%) of 125 patients with complete notification data met the criteria for confirmed SARS-CoV-2 infection, five (4%) met the criteria for probable SARS-CoV-2 infection, and five (4%) met the criteria for possible SARS-CoV-2 infection. 77 (62%) of 125 patients presented with the broad clinical syndrome of a cerebrovascular event, of whom 57 (74%) had an ischaemic stroke and nine (12%) an intracerebral haemorrhage. A clinical diagnosis of CNS vasculitis was reported in one (1%) patient with an unusual and otherwise unexplained infarct of the corpus callosum and imaging appearances suggestive of vasculitis; however, the full angiographic report and pathological confirmation were not provided. Beyond cerebrovascular events, 39 (31%) of 125 patients presented with altered mental status, comprising nine (23%) patients with unspecified encephalopathy and seven (18%) patients with both clinical symptoms or signs of encephalopathy and evidence of CNS inflammation meeting the clinical case definition for encephalitis. All seven patients with encephalitis met the criteria for confirmed SARS-CoV-2 infection. The remaining 23 (59%) patients with altered mental status fulfilled the clinical case definitions for psychiatric diagnoses as classified by the notifying psychiatrist or neuropsychiatrist. Only two (9%) of 23 patients had exacerbations of existing enduring mental illness. Ten (43%) of 23 patients with neuropsychiatric disorders had new-onset psychosis, six (26%) had a neurocognitive (dementia-like) syndrome, and seven (30%) had an other psychiatric disorder, including one case of catatonia and one case of mania.
Age data were available for 74 (96%) of 77 patients with cerebrovascular events and 37 (95%) of 39 patients with altered mental status. 18 (49%) of 37 patients with altered mental status were younger than 60 years and 19 (51%) were older than 60 years, whereas 13 (18%) of 74 patients with cerebrovascular events were younger than 60 years versus 61 (82%) patients older than 60 years.
You can read the full article here: The Lancet