Neurological diagnoses for vaccine safety study

[helenmcd]

Codelists for vaccine safety study protocol aiming to investigate association of COVID vaccinations with Guillain Barre syndrome, transverse myelitis and Bell's palsy.

Codelists for neurological conditions needed: Outcomes: (1) GBS (2) transverse myelitis (3) Bell's palsy Exclusion criteria for transverse myelitis (chronic conditions which could mean discrete episodes of transverse myelitis are not coded): multiple sclerosis, neuromyelitis optica, or acute disseminated encephalomyelitis (ADEM)

Outcomes will need ICD-10 codes for SUS and mortality, and CTV3 for TPP primary care data. Bell's palsy will additionally use the SNOMED code in the ECDS dataset to capture emergency care attendances.

[helenmcd]

(1) Emergency care dataset dictionary search.

Searched ECDS data dictionary re Bell's palsy.
The ECDS data dictionary is here. We will need to use the diagnosis fields, not the presenting complaint. https://datadictionary.nhs.uk/data_sets/cds_v6-2/cds_v6-2-1_type_011_-_emergency_care_cds.html

The diagnosis fields are coded in SNOMED using a restricted reference set, as described here https://datadictionary.nhs.uk/data_elements/emergency_care_diagnosis__snomed_ct_.html https://dd4c.digital.nhs.uk/dd4c/publishedmetadatas/intid/710 The list of SNOMED codes is here: https://termbrowser.nhs.uk/?perspective=full&conceptId1=991411000000109&edition=uk-edition&release=v20210512&server=https://termbrowser.nhs.uk/sct-browser-api/snomed&langRefset=900000000000508004

This includes one SNOMED code for Bell's palsy: 193093009 Bell’s palsy (disorder)

[helenmcd]

(2) Search ICD-10 codes for GBS, transverse myelitis and Bell's palsy

The Brighton collaboration standardised case definitions and companion guides for adverse events include recommended ICD-10 codes for each of these adverse events. These are available here https://brightoncollaboration.us/category/pubs-tools/case-definitions/

a) Facial nerve palsy

https://brightoncollaboration.us/facial-nerve-palsy-case-definition-companion-guide/ Recommends G51.0

Looked this up in WHO ICD-10 code browser (2019): G51.0 Bell palsy Facial palsy (droop) (weakness) due to lower motor neuron [LMN] lesion Facial palsy NOS Excl.: facial palsy due to: upper motor neuron [UMN] lesion (G83.6)

Searched WHO ICD 10 browser 2019 version - "facial nerve" "Bell" and G50-59 Nerve, nerve root and plexus disorders Other candidates G51 Facial nerve disorders G51.8 Other disorders of facial nerve, and G51.9 Disorder of facial nerve, unspecified Considered these too vague to define Bell's palsy.

Code to use: G51.0 Bell palsy, consistent with Brighton Collaboration

b) GBS and Miller Fisher syndrome

https://brightoncollaboration.us/guillain-barre-and-miller-fisher-syndromes-case-definition-companion-guide/ Recommends G61.0

WHO ICD-10 code browser (2019): G61.0 Guillain-Barré syndrome Includes Acute (post-)infective polyneuritis, Miller Fisher Syndrome

Searched terms "guillain", "fisher" "inflammatory polyneuropathy" (and spelling variants), "ascending paralysis", "acute polyneuropathy", "acute polyneuritis", "demyelinating" G60-G64 Polyneuropathies and other disorders of the peripheral nervous system and its links to excluded related conditions

Other codes considered too broad

• G61 Inflammatory polyneuropathy
• G61.8 Other inflammatory polyneuropathies
• G61.9 Inflammatory polyneuropathy, unspecified
• G62.9 Polyneuropathy, unspecified

Code to use: G61.0 Guillain-Barré syndrome, consistent with Brighton Collaboration

c) transverse myelitis https://brightoncollaboration.us/aesi-case-definition-companion-guide-acute-myelitis/ The Brighton definition covers all acute myelitis, not limited to acute transverse myelitis.

There are separate Brighton collaboration definitions for encephalitis and ADEM but the codelists are overlapping (as myelitis may present with encephalitis or as part of ADEM) so the acute myelitis codelist comprises:

• G37.9 described as Myelitis, transverse in the Brighton template, and Demyelinating disease of central nervous system, unspecified in the WHO ICD-10 browser (2019)
• G37.3 Acute transverse myelitis in demyelinating disease of central nervous system
• Acute transverse myelitis NOS
• Excl.: multiple sclerosis (G35), neuromyelitis optica [Devic] (G36.0)
• G04.00, G04.01, G04.02 Acute disseminated encephalitis (unspecified, postinfectious and postimmunisation respectively)

Searched WHO browser for additional codes using terms "transverse", "acute myelitis", G00-G09 Inflammatory diseases of the central nervous system

Did not include codes which are not specific to acute transverse myelitis, e.g.

• G04 Encephalitis, myelitis and encephalomyelitis includes acute ascending myelitis and meningoencephalitis but excludes acute transverse myelitis e.g. G04.0 Acute disseminated encephalitis Encephalitis Encephalomyelitis | postimmunization
• G05 Encephalitis, myelitis and encephalomyelitis in diseases classified elsewhere e.g. G05.0 Encephalitis, myelitis and encephalomyelitis in bacterial diseases classified elsewhere includes syphilitic acute ascending transverse myelitis, acute TB myelitis, etc similarly G05.1 (viral), G05.2 (parasitic and other infectious and G05.8 (...in other disease classified elsewhere)

We're trying to identify the specific outcome of acute transverse myelitis not occurring as part of a wider disease process such as ADEM So propose to use only: G37.3 Acute transverse myelitis in demyelinating disease of central nervous system

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Summary proposal (a) Bell's palsy G51.0 Bell palsy, consistent with Brighton Collaboration

(b) Guillain Barre Syndrome G61.0 Guillain-Barré syndrome, consistent with Brighton Collaboration

(c) Acute transverse myelitis G37.3 Acute transverse myelitis in demyelinating disease of central nervous system this is narrower than the Brighton collaboration definition Might be useful to ask for neuro review of the transverse myelitis codelist once we've also got a CTV3 codelist draft and a codelist proposal for ADEM/MS/neuromyelitis optica

[annaschultze]

(1) Emergency care dataset dictionary search.

Searched ECDS data dictionary re Bell's palsy. The ECDS data dictionary is here. We will need to use the diagnosis fields, not the presenting complaint. https://datadictionary.nhs.uk/data_sets/cds_v6-2/cds_v6-2-1_type_011_-_emergency_care_cds.html

The diagnosis fields are coded in SNOMED using a restricted reference set, as described here https://datadictionary.nhs.uk/data_elements/emergency_care_diagnosis__snomed_ct_.html https://dd4c.digital.nhs.uk/dd4c/publishedmetadatas/intid/710 The list of SNOMED codes is here: https://termbrowser.nhs.uk/?perspective=full&conceptId1=991411000000109&edition=uk-edition&release=v20210512&server=https://termbrowser.nhs.uk/sct-browser-api/snomed&langRefset=900000000000508004

This includes one SNOMED code for Bell's palsy: 193093009 Bell’s palsy (disorder)

I wasn't sure if I should review the above links, but your search strategy seems sensible. In terms of the field to search, the OpenSAFELY function can only query a single field, and it's not clear to me which one it is (https://docs.opensafely.org/study-def-variables/#cohortextractor.patients.attended_emergency_care). @johntaz do you know? We should ask an engineer otherwise.

[annaschultze]

(2) Search ICD-10 codes for GBS, transverse myelitis and Bell's palsy

The Brighton collaboration standardised case definitions and companion guides for adverse events include recommended ICD-10 codes for each of these adverse events. These are available here https://brightoncollaboration.us/category/pubs-tools/case-definitions/

• Facial nerve palsy https://brightoncollaboration.us/facial-nerve-palsy-case-definition-companion-guide/ Recommends G51.0

Looked this up in WHO ICD-10 code browser (2019): G51.0 Bell palsy Facial palsy (droop) (weakness) due to lower motor neuron [LMN] lesion Facial palsy NOS Excl.: facial palsy due to: upper motor neuron [UMN] lesion (G83.6)

Searched WHO ICD 10 browser 2019 version - "facial nerve" "Bell" and G50-59 Nerve, nerve root and plexus disorders Other candidates G51 Facial nerve disorders G51.8 Other disorders of facial nerve, and G51.9 Disorder of facial nerve, unspecified Considered these too vague to define Bell's palsy.

Code to use: G51.0 Bell palsy

Seems sensible as well, would be happy to add epi sign off. Let me know if you want me to add to opencodelists.

[helenmcd]

(1) Emergency care dataset dictionary search. Searched ECDS data dictionary re Bell's palsy. The ECDS data dictionary is here. We will need to use the diagnosis fields, not the presenting complaint. https://datadictionary.nhs.uk/data_sets/cds_v6-2/cds_v6-2-1_type_011_-_emergency_care_cds.html The diagnosis fields are coded in SNOMED using a restricted reference set, as described here https://datadictionary.nhs.uk/data_elements/emergency_care_diagnosis__snomed_ct_.html https://dd4c.digital.nhs.uk/dd4c/publishedmetadatas/intid/710 The list of SNOMED codes is here: https://termbrowser.nhs.uk/?perspective=full&conceptId1=991411000000109&edition=uk-edition&release=v20210512&server=https://termbrowser.nhs.uk/sct-browser-api/snomed&langRefset=900000000000508004 This includes one SNOMED code for Bell's palsy: 193093009 Bell’s palsy (disorder)

I wasn't sure if I should review the above links, but your search strategy seems sensible. In terms of the field to search, the OpenSAFELY function can only query a single field, and it's not clear to me which one it is (https://docs.opensafely.org/study-def-variables/#cohortextractor.patients.attended_emergency_care). @johntaz do you know? We should ask an engineer otherwise.

Thanks Anna. I put the links in for reference because it took me some time browsing to find the reference set of SNOMED codes to search - don't think they need review!

It looks to me like the field with_these_diagnoses is the relevant option

[johntaz]

@annaschultze - sorry I've not used attended_emergency_care before and couldn't work out which it uses.

@helenmcd I've made a start on the CTV3 versions using the codelist builder for you to edit/review:

(a) Bell's palsy https://www.opencodelists.org/builder/01a0c47f/

(b) Guillain Barre Syndrome https://www.opencodelists.org/builder/33bfaae9/

(c) Acute transverse myelitis https://www.opencodelists.org/builder/68915149/ With this one, there were similar issues RE non-specific codes (e.g. F037. and F03..)

Exclusion criteria for transverse myelitis (chronic conditions which could mean discrete episodes of transverse myelitis are not coded): multiple sclerosis, neuromyelitis optica, or acute disseminated encephalomyelitis (ADEM)

Do we have a codelist(s) for this exclusion criteria or do we need to draft one?

[helenmcd]

Search for CTV3 codes for Bell's palsy

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Looked for existing Read codelists of Bell's palsy in vaccine safety studies:

• Wijnans et al PLoS One. 2017 https://pubmed.ncbi.nlm.nih.gov/28467420/ Read v2 F310.00 Bell's palsy

• Leite et al Pharmacoepidemiol Drug Saf. 2017 https://pubmed.ncbi.nlm.nih.gov/28156036/ Read v2 list: 1476 H/O: Bell's palsy F310.00 Bell's (facial) palsy F31z.00 Facial nerve disorder NOS F31..00 Facial nerve disorders 2BR6.00 O/E -cranial nerve 7-palsy-LMN 2BR7.00 O/E -cranial 7 -paralysis -LMN

• Hall et al. Pharmacoepidemiol Drug Saf. 2018 https://pubmed.ncbi.nlm.nih.gov/29152808/ -Much broader as aiming for sensitive 'possible' outcomes 1B32300 Facial weakness 2BR6.00 O/E -cranial nerve 7-palsy-LMN 2BR7.00 O/E -cranial 7 -paralysis -LMN 2BR9.00 O/E - cranial 7 -paralysis-UMN F31..00 Facial nerve disorders F310.00 Bell's (facial) palsy F31y.00 Other facial nerve disorders F31yz00 Other facial nerve disorder NOS F31z.00 Facial nerve disorder NOS F32..00 Other cranial nerve disorders F326.00 Multiple cranial nerve palsies F326100 Polyneuritis cranialis F326300 Multiple cranial nerve palsies in sarcoidosis F326400 Multiple cranial nerve palsies in neoplastic disease F326z00 Multiple cranial nerve palsies NOS F32z.00 Cranial nerve disorder NOS Fyu6400 [X]Other cranial nerve disorders/other diseases CE SJ14.11 Seventh cranial nerve injury

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Searched for CTV3 codes in code browser https://www.opencodelists.org/codelist/user/helen-mcdonald/bells-palsy/5cff9de2/#search-results Included all codes possibly relevant - generated 55 codes for consideration, sorted here helen-mcdonald-bells-palsy-5cff9de2.xls

Proposed approach Include 2BR6. | O/E -cranial nerve 7-palsy-LMN 2BR7. | O/E -cranial 7 -paralysis -LMN F31.. | Disorder of facial nerve F310. | Bell's palsy F31z. | Facial nerve disorder NOS X009n | Facial neuropathy X76nD | Facial weakness, lower motor neurone XE18F | Bell's palsy &/or facial palsy Y6712 | Facial nerve disorders

Discuss 1476 | H/O: Bell's palsy | propose to include F31y. | Other facial nerve disorders | propose not to include F31yz | Other facial nerve disorder NOS | propose not to include Fyu61 | [X]Other disorders of facial nerve | propose not to include

Rationale

• Don't include traumatic facial nerve injury (not a plausible vaccine outcome, exposure to traumatic injury may be affected by pandemic timing e.g. lockdown reducing travel)
• Not including decompression of facial nerve (not usually recommended for Bell's palsy, more likely to be due to other cause)
• Not including cranial nerve palsy which don't specify that affecting CN7
• Not including facial nerve palsy with a specified aetiology e.g. zoster, mastoiditis
• As Leite et al, suggest to include disorders of the facial nerve without a specified aetiology - these will be a mixture of causes but seem reasonably likely to include Bell's palsy cases
• This study is interested in incident Bell's palsy - suggest including H/O Bell's palsy as per Leite et al in case this reflects primary care recording of a recent ED attendance?
• 'Other facial nerve disorders' suggests an aetiology is available but not coded in which case would not include for Bell's palsy

[helenmcd]

Transverse myelitis CTV3 codes

Reviewed whether we can use existing codelist for this study https://www.opencodelists.org/codelist/opensafely/transverse-myelitis/2020-09-23/ F037. | Transverse myelitis X001Z | Acute viral transverse myelitis X005j | Acute non-infective transverse myelitis Github issue

Key decisions in pre-existing codelist

1. One higher level code that is now extinct that grouped transverse myelitis in with encephalitis and encephalomyelitis was excluded (F03..)
2. Did not include code for post-immunisation myelitis
3. Doesn't include Varicella transverse myelitis(X001a) as a child of Acute viral transverse myelitis

For this study

1. Seems appropriate for this study too - we want to ascertain the specific outcome of acute transverse myelitis, and extinct code should not be used in our very recent study period
2. We may want to include post-immunisation myelitis in this study if this is likely to capture transverse myelitis among vaccinated individuals, otherwise would underestimate risk in post-vaccination window
3. Zoster transverse myelitis is not the safety outcome of interest - possible that a recent COVID vaccination may affect coding of transverse myelitis aetiology but seems likely that would be coded as zoster transverse myelitis if zoster is the cause

Reviewed results of search by @johntaz (thank you!) no other codes found to include.

Will ask neurology advice on post-immunisation myelitis to check, but think we should include this for this study, together with the codes in the existing codelist.

Postscript: On searching, can find code for 'Post-immunisation encephalomyelitis' and or similarly encephalitis but cannot find code for post-immunis/zation myelitis in either OpenSAFELY CTV code search nor CTV3 dictionary

@CarolineMorton shared link to original search results - the search was in SNOMED and included a SNOMED code Post-immunization myelitis (429436007) - however this does not appear to have a direct equivalent in CTV3.

Propose to use existing CTV3 codelist for transverse myelitis https://www.opencodelists.org/codelist/opensafely/transverse-myelitis/2020-09-23

[helenmcd]

Guillain Barre CTV3 codes

Reviewed Read v2 codelist by Leite et al for vaccine safety surveillance F370000 | Guillain-Barre syndrome F370200 | Miller-Fisher syndrome F370.00 | Acute infective polyneuritis F37X.00 | Inflammatory polyneuropathy, unspecified F37y.00 | Other toxic or inflammatory neuropathy F37z.00 | Toxic or inflammatory neuropathy NOS F370z00 | Acute infective polyneuritis NOS F370100 | Postinfectious polyneuritis F37..00 | Inflammatory and toxic neuropathy Fyu7100 | [X]Other inflammatory polyneuropathies Fyu7B00 | [X]Inflammatory polyneuropathy, unspecified F21X.00 | Acute disseminated demyelination, unspecified Fyu4200 | [X]Acute disseminated demyelination, unspecified Fyu4000 | [X]Other specified acute disseminated demyelination

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Initial search for CTV3 codelists

Kept broad list of possible codes https://www.opencodelists.org/codelist/user/helen-mcdonald/guillain-barre/4955aa99/#full-list

In next draft, removed

• chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic progressive polyneuropathy, motor neuropathy with multiple conduction block,
• unspecified 'polyneuropathy' codes as these are too broad and likely be used primarily for more common conditions such as diabetic neuropathy

16 codes remain https://www.opencodelists.org/codelist/user/helen-mcdonald/guillain-barre/30463764/ Would like advice before removing:

• Drug-related polyneuropathy(F376.), Other toxic agent polyneuropathy(F377.), Drug &/or toxic polyneuropathy(XE18P)
• Demyelinating sensorimotor neuropathy(X00CG)
• Subacute inflammatory demyelinating polyradiculoneuropathy(Xa0Kt)

Decision about whether to include Polyneuritis cranialis(F3261) - if including, should also add ICD10 code for this.

[helenmcd]

Feedback from neurologist Arina Tamborska at Liverpool on the GBS CTV3 codes shortlist

GBS codes - Yes F370. Acute infective polyneuritis F3700 Guillain-Barre syndrome F3701 Post-infectious polyneuritis F370z Acute infective polyneuritis NOS F37z. (Toxic or inflamm neuropathy NOS) or (polyneuropathy unspec) Fyu40 [X]Other specified acute disseminated demyelination – this is likely to refer to central nervous system disorders so I would exclude Fyu42 [X]Acute disseminated demyelination, unspecified – same as above, exclude Fyu7B [X]Inflammatory polyneuropathy, unspecified X00AV Miller-Fisher variant of Guillain-Barre syndrome XE18N Acute infective polyneuritis (& [Guillain-Barre syndrome])

Considered for GBS codes - No XE18P Drug &/or toxic polyneuropathy X00CG Demyelinating sensorimotor neuropathy – include (in the acute form, this is effectively a description of the most common variant of GBS; chronic form = CIDP) Xa0Kt Subacute inflammatory demyelinating polyradiculoneuropathy F376. Drug-related polyneuropathy F377. Other toxic agent polyneuropathy F3261 Polyneuritis cranialis – agree to exclude. While idiopathic inflammatory polyneuritis cranialis may be considered as a GBS variant, it is less established than Miller Fisher or other variants and I think the risk is that you’d pick up cranial neuropathies unrelated to GBS at all (rather than missing actual GBS cases).

[helenmcd]

Search for codes for chronic inflammatory demyelinating polyneuropathy (CIDP) This is a codelist to exclude people with CIDP who would not be subsequently diagnosed with Guillain Barre syndrome (since GBS is an acute illness with the same presentation as CIDP, which is chronic).

(1) CTV3 Searched for CTV3 codes using opencodelist browser

• search terms polyneuropathy, chronic relapsing, demyelination, demyelinat, CIDP, MADSAM, Lewis, Sumner, multifocal acquired, multifocal motor, sensory and motor.
• excluded unrelated terms and polyneuropathy other specified aetiology e.g. diabetic polyneuropathy, hereditary polyneuropathies

Obtained longlist of 15 codes for review, sorted as below:

To include:

• Chronic inflammatory demyelinating polyradiculoneuropathy(X00AW)
• Chr inflamm demyelinat polyradiculoneuropathy with cns demye(X00AX)
• Subacute inflammatory demyelinating polyradiculoneuropathy(Xa0Kt)

Will ask for neuro advice on:

• Motor neuropathy with multiple conduction block(X00Ay)
• Neuropathy with anti-GM1 antibodies(X00Az)
• [X]Inflammatory polyneuropathy, unspecified(Fyu7B)
• Idiopathic progressive polyneuropathy(F364.) - (hereditary condition but will check in case it may also be used for CIDP)

Propose not to include unspecified polyneuropathies (too general- unlikely to be CIDP, wouldn't preclude GBS diagnosis, and might even be en route to GBS diagnosis):

• Neuropathy: [peripheral] or polyneuropathy
• Polyneuropathy(F366.)
• Polyneuritis(Xa7m5)
• Polyneuropathy unspecified(XaB3q)
• [X]Other specified polyneuropathies(Fyu72)
• [X]Polyneuropathy, unspecified(Fyu7C)
• Polyneuropathy in disease EC(F374.)
• Polyneuropathy in disease NOS(F374z)

(2) ICD-10 Searched for ICD-10 codes using WHO 2019 browser

• searched using term searches (as above for CTV3 search, +polyradiculopathy)
• and sections G60-G64 Polyneuropathies and other disorders of the peripheral nervous system

couldn't find any terms specific to CIDP, seems it would be coded under

• G62.8 Other specified polyneuropathies
• or G61.8 Other inflammatory polyneuropathies these are too broad to use as an exclusion term to indicate people not eligible for GBS diagnosis.

[helenmcd]

Search for codes for NMO, MS and ADEM

This is for a codelist for people who have diseases which mean that an episode of transverse myelitis might not be recorded as a discrete event - conditions advised by neurology team (Tom Solomon, Arina Tamborska, Bhaghteshwar Singh) at Liverpool are multiple sclerosis, clinically isolated syndrome, neuromyelitis optica and Acute disseminated encephalomyelitis (ADEM)

Existing codelists There is a codelist in opensafely for MS https://www.opencodelists.org/codelist/opensafely/multiple-sclerosis/2020-05-12/ noted that this was produced by mapping a Read 2 codelist to CTV3, and it doesn't include Y codes e.g. Y10b7 Multiple Sclerosis or Y1015 Multiple Sclerosis, so will conduct a fresh search in CTV3, then check for any omissions using the existing codelist.