Title

Neurological complications of COVID-19

 

Lead Investigator: Dr Rachel Kneen as part of the CoroNerve Study Group.
Consultant Paediatric Neurologist and Honorary Senior Clinical Lecturer. Institute of Infection and Global Health, University of Liverpool; Alder Hey Children’s NHS Foundation Trust.

Study website: https://www.coronerve.com/

Contact: Dr Benedict Michael <Benedict.Michael@liverpool.ac.uk>

Additional investigators:

The CoroNerve Study Group: Dr Benedict D Michael, Dr Rhys H Thomas, Dr Ian Galea, Dr Ara Varatharaj, Dr Mark Ellul, and Professor Sarah Pett.

The CoroNerve Steering Committee: Dr Nicholas WS Davies, Dr Hadi Manji, Dr Michael Zandi, Dr Laura Benjamin, Professor Tom Solomon, Dr Jonathan Coles, and Dr Ava Easton. 


Clinical Case Definition
Acute neurological syndrome, as defined below, in patients with evidence of suspected or proven COVID-19

INCLUSION CRITERIA:
Age range for cases: 0-18 years

Proven COVID-19: Confirmed by polymerase chain reaction from clinical samples (sputum, nasal/throat swab, bronchioalveolar lavage, cerebrospinal fluid) or serology
Probably COVID-19: Chest radiograph compatible and clinical suspicion, but not meeting ‘proven’ criteria
Possible COVID-19: Clinical suspicion of COVID-19 but not meeting above criteria.

Encephalopathy 

New-onset altereation in consciousness, behaviour, personality, and/or cognition

  • Delirium (e.g. metabolic disturbance, iatrogenic)
  • Encephalopathy attributable to fever/sepsis
  • Encephalopathy attributable to hypoxia-ischaemia
  • Posterior reversible encephalopathy syndrome (PRES)
  • Malignant cerebral oedema
  • Mild encephalopathy with a reversible splenial lesion (MERS)
  • Acute infantile encephalopathy predominantly affecting the frontal lobes (AIEF)
  • Encephalopathy: other 

Encephalitis
New-onset encephalopathy with evidence of inflammation in the CNS [cerebrospinal fluid (CSF) white cell count >4/ml, protein >0.45g/dL, or MRI consistent with parenchymal  inflammation]

Encephalitis    

  • Viral encephalitis
    • Due to SARS-CoV-2 (CSF or tissue positive by PCR or intrathecal antibody synthesis)
    • Other viral pathogen (e.g. CSF PCR positive Herpes simplex virus)
    • Acute Disseminated Encephalomyelitis (ADEM)- by MRI criteria
    • Acute Necrotising Encephalitis- by MRI criteria
    • Acute Haemorrhagic Leukoencephalopathy- by MRI criteria
  • Limbic encephalitis
    • Antibody-mediated encephalitis (recognised antibody in serum or CSF)
    • Aetiology unknown
  • Encephalitis: other   

Meningitis  
One or more of headache, fever, meningism (neck stiffness, photophobia) in the absence of significant encephalopathy; with evidence of inflammation in the CNS  [cerebrospinal fluid (CSF) white cell count >4/ml, protein >0.45g/dL, or MRI consistent with meningeal inflammation]

Meningitis

  • Aseptic meningitis
    • Viral meningitis due to SARS-CoV-2
    • Other proven viral meningitis
    • Pathogen unknown
  • Meningitis: other

Meningoencephalitis (if encephalopathy present)

Central demyelination
Acute symptoms and signs associated with typical neuroimaging features on MRI best attributed to demyelination, with or without oligoclonal bands in CSF/serum

  • Multiple sclerosis
  • Neuromyelitis Optic-Spectrum Disorder
    • Positive for Aquaporin-4 antibodies
    • Positive for anti-MOG antibodies
    • No antibodies identified
  • Central demyelination: other 

Cerebellar syndrome
New onset symptoms or signs in keeping with cerebellar dysfunction such as dysarthria, ataxia or nystagmus (not attributable to a cerebrovascular accident)

Acute ataxia

Cerebellar syndrome: other

Myelitis
Sensory and/or motor symptoms and signs attributable to a spinal cord lesion, with evidence of inflammation in the CNS [cerebrospinal fluid (CSF) white cell count >4/ml, protein >0.45g/dL, oligoclonal bands, or MRI consistent with parenchymal  inflammation]

  • Direct viral myelitis
    • SARS-CoV-2 positive PCR in CSF and/or intrathecal antibody synthesis
    • Other pathogen (e.g. varicella zoster)
  • Para/post-viral myelitis
    • SARS-CoV2 negative PCR in CSF and/or no intrathecal antibody synthesis
  • Acute flaccid myelitis (lower motor neurone signs e.g. flaccid, areflexic limb[s] without sensory signs)
  • Myelitis: other         Free text


Direct viral radiculitis
Sensory and/or motor symptoms and signs attributable to inflammation of the spinal nerve roots.

Direct viral radiculitis due to SARS-CoV-2

  • SARS-CoV-2 positive PCR in CSF and/or intrathecal antibody synthesis
  • Other pathogen (e.g. enterovirus)

Guillain-Barre syndrome and variants

Guillain-Barre syndrome (Ascending sensory-motor flaccid, paralysis – typically areflexic)

Miller-Fisher syndrome (Ophthalmoplegia, ataxia, and areflexia)

Guillain-Barre syndrome and variants: other   Free text

Peripheral neuropathy 
Sensory and/or motor symptoms and signs attributable to peripheral nerve pathology.

  • Neuropathy attributable to critical illness (e.g. prolonged ITU admission)
  • Peripheral neuropathy: other                       

Myositis      
Motor symptoms and/or signs attributable to muscle inflammation with elevation of peripheral muscle enzymes (e.g. creatinine kinase- CK).          

  • Myopathy attributable to critical illness (e.g. prolonged ITU admission)
  • Rhabdomyolysis (e.g. CK >5 times the upper limit of normal and/or acute renal failure)
  • Myositis: other                       

Cerebrovascular
Symptoms, signs, and neuroimaging consistent with an ischaemic or haemorrhagic cerebrovascular accident, cerebral haemorrhage, or venous thrombosis.

  • Transient ischaemic attack (symptoms/signs <24 hours)
  • Ischaemic stroke - large artery (on neuroimaging)
  • Ischaemic stroke – lacunar (on neuroimaging)
  • Cerebral haemorrhage (on neuroimaging)
  • Sub-arachnoid haemorrhage (on neuroimaging)
  • Cerebral vasculitis (angiographic beading and/or inflammation in CSF and/or clinical suspicion)
  • Cerebral vein / sinus thrombosis (on neuroimaging)
  • Cerebrovascular: other   Free text                       

Seizures
New-onset seizures thought to be attributable to COVID19 disease. (Not typically seizures provoked by infection in some one with pre-existing epilepsy – unless their epilepsy presentation is radically novel- e.g .refractory status epilepticus)

Provoked seizure (e.g. febrile seizure- typically aged <5yrs old with full recovery)
Single acute symptomatic seizure

Multiple symptomatic seizures

Status epilepticus

  • Convulsive status epilepticus (>30minutes of continuous convulsive seizures or repeated seizures without complete recovery between)
  • Non-convulsive status epilepticus (>30minutes of continuous subtle motor signs or electroencephalographic evidence seizures or repeated clinical/EEG evidence without complete recovery between)
  • New-onset refractory status epilepticus (as above lasting >1-2 days continuously)

Faciobrachial dystonic seizures (unilateral or bilateral synchronous brachial and facial dystonic attacks)

Seizures: other                     

Movement Disorder
New onset movement disorder-  such as but not limited to chorea, tremor and dyskinesia

  • Hyperkinetic
    • Choreathetosis (writhing movements)
    • Ballismus (large amplitude brief movements)
  • Hypokinetic
    • Parkinsonism (rigidity, bradykinesia, pill-rolling rest tremor)
  • Dystonia
  • Tremor (other than rest tremor)
  • Movement Disorder: other                       

Sleep Disorder
New onset sleep disorder – typically causing distress such as a change to overall health, safety and quality of life

  • Narcolepsy
  • Other central hypersomnia
  • Parasomnias
  • Circadian rhythm sleep-wake disorder
  • Sleep Disorder: other                        

Psychiatric syndromes
These may be a new presentation of a significant mental health symptom, such as psychosis – or a significant change in someone with an existing mental health disorder (in accordance with joint RCPsych Neuropsychiatry Faculty and ABN working group)

  • Psychosis
  • Major depression
  • Mania
  • Anxiety
  • Obsessive-compulsive or related syndrome
  • Tics
  • Catatonia
  • Impulse control syndrome
  • Neurocognitive (dementia-like) syndrome
  • Personality change
  • Apathy
  • Chronic fatigue
  • Post-traumatic stress disorder
  • Functional neurological disorder
  • Other dissociative syndromes
  • Psychiatric syndromes: other                           

Neuromuscular junction syndromes
Primarily motor weakness disorder with supportive electrophysiology, antibody-status, or convincing clinical diagnosis

  • Myasthenia gravis (e.g. neurophysiological evidence of decremental responses, jitter on single-fibre, and/or acetylcholine receptor/MUSK antibody positive)
  • Lambert-Eaton syndrome (e.g. neurophysiological evidence of incremental responses and/or voltage-gated calcium channel antibody positive)
  • Neuromuscular junction syndromes: other                          

Brainstem syndromes
Defined by the presence of specific symptoms that can be localised to the brainstem– does not need to be supported by neuroimaging changes. One or more of the following may be present.

  • Locked in syndrome
  • Bulbar/pseudobulbar palsies
  • Eye movement disorder / nystagmus
  • Vertigo
  • Neurogenic ECG changes / cardiac arrythmia
  • Unexplained coma
  • Central apnoea
  • Brainstem syndromes: other                        

Headache
New-onset headache disorder not attributable to an exacerbation of chronic disorder (e.g. migraine)      

Migrainous (unliateral throbbing, with photo-, phono-, osmophobia, and nausea/vomiting; with/without aura)

Trigeminal autonomic cephalgia (e.g. cluster headache, hemicrania continua)

Other
                      

EXCLUSION CRITERIA:

No evidence of active or recent COVID-19 Infection.

BACKGROUND:

Para- and post-viral acute neurological syndromes are an important and treatable cause of significant neurological morbidity and mortality. However, evidence in the literature is limited to case reports and very small case series, and there remain many answered questions including which anti-inflammatory therapy to give to which patients.

During the 2009/2010 H1N1 (swine flu) pandemic we identified many cases of severe neurological complications including Acute Necrotising Encephalopathy (ANE) and Acute Leucoencephalopathy through the BPNSU and British Neurological Surveillance Unit (BNSU). Recently some have identified cases of severe acute CNS inflammatory syndromes associated with the novel COVID-19 strain. However, epidemiological and clinical data are not known. Additionally, it is unclear if the COVID-19 strain accounts for a significant proportion of these. These data are needed to direct future studies and public health programmes.

Parallel studies are underway through the Association of British Neurologists, the British Association os Stroke Physicians, the Royal College of Psychiatrists, and key partners.

Specific research question

  • What are the demographic, clinical, laboratory and radiological features of patients presenting with acute neurological syndromes during or following coronavirus infection?
  • What treatments do they receive?
  • What are their outcomes?

Aims
We will use the extensive network of neurologists who submit data to the British Paediatric Neurological Surveillance Unit (BPNSU) to identify cases of acute neurological syndromes associated with COVID-19, through direct infection and para-infectious or post-infectious presentations in the UK.

Objectives
i. To determine the demographic, clinical, laboratory and radiographic features of patients presenting with acute neurological syndromes during or within 6 weeks of virologically proven coronavirus infection
ii. To determine the proportion receiving immune and associated therapies and what these are.
iii. To determine the clinical outcomes of patients which each neurological syndrome relative to baseline features and treatments received.