Appendix 2: PRISMA-P checklist with recommended items to address in a systematic review protocol; table adapted from [1].

Section and topic Item No Checklist item

Administrative informationTitle: Identification 1a Chikungunya fever in neurointensive care: symptoms and management. Case report and systematic review. Update 1b -Registration 2 Our systematic review protocol was not registered.

Authors: Contact 3a T. Cerny, Neurointensive Care Unit, University Hospital Zurich; and University of Zurich, t.cerny@uzh.ch

E. Keller, Neurointensive Care Unit, University Hospital Zurich, emanuela.keller@usz.chCorresponding author: Prof. Dr. med. Emanuela Keller Head of Neurointensive Care Unit University Hospital Zurich Frauenklinikstrasse 10 CH-8091 Zurich/ Switzerland

Contributions 3b EK is the guarantor. Both TC and EK contributed to the conception and design of the planned systematic review, to the development of the eligibility criteria and the data extraction items and codes. TC developed the search strategy, performed acquisition of data and statistical analysis. TC drafted the article and EK provided critical revision of the article. Both authors read, provided feedback and approved the final manuscript.

Amendments 4 In the event of protocol amendments, we will give the date of each amendment, describe the change and its rationale in the list annexed to this document. Changes will not be incorporated into the original protocol.

Support: Sources 5a No funding has been received for this work. Sponsor 5b No sponsor was involved. Role of sponsor or funder

5c -

Introduction

Rationale 6 Although Chikungunya fever (CHIKF) has been known to cause neurological symptoms since its first scientific description in the 1950s, a striking rise in the incidence of neurological manifestations has been observed following the spread of CHIKF into the Indian Ocean in 2004/05. Thereby an adapting mutation occurred, making the mosquito species Aedes albopictus a very efficient vector of Chikungunya virus (CHIKV), which in turn eased its spread in previously unaffected areas and led to a high attack rate and huge patient numbers. Now, after a decade of recurrent CHIKF outbreaks, it is evident that CHIKV is able to cause an astonishingly broad variety of neurological symptoms, some of which are extremely life-threatening in nature. Given that CHIKF will continue its spread to the Mediterranean and Gulf Coast region in the years to come, Neuro-ICUs in the western world will encounter these complications more frequently. However, to date, there is no explicit systematic review on symptoms, diagnosis and treatment of „Neuro-Chikungunya“ (CDSR and DARE retrieved Nov’15). For this reason, all existing articles reporting neurological symptoms due to CHIKF are systematically reviewed, in order to provide a sound overview of its neuropathogenic potency and possible therapeutic options. Hopefully, this will rise the awareness of Neuro-Chikungunya and foster further research on the pathophysiology and therapeutic possibilities of neurological impairment in CHIKF.

Objectives 7 To assess - the distribution and severity of central and peripheral nervous system affection in confirmed CHIKF-cases showing neurological symptoms with regard to patient age, time from disease onset and other discriminating factors becoming evident in the course of systematic case analysis. - the diagnostics deployed and therapies used in those cases- the outcome of those cases

MethodsEligibility criteria

Eligibility criteria

8 PICOS (where applicable to this type of review)- Population: Patients of any age with confirmed CHIKV infection in acute care hospital setting showing neuro-

logical symptoms. Confirmed CHIKV infection was defined according to laboratory criteria described by [2]. Patients with concurrent confirmed infection (such as Dengue, West Nile, Japanese encephalitis virus) or with antecedent of vaccination within one month prior to onset of symptoms were excluded. Neurological symptoms have to be reported as specific neurological status findings and/or neurological syndromes for each individual patient; ideally including information regarding patient age, time from disease onset, diagnostics and therapies deployed. Neurological symptoms excluded: - isolated paresthesia of hands (often entrapment neuropathy due to carpal tunnel syndrome caused by CHIKV-induced arthropathy).- isolated seizure in children (possibly simple febrile seizure; however, seizure included if declared as

complex, atypical, accompanied by prolonged unconsciousness etc. and thus probably indicating CNS-infection).

continued - Intervention: [NA]- Comparison: [NA]- Outcomes: [NA]- Study design: Case report or case series or observational study, reporting information on each individual patient

regarding items such as patient age, type of neurological symptoms, time from disease onset to onset of neurological symptoms, diagnostics and therapy deployed, outcome.

- Minimal requirement: Patient age AND neurological symptoms reported for every single patient.

Report characteristics:- Publication type: original article, case report, case series or scientific letter in peer reviewed journal -- note: neurological symptoms do not have to be mentioned explicitly in the article’s title or abstract, article qualifies also if dedicating a substantial part (e.g., section, denominated by subtitle) on neurological symptoms in CHIKF cases reported in the article.- Publication period: 2000 - present (~2001: emergence of relevant ECSA-strand; ~2004: adapting mutation to Ae. albopictus)- Language: English, French, German (other: if translator is found) - Publication status: only published material (e-pub, print)

Information sources 9 - Electronic databases: -- MedLine (1946 - present), Provider: PubMed and OVID -- Embase (1974 - present), Provider: EMBASE -- Cochrane library (central register) -- Web of Science -- Scopus- Other supplementary approaches: -- Scanning reference lists of articles identified as eligible -- if authors are contacted to obtain missing/unpublished data, we will state in the final article who was contacted and what kind of data was obtained.

Search strategy 10 The search strategy is derived from the eligibility criteria described above (Item 8). Limits are going to be imposed regarding publication years (2000 - present, explanation see Item 8). In contrast, no study design, publication type, language nor publication status limits will be imposed on the search, as some articles might be missed by doing so. Instead, those limits are going to be applied during the process of title/abstract and full-text screening.The following search strategy will be performed using f.ex. EMBASE:• 'chikungunya'/exp OR 'chikungunya':ab,ti AND [humans]/lim AND• 'neurologic disease'/exp OR 'neurologic disease' OR (neurol* NEAR/3 (manifest* OR complicat* OR sympt*)):ab,ti OR 'neuro chikungunya':ab,ti OR meningitis:ab,ti OR meningoencephalitis:ab,ti OR

encephalitis:ab,ti OR encephalopathy:ab,ti OR cerebritis:ab,ti OR cerebellitis:ab,ti OR rhombencephalitis:ab,ti OR bickerstaff:ab,ti OR 'brain stem':ab,ti OR bulbar:ab,ti OR encephalomyelitis:ab,ti OR adem:ab,ti OR 'neuromyelitis optica':ab,ti OR myel*:ab,ti OR radicul*:ab,ti OR neuropath*:ab,ti OR 'guillain barré':ab,ti OR guillain:ab,ti OR gbs:ab,ti OR aman:ab,ti OR amsan:ab,ti OR 'polyneuritis cranialis':ab,ti OR cidp:ab,ti OR 'miller fisher':ab,ti OR mfs:ab,ti OR 'optic neuritis':ab,ti OR 'optic neuropathy':ab,ti OR 'auditory neuropathy':ab,ti OR 'vestibulocochlear neuropathy':ab,ti OR 'cranial nerve deficit':ab,ti OR 'cranial nerve involvement':ab,ti OR paralysis:ab,ti OR areflexia:ab,ti OR myoclonus:ab,ti OR ataxia:ab,ti

• Limits: publication years 2000 - presentStudy records: Data management 11a All database search results will be exported to EndNote, whose “find duplicates“ function will be used to

de-duplicate the records found. After completion of the selection process (see item 11b), information from the articles included in the systematic review is going to be extracted into a predefined SPSS-data file (see item 11c). IBM©-SPSS©-software (version 22) is going to be used to perform the descriptive statistical analysis and, if reasonable, search for correlations.

Selection process 11b The records yielded by the search after duplicates removed are going to be screened based on title and abstract applying the predefined eligibility criteria. Due to limited resources and given that eligibility criteria are very straightforward and broad in the case of this systematic review, the selection process will be performed by only one investigator (TC). Selected articles will be then assessed for eligibility based on full-text. The reasons for excluding articles will be stated, as will be the number of articles that could not be obtained in full-text.A summary of the whole process will be presented by means of a PRISMA flow chart.

Data collection process

11c Data is going to be extracted into an a priori developed Excel- (and thereafter SPSS-) data file, which will be pilot tested on 10 randomly selected, included studies. We will state if the extraction file was refined thereafter. Extraction will be done twice with an interval of two months by TC.In case of missing data prompting an enquiry, we will state who was how contacted and what data was obtained.

Data items 12 Following items were extracted from the articles included in the systematic review (selection of items, for a complete list of items with value codes and definitions see appendix A):- Source (author(s), publication year)- Case description (country of description/of patient origin (if travelled), case year, patient sex/age/comorbidities)- Neurological symptoms -- CNS symptoms (section affected, diagnosis, noteworthy symptoms, time from disease onset) -- PNS symptoms (section affected, diagnosis, noteworthy symptoms, time from disease onset)- Other symptoms (fever, rash, arthralgia, other atypical symptoms)- Diagnostics (other pathogens excluded, ChikV tests in blood/CSF, CSF cell count and total protein, neuropathogenic antibodies in blood/CSF, imaging, EEG, ENMG)- Therapy (interventions targeted at improving neurological symptoms, therapy response, challenges to the ICU)

- Outcome (categorized as: full/partial/no recovery or lethal on the one hand, and using the modified Rankin scale on the other) Simplifications will be made in order to regroup neurological symptoms and diagnoses into a manageable and reasonable number of categories: f.ex. assumptions will be made concerning clinical jargon, such as “neck rigidity“ = meningism etc. For more details see definitions of diagnoses in Appendix A.

Outcomes and prioritization

13 There will be no outcomes in a strict sense in the planned systematic review as there will be no intervention. However, the neurological manifestations in CHIKF patients investigated in the planned review can be thought of as primary outcomes, similar to adverse effects of a drug trial. Neurological recovery and lethality can be thought of as secondary outcomes.

Risk of bias in individual studies

14 Before starting the main search, we will assess possible sources of bias in individual studies using the individual components approach [3]. We will state if the risk assessment had an influence on the subsequent data synthesis, such as exclusion of an article from the analysis, or if it prompted a subgroup analysis of the articles considered “non-biased”.

Data synthesis: criteria for data synthesis

15a Given the nature of the planned systematic review, the included studies are expected to be more or less homogenous. The required common study design - reports on patients with chikungunya fever showing neurological symptoms - is very basic and is going to be secured by the search criteria and eligibility criteria. Most data items are - if reported - comparable by nature (age, central vs. peripheral neurological manifestations, antibodies present yes/no etc.). See Item 15b and 15c for further information on management of missing values/divergent data format.

summary measures & synthesis methods

15b Summary measures are mainly going to be the reported neurological symptoms, but encompass also the other variables stated under Item 12. Data is going to be synthesized by means of descriptive statistics; examples are: - distribution pattern of neurological manifestations regarding to age group- distribution pattern of neurological manifestations regarding to time from disease onset, diagnostic markers etc.Meta-analysis is not going to be applicable to this type of systematic review.

additional analyses 15c Subgroup analyses will be performed to explore sources of heterogeneity, such as:- age, sex- time from disease onset (fever, rash, arthralgia) to occurrence of neurological symptoms- treatment etc.

15d A narrative synthesis of the results will be provided.Meta-bias(es) 16 An assessment of the risk of bias across studies is going to be performed before starting the main search, that is, as

to how classical sources of bias (publication bias, multiple (duplicate) publication bias, location bias, citation bias, language bias, outcome reporting bias on large scale etc.) could be present in the investigation planned and what other concepts of bias have to be considered. We will state if the risk assessment had an influence on the planned data synthesis.

Confidence in cumulative evidence

17 The quality of the gathered statistical evidence is going to be discussed. The character of this discussion will be shaped by the total number of Neuro-Chikungunya cases found in the scientific literature.

List of Amendments:

Date Section Original protocol Revised protocol Rationale

Jan 2016 3a: author contributions

Stating EK and TC Author added: PG (Patrick Gérardin, INSERM CIC 1410, CHU de la Réunion, Saint Pierre, Reunion, France; Université de La Réunion, CNRS 9192, INSERM U1187, IRD 249, CHU Réunion, Unité Mixte 134 Processus Infectieux en Milieu Insulaire Tropical (PIMIT), CYROI, Sainte-Clotilde, Reunion France). PG provided extensive data, and a critical review for consistency, errors and intellectual content. PG has read, provided feedback and approved the final manuscript.

Author added: JL (Jerôme Lemant, Intensivist, Intensive Care Unit, CHU de la Réunion, Saint Pierre, Reunion France).JL provided extensive data, and a critical review for consistency, errors and intellectual content. JL has read, provided feedback and approved the final manuscript.

All authors of case reports/case series were contacted to provide clarifications on not stated or ambiguously stated data.

In the case of PG and JL – both being authors of a big case series resp. cohort study – the provision of that information meant a workload of >10 hours. That is why Co-authorship has been granted to these two researchers.

February 2016 15c: Data synthesis: additional analyses

Subgroup analyses will be performed to explore sources of heterogeneity

Case report assessment added:Before descriptive statistical analysis, all cases are assessed for quality using a clinical diagnostic algorithm. This algorithm classifies the case reports into three quality categories: category A =probable Neuro-Chikungunya case, category B =plausible) and category C =disputable. Only the A- and B-cases are considered for further analysis.

The systematic review of the literature revealed that the quality of case reports varies quite a lot. Thus, the need for a case report assessment became evident. By introducing a sound assessment, the strength of the evidence is improved.

February 2016 3a: author contributions

Stating EK and TC Author added: US (Urs Schwarz, Neurologist, Department of Neurology, University Hospital Zurich, Zurich, Switzerland). US contributed to methods (case report assessment algorithm) and provided a critical review for consistency, errors and intellectual content. US has read, provided feedback and approved the final manuscript.

US helped to develop the case report assessment algorithm, i.e. what elements (clinical, diagnostical) should be included, in which order.

February 2016 Appendix 1: other DDs and etiologies

Item did not exist New items: Clin pres consistent, no DD more probableClin pres consistent_described Etiol_sufficiently exclud

New items are introduced and coded (based on information from existing items) so that the case report assessment algorithm (see above) can be run fully automatically within SPSS. This allows for an unbiased assessment of the case reports.

March 2016 1a, Title “Chikungunya fever “The range of neurological complications in Chikungunya Adding the case report assessment (see

in neurointensive care: symptoms and management. Case report and systematic review.”

fever: case report and systematic review of 130 cases” above) puts the focus on scrutinizing the existing evidence; therefore, the title is changed so that it reflects the extent of the work.

July 2016 3a: author contributions

Stating EK and TC Author added: MS (Megan Schwarz, Biologist and Virologist, Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA)MS contributed to methods, data extraction, statistical analysis, results and discussion, and provided a critical review for consistency, errors and intellectual content. MS has read, provided feedback and approved the final manuscript.

Analysis of the 130 cases showed two distinct patterns of pathomechanism (direct viral vs. autoimmune). We decided to involve a virologist to perform a subgroup analysis of the existing data set with regard to these two categories, and to embed it within the existing knowledge and relevant literature.

August 2016 11c: Data collection process

„We will state if the extraction file was refined [after pilot-testing the data file]“

Due to word count limits in the targeted publication, the statement is made here:We did refine the extraction data file after pilot testing it. Namely more categories were added in order to extract data available in the case reports to the fullest degree. Also, some categories with multiple nominal answer-classes (f.ex. “ICU-complications“: 1) ventilation 2) intubation 3) sepsis 4) arrhythmia etc.) were restructured into their subgroups so that the extracted information could be coded in a binary way (-> “ICU-ventilation“: yes/no, “ICU-intubation“: yes/no, etc.)

Word count limits in the targeted journal necessitate to document this statement elsewhere.

August 2016 11c: Data collection process

“In case of missing data prompting an enquiry, we will state who was how contacted and what data was obtained.“

Due to word count limits in the targeted publication, the statement is made here:All case reports/series authors were contacted by email. We state in the publication how many authors replied providing additional information on how many cases. The email protocols are collected in a separate word document, which can be requested via email from the corresponding author.

Word count limits in the targeted journal necessitate to document this statement elsewhere.

Appendix A: Data items, values & labels, definitions (abbreviations: n/a = not available)

Data Item Values Labels Remark/Definition

Source_pRwd 0 no1 yes

Land_descrCode 1 Austria2 Belgium3 China4 Denmark5 E6 France mainland7 Germany8 Hungaria9 Italy10 India11 Colombia12 La Réunion, France overseas13 M14 Nepal15 Switzerland16 Singapore17 Thailand18 USA19 UK20 New Zealand21 Netherlands99 n/a missing value

Case_origin 1 Gulf/Caribbean2 South America3 Mediterranean4 West Africa5 East/Central/South Africa6 Indian Ocean7 India/South Asia8 Southeast Asia9 Oceania

99 n/a missing valueCase_year 99 n/a missing valuePat_sex 1 female

2 male99 n/a missing value

Pat_age 99 n/a missing valuePat_agegroup 1 newborn (<1M.)

2 infant (1-12M.)3 child (1-12y.)4 adolescent (13-17y.)5 young adult (18-24y.)6 adult (25-44y.)7 middle aged (45-64y.)8 aged (65+)99 n/a missing value

Pat_comorb 0 none1 metabolic (diabetes, adipositas)2 pulmonary (COPD, bronchiektasia)3 cardiovascular (hypertension, smoking, past

medical history pos. for MI, stroke etc.)If multiple comorbidities are present including stroke or MI, then „3=cardiovascular“ is coded. E.g. Patient with diabetes mellitus and history of myocardial infarction = cardiovascular.

4 gastrointestinal5 hematological6 Allergic (asthma, hay fever)7 immunosuppressed8 neoplasia9 endocrinological10 autoimmune11 neurological (Parkinson, Alzheimer, MS)99 n/a missing value

Comorb_present 0 absent1 present99 no statement

Adipositas 0 no1 yes99 n/a missing value

Diabetes 0 no1 yes99 n/a missing value

cardiovascular 0 no1 yes99 n/a missing value

renal 0 no1 yes99 n/a missing value

pulmonary 0 no1 yes99 n/a missing value

allergic 0 no1 yes99 n/a missing value

immunosuppressed 0 no1 yes99 n/a missing value

alcoholism 0 no1 yes99 n/a missing value

neoplasia 0 no1 yes99 n/a missing value

neurologic 0 no1 yes99 n/a missing value

endocrinologic 0 no1 yes99 n/a missing value

Site_affect 1 central2 peripheral3 both99 n/a missing value

CNS_Dx(Diagnosis as given by Author)

0 no CNS affection Define 0 as missing

1 Meningeal syndrome MESH: A condition characterized by neck stiffness, headache, and other symptoms suggestive of meningeal irritation, but without actual [proof of] inflammation of the meninges.Core clinic:- Headache, neck stiffness

- no altered mental status.Supportive clinic:- positive kernig/brudzinski sign, tense fontanelle, photophobiaDiagnostics:- CSF is normal! (or: code Meningeal Syndrome if no CSF obtained)

2 Meningitis MESH: Inflammation of the coverings of the brain and/or spinal cord. Infections (viral, bacterial, and fungal) are the most common causes of this condition, but subarachnoid hemorrhage, chemical irritation, granulomatous conditions, neoplastic conditions and other inflammatory conditions may produce this syndrome. Core clinic:- same as meningeal syndrome- no altered mental statusDiagnostics:- CSF is pathologic (signs of inflammation)

3 Meningoencephalitis = signs of both meningitis and encephalitis4 Acute encephalopathy = primary or secondary brain dysfunction due to broad variety of causes:

systemic infection, metabolic derangement, inherited metabolic encephalopathies, toxins, hypoxia, trauma, vasculitis, or central nervous system infection.Core clinic:- altered mental status (reduced consciousness or altered cognition, personality or behavior)code this diagnosis if no surrogate clinical markers of brain inflammation present (such as inflammatory CSF change, parenchyma inflammation on imaging).

5 Encephalitis MESH: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Core clinic: (taken from the consensus statement of the International Encephalitis Consortium [4])Major Criterion (required):- altered mental status (defined as decreased or altered level of consciousness, lethargy or personality change) lasting ≥24 h with no alternative cause identified.Minor Criteria (≥2 required1)- Documented fever ≥ 38° C (100.4°F) within the 72 h before or after presentation- Generalized or partial seizures not fully attributable to a preexisting seizure disorder2

- New onset of focal neurologic findings

- CSF WBC count ≥ 5/cubic mm- Abnormality of brain parenchyma on neuroimaging suggestive of encephalitis that is either new from prior studies or appears acute in onset- Abnormality on electroencephalography that is consistent with encephalitis and not attributable to another cause

1 the IEC consensus statement subdivides encephalitis cases further according to number of minor criteria met as follows: “2 required for possible encephalitis; ≥3 required for probable or confirmedencephalitis“ [4]. For reasons of feasibility, in this review the two categories will be taken together to form the diagnosis of “encephalitis“.2 In children, “seizure“ is considered in this review only then as a valid minor criterion if complex febrile seizures are present as a possible surrogate clinical marker for primary brain damage. Thereby, complex febrile seizures are defined as seizures with at least 1 of the following features: infant 1 year old, child 5 years old, duration more than 15 minutes, focal deficit, repeated seizures within 24 hours, focal seizures [5].

6 Atypical encephalitis = acute febrile encephalopathy meeting the criteria of encephalitis, but with absence of focal findings on neurologic examination [6].

7 Bickerstaff encephalitis OrphaNet ([accessed 04.12.-07.12.2015]): Bickerstaff's brainstem encephalitis (BBE) is a rare post-infectious neurological disease characterized by the association of external ophthalmoplegia, ataxia, lower limb areflexia, extensor plantar response and disturbance of consciousness (drowsiness, stupor or coma). Core Clinic:- External Ophthalmoparesis/-plegia- Ataxia- HypersomnolenceSupportive clinic:- antecedent upper respiratory or gastrointestinal tract infection- external ophthalmoplegia is progressive (within 4 weeks of onset) and relatively symmetrical- Flaccid symmetrical tetraparesis may be present (in 50%)- deep or superficial sensory impairment (lower limb areflexia)- facial weakness, bulbar palsy, internal ophthalmoplegia, blepharoptosis

and nystagmus- in acute phase of disease, BBE may resemble 'brain-death'

Diagnostics:- Associated with anti-GQ1bFurther sources: [7].

8 ADEM MESH and Emtree: An acute or subacute inflammatory process of the CNS characterized histologically by multiple foci of perivascular demyelination. It is believed to be a manifestation of an autoimmune attack on the myelin of the central nervous system. Symptom onset usually occurs several days after an acute viral infection or immunization, but it may coincide with the onset of infection or rarely no antecedent event can be identified. Many survivors have residual neurologic deficits.Core clinic:- subacute encephalopathy (confusion, lethargy, somnolence progressing

to coma that can be fatal) with fever and headache - multifocal neurologic symptoms (very variable, according to localization of lesions)Supportive clinic:- Interval between viral infection/immunization and symptom onset 2 days - 4 weeks Diagnostic:- MRI: multifocal lesions (hyperintens in T2, iso- or hypointens in T1) in

supra- and infratentorial white matter. If myelon affected, usually thoracal part. - CSF: very variable from normal (seldomly) to acute inflammatory: increased cell count (> 200 cells/μl possible), predominantly lymphocytic, initially neutrophil predominance possible. Total protein can be highly elevated (more than in multiple sclerosis).Further sources: [8]

9 Myelitis MESH: Inflammation of the spinal cord. Relatively common etiologies include infections, autoimmune disease, and ischemia. Core clinic:- motor weakness, sensory loss, localized pain, incontinence, other signs of autonomic dysfunction.

10 Neuromyelitis optica MESH and Emtree: A syndrome characterized by acute optic neuritis in combination with acute transverse myelitis. Demyelinating and/or necrotizing lesions form in one or both optic nerves and in the spinal cord. The onset of optic neuritis and myelitis may be simultaneous or separated by several months.

- clinic: diminution of vision and possibly blindness, flaccid paralysis of the extremities, and sensory and genitourinary disturbances Further sources: [9], Dorland's Medical Dictionary, 32nd edition.

11 Myeloradiculopathy Emtree: disease of the spinal cord and spinal nerve roots; called also radiculomyelopathy.Further sources: Dorland's Medical Dictionary, 32nd edition.

12 Myeloradiculoneuropathy Disease of the spinal cord, nerve roots and nerves.13 Encephalomyeloradiculopathy Disease of the encephalon, spinal cord and nerve roots14 Complex febrile seizure Seizures with at least 1 of the following features: history of neurologic

disease, infant <1 year old, child >5 years old, duration more than 15 minutes, neurologic deficit, repeated seizures within 24 hours, and focal seizures [5].

99 n/a missing valueCNS_section 0 no CNS affection Assignment is made based on clinical findings allowing for localization

and/or results of imaging, EEG, ENMG etc.1 Meninges2 Encephalon3 Cerebrum4 Brain stem5 Cerebellum6 Encephalon & Myelon7 Myelon99 n/a

CNS_Dx_corr 0a no CNS affection For Definitions see „CNS_Dx“ The CNS_Dx_corr field is used to code an alternative diagnosis if the data provided in the case report suggests another diagnosis than the one given by the author. If there is no such discrepancy evident, the same Dx is coded as in CNS_Dx.In addition, the Dx_corr field it is used to give a diagnosis in case the original authors did not give a diagnosis.

1 Meningeal syndrome2 Meningitis3 Meningoencephalitis4 Acute encephalopathy5 Encephalitis6 Atypical encephalitis7 Bickerstaff encephalitis8 ADEM9 Neuromyelitis optica10 Myelitis11 Myeloradiculopathy12 Myeloradiculoneuropathy13 Encephalomyeloradiculopathy14 Complex febrile seizure99 n/a missing value

CNS_tfdo Time from disease onset is defined as:

99 n/a

time from occurrence of first symptoms (fever, rash, arthralgia) to occurrence of neurological symptoms. The latter point in time can be described explicitly in the case report and can thus occur before hospitalization; if not described explicitly the day of hospitalization is used (description upon neurological examination). missing value

PNS_Dx(Diagnosis as given by Author)

0 no PNS affection Define 0 as missing

1 Polyradiculoneuropathy, NOS MESH: Diseases characterized by injury or dysfunction involving multiple peripheral nerves and nerve roots. The process may primarily affect myelin or nerve axons. Diagnostics: CSF albuminocytological dissociation, ENMG changes

2 Classic GBS (AIDP) = Acute inflammatory demyelinating polyradiculoneuropathy = primarily demyelinating process.Core Clinic: - Weakness and areflexia/hyporeflexia in all four limbs- No/minimal ataxia- no hypersomnolenceSupportive clinic:- Antecedent infectious symptoms (in up to 30% C. jejuni Gastroenteritis)- Weakness usually starts in the legs and ascends but may start in the arms [spreading to legs thereafter]- mild or moderate Weakness or complete tetraparesis- Cranial-nerves may be involved (in 50% N. facialis)- respiratory muscles may be involved - autonomous dysfunction (often subclinic)- Nadir often within 2 weeks, in 90% within 4 weeks.Diagnostics: - Electrophysiological evidence of demyelinating neuropathy (decreased nerve conduction velocity, pathologic F-waves)- CSF after 1 week: albuminocytological dissociation (with less than 10-30 cells/µl (max. 50/µl))Sources: [10,7,11,12]

3 PCB variant of GBS Pharyngo-cervico-brachial variant Core clinic:- oropharyngeal weakness + neck weakness + arm weakness + arm areflexia/ hyporeflexia- no prominent leg weakness

- No/minimal ataxia- no hypersomnolenceSupportive clinic:- Antecedent infectious symptomsDiagnostics:- CSF: albuminocytological dissociation- NCS: axonal neuropathy- IgG anti-GT1a (50%) or anti-GQ1b antibodiesSources: [13,7]

4 Paraparetic GBS Core clinic:- isolated lower limbs weakness - No/minimal ataxia- no hypersomnolenceSources: [7]

5 Isolated facial GBS Official term: “Bilateral facial weakness with paraesthesias“Core clinic:- isolated facial weakness - No/minimal ataxia- no hypersomnolenceSources: [7]

6 AMAN Core clinic: - like classic GBS, but faster and more severe - only motor deficitsDiagnostics:- ENMG: primarily axonal neuropathy- GM1-AkSources: [14,12]

7 AMSAN Core clinic: - like classic GBS, but faster and more severe - sensory and motor deficitsDiagnostics:- ENMG: primarily axonal neuropathy- GM1-AkSources: [14,12]

8 Polyneuritis cranialis Core clinic: - oropharyngeal weakness (~PCB) with ophthalmoparesis (MFS)- No ataxia (unlike MFS!)- No hypersomnolenceSupportive clinic:

- bilateral facial palsySources: [15,16]

9 Miller-Fisher-Syndrome MESH: A variant of the GBS-spectrum characterized by acute onset of oculomotor dysfunction, ataxia, and loss of deep tendon reflexes.Core clinic:- Ophthalmoparesis/-plegia and a-/hyporeflexia- ataxia (due to peripheral sensory nerve dysfunction)- No hypersomnolence - Absence of limb/trunk weakness (Presence of limb weakness = MFS-GBS-Overlap)Supportive clinic:- Absence of certain features indicates incomplete MFS- Facial weakness and sensory loss may also occur- ataxia is produced by peripheral sensory nerve dysfunction and not by cerebellar injuryDiagnostics: - ENMG: axonal neuropathy - GQ1b-Ak in 95% present Further sources: [14,7]

10 MFS-GBS-Overlap Core clinic:- Ophthalmoparesis/-plegia and a-/hyporeflexia- ataxia (peripheral sensory nerve dysfunction)- No hypersomnolence - Presence of limb weakness

11 CIDP = chronic inflammatory demyelinating polyradiculoneuropathy Core clinic: slowly progressive paresis / paresthesia of proximal legsSources: [14,12]

12 MMN = Multifocal motor neuropathy: chronic autoimmune-inflammatory, purely motoric neuropathyCore clinic: - weakness, muscle atrophy and cramping mostly of the arms, usually beginning in one or both hands- asymmetric Diagnostics:- ENMG shows conduction blocks of motor nerves Sources: [14,12]

13 MADSAM = multifocal acquired demyelinating sensory and motor neuropathy (Lewis-Sumner-Syndrom): chronic autoimmune-inflammatory, sensory and motor neuropathy

Core clinic: - asymmetric paresis and hypesthesiasSources: [14,12]

14 Optic neuritis MESH: Inflammation of the optic nerve. Commonly associated conditions include autoimmune disorders, infections, and granulomatous diseases. Inflammation may occur in the portion of the nerve within the globe (neuropapillitis or anterior optic neuritis) or the portion behind the globe (retrobulbar neuritis or posterior optic neuritis).Core clinic:- defective vision (color vision, contrast sensitivity) that may progress to severe visual loss - retro-orbital pain that is aggravated by eye movementDiagnostics:- RAPD, Fundus (optic disc hyperemi, edema etc.), Visual field defects, Visual evoked potentials etc.

15 Neuroretinitis Def: A vascular opticus process: vasculitis of prelaminary arterioles of the papilla with secondarily spreading submacular transudate and stellate lipid deposits. Idiopathic neuroretinitis is caused by a broad variety of infectious and non-infectious intraocular as well as systemic diseases. Its pathogenetic common ground is a local or generalized (post-)infectious immunvasculitis, mediated by pathogen-specific mechanisms. [Bialasiewicz, AA. (2000), Neuroretinitis, Ophthalmologe 2000; 97: 374–391.]Core clinic:- uni- or bilaterally defective vision (acuity, color vision, contrast sensitivity)- in 50% Fever, fatigue, night sweat- possibly retro-orbital pain, aggravated by eye movementDiagnostics:- RAPD, Fundus, Visual field defects, Fluorescein Angiography, Electroretinogram, VEPs etc.Sources: [17]

16 Auditory neuropathy Emtree: auditory neuropathy = neuropathy in the eighth cranial nerve with apparently normal function of the outer hair cells but dysfunction of the inner hair cells or cochlear nerve.

17 Peripheral polyneuropathy Emtree: neuropathy of several peripheral nerves simultaneously; called also multiple or peripheral neuropathy.

18 Neuromyelitis optica MESH and Emtree: A syndrome characterized by acute optic neuritis in combination with acute transverse myelitis. Demyelinating and/or necrotizing lesions form in one or both optic nerves and in the spinal

cord. The onset of optic neuritis and myelitis may be simultaneous or separated by several months.Core clinic: - diminution of vision and possibly blindness- flaccid paralysis of the extremities- sensory and genitourinary disturbances Further sources: [9], Dorland's Medical Dictionary, 32nd edition.

19 Myeloradiculopathy Emtree: disease of the spinal cord and spinal nerve roots; called also radiculomyelopathy.

20 Myeloradiculoneuropathy = disease of the spinal cord, nerve roots and nerves.21 Hypokalemic paralysis = acute-onset flaccid paralysis associated with low plasma potassium

(<3.5 mEq/L). Hypokalemic paralysis can be idiopathic (e.g. familial hypokalemic paralysis) or secondary. Secondary hypokalemic paralysis is usually associated with renal (distal RTA) and gastrointestinal disorders, furthermore with thyrotoxicosis, dengue viral infection, Gitelman syndrome, and Conn's syndrome. Source: [18]

22 Encephalomyeloradiculopathy disease of the encephalon, spinal cord and nerve roots99 n/a missing value

PNS_section 0 no PNS affection Assignment is made based on clinical findings allowing for localization and/or results of imaging, EEG, ENMG etc.

missing value

1 Radiculopathy2 Radiculoneuropathy3 Radiculoneuropathy incl. cranial nerves4 Neuropathy of cranial nerves5 Peripheral neuropathy6 Myopathy99 n/a

PNS_Dx_corr 0 no PNS affection For Definitions see „PNS_Dx“.The PNS_Dx_corr field is used to code an alternative diagnosis if the data provided in the case report suggests another diagnosis than the one given by the author. If there is no such discrepancy evident, the same Dx is coded as in PNS_Dx.In addition, the Dx_corr field it is used to give a diagnosis in case the original authors did not give a diagnosis.

1 GBS-Spectrum, NOS2 Classic GBS (AIDP)3 PCB variant of GBS4 Paraparetic GBS5 Isolated facial GBS6 AMAN7 AMSAN8 Polyneuritis cranialis9 Miller-Fisher-Syndrome10 MFS-GBS-Overlap

11 CIDP12 MMN13 MADSAM14 Optic neuritis15 Neuroretinitis16 Auditory neuropathy17 Peripheral polyneuropathy18 Neuromyelitis optica19 Myeloradiculopathy20 Myeloradiculoneuropathy21 Hypokalemic paralysis22 Encephalomyeloradiculopathy99 n/a

PNS_Dx_tfdo

99 n/a

Time from disease onset is defined as:time from occurrence of first symptoms (fever, rash, arthralgia) to occurrence of neurological symptoms. The latter point in time can be described explicitly in the case report and can thus occur before hospitalization; if not described explicitly the day of hospitalization is used (description upon neurological examination).Example: Fever on Day 1. Lower limb weakness on day 16. Tfdo = 15.

missing valueOther_fever 0 no fever Code 1 if symptom is described in case report.

Code 0 if symptom is not mentioned, but in general (other) initial symptoms are described. Code 99 (missing value) if no initial symptoms are described at all.

1 fever (≥38.0°C)99 n/a

Other_rash 0 no rash1 rash99 n/a

Other_arthr 0 no arthralgia1 arthralgia99 n/a

Other_syst 0 no other syst. sympt.1 other syst. sympt.99 n/a

Clin_pres_consistent 0 Not consistent, or other DD more probable For consistency see CNS/PNS-Dx definitions1 Clinical signs consistent with Dx

Clin_pres_descr String Reason noted if inconsistencyEtiol_exclud_descr String All etiologies excluded by authors are notedEtiol_exclud_suff 0 Frequent etiologies of neurological affection at According to sources noted under CNS_Dx and PNS_Dx

stake not excluded Special rules:- in encephalitis: at least one common viral cause of encephalitis had to be excluded, while it was left to authors discretion which one are relevant in that respective area, season and clinical setting.- in GBS: C. jejuni was considered the most common causative agent, hence this one had to be excluded at least.

1 Other etiologies sufficiently excludedBlood_rtPCR 0 neg.

1 pos.99 n/a missing value

Blood_rtPCR_tfdo 99a n.s. time from occurrence of first symptoms (fever, rash, arthralgia) to specimen retrieval.Example: Fever on day 1. Serologic testing for IgM on day 5. Tfdo = 4 days.

Blood_IgM 0 neg. Assumption: positive CHIK hemagglutination-inhibition (HI) antibody titer is going to be coded as “IgM positive, IgG negative“, as both immuneglobulines can account for HI-test positivity, but presence of IgM is more probable in the acute setting encountered in most case reports.missing value

1 pos.

99 n/aBlood_IgM_tfdo

99 n/a

time from occurrence of first symptoms (fever, rash, arthralgia) to specimen retrieval.missing value

Blood_IgG 0 neg.

missing value1 pos.99 n/a

Blood_IgG_tfdo

99 n/a

time from occurrence of first symptoms (fever, rash, arthralgia) to specimen retrieval.missing value

Blood_NeuroAb 0 neg.1 pos.99 n/a missing value

CSF_rtPCR 0 neg.1 pos.99 n/a missing value

CSF_rtPCR_tfdo

99 n/a

time from occurrence of first symptoms (fever, rash, arthralgia) to specimen retrieval.missing value

CSF_IgM 0 neg.

1 pos.99 n/a missing value

CSF_IgM_tfdo

99 n/a

time from occurrence of first symptoms (fever, rash, arthralgia) to specimen retrieval.missing value

CSF_IgG 0 neg.1 pos.99 n/a missing value

CSF_IgG_tfdo

99 n/a

time from occurrence of first symptoms (fever, rash, arthralgia) to specimen retrieval.missing value

CSF_NeuroAb 0 neg.1 pos.99 n/a missing value

CSF_basic 0 normal Cells < 5/µl, total protein 5 - 40mg/dl1 exsudative CSF-Syndrome Cells > 100/µl, total protein slightly elevated*2 transsudative CSF-Syndrome Cells 5-100/µl, total protein < 100mg/dl*3 Guillain-Barré CSF-Syndrome Cells 0 - 50/µl, total protein ca. 100-200mg/dl **

(cytoalbuminologic dissociation)4 Nonne-Froin CSF-Syndrome Cells < 5/µl, total protein >100-200mg/dl5 Immunoactive CSF-Syndrome Cells 5 - 50/µl (evt. 5-100/µl), total protein < 80mg/dl99 n/a missing value

* greater significance is attached to cell count. Thus, f.ex. cells 68/µl & total protein 150mg/dl is considered transsudative, cells 160/µl & total protein 80mg/dl is considered exsudative.** in 2nd week after disease onset; if CSF obtained earlier, total protein can be lower. In case blood is present and clinical history not suggestive of subarachnoidal hemorrhage a traumatic tap is assumed and the following rules are applied: 1 white blood cell subtracted for every 500rbc, 10mg/dl protein subtracted for every 1'000 rbcSources for CSF-syndromes: [19,11]

CSF_wbc 99 n/a missing valueCSF_totProt 99 n/a missing valueCSF_basic_tfdo

99 n/a

time from occurrence of first symptoms (fever, rash, arthralgia) to specimen retrieval.missing value

Imaging 0 not obtained Assumption: If no imaging modality is mentioned, “not obtained“ is coded.

1 MRI2 CT3 US99 n/a missing value

Code this if unclear which imaging modality was used, but imaging study is mentioned.

Imag_tfdo

99 n/a

time from occurrence of first symptoms (fever, rash, arthralgia) to imaging study. missing value

Imag_result 0 no finding1 path. finding99 n/a missing value

EEG 0 not obtained Assumption: If no EEG result is mentioned, „not obtained“ is coded.1 obtained

EEG_tfdo

99 n/a

time from occurrence of first symptoms (fever, rash, arthralgia) to EEG study.missing value

EEG_result 0 no finding1 focal changes2 diffuse slowing3 pathologic but n.s.99 n/a missing value

ENMG / other NCS 0 not obtained Assumption: If no ENMG result is indicated, „not obtained“ is coded.Visual evoked potentials (VEP), Auditory evoked potentials (AEP, BERA etc.) are considered as NCS.

1 obtainedENMG_tfdo

99 n/a

time from occurrence of first symptoms (fever, rash, arthralgia) to ENMG study.missing value

ENMG_result 0 no finding1 axonal damage2 demyelinating3 combined4 pathologic but n.s.99 n/a missing value

Therapy 0 conservative1 CTC2 ivIg3 PlasmaEx

4 CYC5 CTC + PlasmaEx6 CTC + ivIg99 n/a missing value

Therapy_tfdo

99 n/a

time from occurrence of first symptoms (fever, rash, arthralgia) to onset of therapymissing value

Therapy_tfNo

99 n/a

time from occurrence of neurological symptoms to onset of therapymissing value

Therapy_resp 0 no response1 partial response2 good response99 n/a

PathMech_susp 0 unclear This item is coded based on previous items’ values:- supportive for „direct neurotoxic“: short CNS_tfdo (<7d.), serum/CSF rtPCR pos. and Immunoglobulins neg. - supportive for „immunologic“: CNS_Dx= ADEM, Bickerstaff, GBS spectrum, Miller-Fisher-Syndrome, Neuromyelitis optica, CNS/PNS_tfdo >7-14 d., serum/CSF rtPCR neg. and/or Immunoglobulins positive, detection of antibodies associated with presumably neuroimmunological disorders (such as Anti- GQ1b, -GT1a, -NMO etc.)- “unclear“ coded if evidence points in both directions- “combined“ coded if biphasic disease pattern with first neurotoxic and secondly immunologic affection

1 direct neurotoxic2 immunologic3 combined99a n.s.

PathMech_ther 0 direct neurotoxic This item is coded based on previous item “therapy“: - conservative treatment -> “direct neurotoxic“- all kinds of immunomodulating treatment -> “immunologic“ missing value

1 immunologic

99 n/aICU_compl_present 0 present No complications requiring admission to intensive care unit (ICU)

1 present complications requiring admission to intensive care unit (ICU)99 n/a Code 99 if complications requiring ICU-Support possible or probable

given nature of main diagnosis, but not exactly stated in case report.ICU_Chall_biggest(most severe complication present)

0 none Code „none“ if stated so in case report or if very probably no complications requiring ICU-Support given nature of main diagnosis.

1 altered mental status If multiple complications reported (e.g. seizure=2 and respiratory failure=4), code the complication with the higher value (e.g.: 2 seizure

4=respiratory failure.3 unconscious (GCS≤8), intubation4 resp. failure, ventilation5 cardiovascular (MI, HF, Arr., hemodynamic)6 infection, SIRS, DIC, sepsis7 intracranial hypertension99 n/a Code 99 if complications requiring ICU-Support possible or probable

given nature of main diagnosis, but not exactly stated in case report.AMS 0 no

1 yes99 n/a missing value

Seizure 0 no1 yes99 n/a missing value

UC_Intub 0 no1 yes99 n/a missing value

Vent 0 no1 yes99 n/a missing value

CardioV 0 no1 yes99 n/a missing value

InfSiSe 0 no1 yes99 n/a missing value

IntraHT 0 no1 yes99 n/a missing value

ICU_compl_severe(semiquantitative scale of severity)

0 no complications No complications requiring admission to intensive care unit (ICU)

1 moderate complications Moderate complications (ICU-Chall_biggest 1-3)2 severe complications severe complications (ICU-Chall_biggest 4-7)99 n/a missing value

Outcome_semiquant 0 no symptoms, full recovery Due to variable ways of reporting, point in time when outcome is assessed is defined as last patient contact, be it on hospital discharge or at last follow-up. In newborns (<1Mo.) and infants (1-12Mo.) without evident sequelae without neurodevelopmental follow up code 99,

1 partial recovery2 no recovery3 dead99 n/a

as outcome cannot be assessed in a meaningful way.Outcome_mRS 0 no symptoms Comments under “Outcome_semiquant“ apply to Outcome_mRS, too.

1 no significant disability Able to carry out all usual activities, despite some symptoms.2 slight disability Able to look after own affairs without assistance, but unable to carry out

all previous activities.In case of residual arthralgia, code 2

3 moderate disability Requires some help, but able to walk unassisted.4 moderately severe disability Unable to attend to own bodily needs without assistance, and unable to

walk unassisted.5 severe disability Requires constant nursing care and attention, bedridden, incontinent.6 dead99 n/a missing value

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