Clinical predictors of encephalitis in UK adults–A multi-centre prospective observational cohort study

Sylviane Defres; Kukatharmini Tharmaratnam; Benedict D Michael; Mark Ellul; Nicholas W S Davies; Ava Easton; Michael J Griffiths; Maneesh Bhojak; Kumar Das; Hayley Hardwick; Chris Cheyne; Rachel Kneen; Antonieta Medina-Lara; Anne Christine Salter; Nicholas J Beeching; Enitan Carrol; Angela Vincent; ENCEPH UK study group; Marta Garcia-Finana; Tom Solomon

doi:10.1371/journal.pone.0282645

. 2023 Aug 23;18(8):e0282645. doi: 10.1371/journal.pone.0282645

Clinical predictors of encephalitis in UK adults–A multi-centre prospective observational cohort study

Sylviane Defres ^1,^2,^3,^4,^*, Kukatharmini Tharmaratnam ⁵, Benedict D Michael ^1,^2,⁶, Mark Ellul ^1,^3,⁶, Nicholas W S Davies ⁷, Ava Easton ^1,⁸, Michael J Griffiths ^1,⁹, Maneesh Bhojak ⁶, Kumar Das ⁶, Hayley Hardwick ¹, Chris Cheyne ⁵, Rachel Kneen ^1,⁹, Antonieta Medina-Lara ¹⁰, Anne Christine Salter ¹¹, Nicholas J Beeching ^2,^3,⁴, Enitan Carrol ^1,¹², Angela Vincent ¹³; ENCEPH UK study group^¶, Marta Garcia-Finana ^5,^#, Tom Solomon ^1,^3,^6,^#

Editor: Rizaldy Taslim Pinzon¹⁴

¹Department of Clinical Infection Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom

²Tropical and Infectious Disease Unit, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom

³National Institute for Health Research (NIHR) Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom

⁴Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

⁵Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom

⁶Department of Neurology, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom

⁷Department of Neurology, Chelsea and Westminster NHS Trust, London, United Kingdom

⁸Encephalitis Society, Malton, United Kingdom

⁹Department of Paediatric Neurology, Alder Hey Hospital Children’s NHS Foundation Trust, Liverpool, United Kingdom

¹⁰Health Economics Group, University of Exeter Medical School, Exeter, United Kingdom

¹¹Patient Representative, Encephalitis Society, Malton, United Kingdom

¹²Department of Paediatric Infectious Diseases, Alder Hey Hospital Children’s NHS Foundation Trust, Liverpool, United Kingdom

¹³Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

¹⁴Duta Wacana Christian University School of Medicine / Bethesda Hospital, INDONESIA

Competing Interests: The authors have declared that no competing interests exist.

¶ Membership of the ENCEPH UK study group is provided in the Acknowledgments.

^✉

* E-mail: sdefres@liverpool.ac.uk

Contributed equally.

Roles

Sylviane Defres: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Writing – original draft, Writing – review & editing

Kukatharmini Tharmaratnam: Formal analysis, Validation, Writing – review & editing

Benedict D Michael: Conceptualization, Methodology, Writing – review & editing

Mark Ellul: Investigation, Methodology, Writing – review & editing

Nicholas W S Davies: Conceptualization, Funding acquisition, Methodology, Validation, Writing – review & editing

Ava Easton: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Writing – review & editing

Michael J Griffiths: Conceptualization, Formal analysis, Funding acquisition, Methodology, Writing – review & editing

Maneesh Bhojak: Data curation, Formal analysis, Methodology, Writing – review & editing

Kumar Das: Data curation, Formal analysis, Methodology, Supervision, Writing – review & editing

Hayley Hardwick: Data curation, Project administration, Resources, Writing – review & editing

Chris Cheyne: Data curation, Methodology, Writing – review & editing

Rachel Kneen: Conceptualization, Funding acquisition, Methodology, Writing – review & editing

Antonieta Medina-Lara: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Resources, Writing – review & editing

Anne Christine Salter: Conceptualization, Methodology, Writing – review & editing

Nicholas J Beeching: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Writing – review & editing

Enitan Carrol: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Writing – review & editing

Angela Vincent: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Supervision, Writing – review & editing

Marta Garcia-Finana: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Supervision, Writing – review & editing

Tom Solomon: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – review & editing

Rizaldy Taslim Pinzon: Editor

PMCID: PMC10446234 PMID: 37611003

Abstract

Objectives

Encephalitis, brain inflammation and swelling, most often caused by an infection or the body’s immune defences, can have devastating consequences, especially if diagnosed late. We looked for clinical predictors of different types of encephalitis to help clinicians consider earlier treatment.

Methods

We conducted a multicentre prospective observational cohort study (ENCEPH-UK) of adults (> 16 years) with suspected encephalitis at 31 UK hospitals. We evaluated clinical features and investigated for infectious and autoimmune causes.

Results

341 patients were enrolled between December 2012 and December 2015 and followed up for 12 months. 233 had encephalitis, of whom 65 (28%) had HSV, 38 (16%) had confirmed or probable autoimmune encephalitis, and 87 (37%) had no cause found. The median time from admission to 1^st dose of aciclovir for those with HSV was 14 hours (IQR 5–50); time to 1^st dose of immunosuppressant for the autoimmune group was 125 hours (IQR 45–250). Compared to non-HSV encephalitis, patients with HSV more often had fever, lower serum sodium and lacked a rash. Those with probable or confirmed autoimmune encephalitis were more likely to be female, have abnormal movements, normal serum sodium levels and a cerebrospinal fluid white cell count < 20 cells x10⁶/L, but they were less likely to have a febrile illness.

Conclusions

Initiation of treatment for autoimmune encephalitis is delayed considerably compared with HSV encephalitis. Clinical features can help identify patients with autoimmune disease and could be used to initiate earlier presumptive therapy.

Introduction

Encephalitis is inflammation and swelling of the brain most often caused by an infection, or by the body’s immune defences [1] Patients typically present with altered consciousness, which may range from mild behavioural abnormality to deep coma. Although there is a long and growing list of potential microbial aetiologies, herpes simplex virus (HSV) remains the most common sporadic infectious cause [2–5]. During the last fifteen years, non-infectious immune-mediated causes of encephalitis have also been recognised with increasing frequency, especially associated with antibodies against the N-methyl-D-aspartate receptor (NMDAR), leucine-rich glioma inactivated 1 (LGI-1) protein which is part of the voltage gated potassium channel complex and glutamic acid decarboxylase (GAD) [6–9].

The outcome of encephalitis is improved with prompt recognition and initiation of appropriate treatment. Several studies have shown that for HSV encephalitis, starting the antiviral drug aciclovir within 48 hours of hospital admission is associated with a better outcome [10]. The drug is therefore typically started as soon as encephalitis is suspected. In NMDAR encephalitis retrospective studies have shown that better outcomes are also associated with earlier immunomodulatory treatment [11]. However, identifying patients with encephalitis, and with particular aetiologies, can be difficult because of the non-specific nature of the symptoms, and overlap of the clinical features for the different causes [3–5, 12–14]. This leads to delays to delays in accessing the appropriate health care and receiving prompt investigation and management [15, 16]. We therefore studied the clinical features of adults presenting with suspected encephalitis and assessed which of the features were associated the different types of encephalitis, in particular HSV and the autoimmune forms, in order to prompt earlier treatment.

Methods

Study population and design

Patients were recruited from 31 hospitals across England, Wales and Scotland in a multicentre, prospective observational cohort study, which was part of a programme of studies by the National Institute for Health Research (NIHR) applied research programme grant on Understanding and improving the Outcome of encephalitis in the UK (ENCEPH-UK). Details of the whole programme can be found at www.encephuk.org.

Patients were eligible if they were aged 16 years or older with clinically suspected encephalitis defined as an acute or sub-acute alteration in consciousness, cognition, personality or behaviour changes for more than 24 hours, along with any two of fever, prodromal illness, new onset seizures, focal neurological signs, pleocytosis (cerebrospinal fluid [CSF] white cell count of > 4 cells x10⁶/L), neuroimaging or electroencephalogram (EEG) compatible with encephalitis; [5] or any clinical suspicion of encephalitis when these investigations had not been completed at the time of recruitment and with no alternative diagnosis evident (Table 1).

Table 1. Inclusion and exclusion criteria for suspected encephalitis.

Suspected encephalitis

Inclusion Criteria
(A) Acute or sub-acute (<4 weeks) alteration in consciousness, cognition, personality or behaviour* persisting for more than 24 hours
• Plus ANY two of:
• Fever (≥ 38°C) / Prodromal illness–acute or sub-acute
• Seizures: New onset
• Focal Neurological Signs–Acute or Sub-acute onset.
• Including
• Focal weakness
• Oromotor dysfunction
• Movement disorders** including Parkinsonism***
• Amnesia
• Pleocytosis: Cerebrospinal fluid white cell count >4 cells/ul
• Neuroimaging: Compatible with encephalitis
• Electroencephalogram (EEG): compatible with encephalitis
* personality / behaviour change including agitation, psychosis, somnolence, insomnia, catatonia, mood lability, altered sleep pattern and (in children): new onset enuresis, or irritability,
** Movement disorders includes chorea, athetosis, dystonia, hemiballismus, stereotypies, orolingual dyskinesia and tics
***bradykinesia, tremor, rigidity and postural instability
OR
(B) Clinical suspicion of encephalitis but above investigations have not yet been completed
OR
(C) Clinical suspicion of encephalitis and the patient died before investigations completed
Exclusion criteria
• Patients with non-infectious or non-immune central nervous system disorders due to hypoxic, ischaemic, vascular, toxic or metabolic causes
• Patients with pre-existing indwelling ventricular devices

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Patients were followed up for 12 months, and the Glasgow Outcome Score (GOS) which ranges from 1 (death) to 5 (full recovery) recorded. The study protocols were approved by participating sites and the National Research Ethics Service (now part of the Health Research Authority) East Midlands Nottingham 1 committee (reference 11/EM/0442). Written consent for entry into the study was obtained from patients or an accompanying relative. Standardised case record forms for clinical, laboratory and radiological data were recorded on a secure online database (Openclinica^TM).

Aetiological testing

All CSF samples had microscopy, culture and polymerase chain reaction (PCR) performed according to national guidelines in the admitting hospitals, regional diagnostic centres or at the University of Liverpool. This included standard first line testing of HSV-1 and 2, varicella zoster virus (VZV), enteroviruses and parechoviruses, and second line testing depending on the clinical presentations [17, 18]. Serum, and where available CSF, were tested for a panel of autoantibodies either at the hospital site, the University of Liverpool, or the University of Oxford [6, 7, 19]. All patients with suspected autoimmune encephalitis had, as a minimum, tests to detect NMDAR, VGKC-complex, glutamic acid decarboxylase (GAD) and paraneoplastic (onconeuronal) antibodies. The standard onconeuronal antibody panel included Hu(D), Yo, CV2/CRMP5, Ri, Ma1, Ma2, amphiphysin, Tr, SOX1, Zic4, titin, recoverin, PKCγ & Purkinje cell antibodies, tested by immunohistochemistry and recombinant immunoblot. Newer antibody tests that became available during the course of the study were incorporated prospectively; these included α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), contactin associated protein–like 2 (CASPR2); dopamine 2 receptor (DR2), dipeptidyl-peptidase–like protein 6 (DPPX), γ-aminobutyric acid (GABA) type A and type B receptors, CV2, metabotropic glutamate receptor 5 (mGluR5), and LGI-1/contactin/CASPR2 testing to replace earlier VGKC-complex. Remaining samples from earlier patients were tested retrospectively if available (this was performed in 35 patients; 2 were classified as autoimmune encephalitis and 33 remained as encephalitis of unknown aetiology). Further analyses were performed in the unknown aetiological group with a history of foreign travel for extended infection screening at the Rare and Imported Pathogen Laboratory, Public Health England, Porton Down.

Methods for analysis

Patients were classified into causes of encephalitis with different degrees of certainty using published case definitions [5–7, 20, 21]. They were reclassified when updated autoimmune case definitions became available (Table 2) [22]. Where the classification was unclear, cases were discussed by a panel of experts and a consensus reached.

Table 2. Case definitions for types of encephalitis.

Clinically diagnosed Encephalitis	Patients with Suspected Encephalitis (defined above) with evidence of brain inflammation from surrogate markers (e.g. on brain imaging or CSF pleocytosis) and no alternative diagnosis made
Viral encephalitis	• Confirmed: Clinically diagnosed encephalitis AND positive CSF PCR for a viral pathogen or intrathecal antibody • Probable: Encephalitis AND detection of an appropriate pathogen by either throat swab, rectal swab or serology
Bacterial or fungal encephalitis	Clinically diagnosed encephalitis AND detection of an appropriate bacterial or fungal pathogen from either blood or CSF by PCR, culture or gram stain
Progressive multifocal leukoencephalopathy (PML)	• Confirmed: 1) clinical features of PML including cognitive decline, speech and language deficits and gait abnormalities; AND 2) neuroimaging findings in keeping; AND 3) presence of JC virus in CSF • Probable: Two of the above criteria met
Autoimmune encephalitis	• Confirmed: rapid progression short term memory loss, altered mental state or psychiatric symptoms AND detection of an appropriate autoimmune antibody from either blood or CSF • Probable: 1) rapid progression short term memory loss, altered mental state or psychiatric symptoms; 2) exclusion of well-defined syndromes of autoimmune encephalitis (Acute disseminated encephalomyelitis, Bickerstaff etc); AND 3) absence of well characterised autoantibody in serum or CSF and at least 2 of: MRI abnormal in keeping with autoimmune encephalitis; CSF pleocytosis; brain biopsy inflammatory infiltrates and excluding other disorders; AND 4) reasonable exclusion of alternative causes • Possible: 1) rapid progression short term memory loss, altered mental state or psychiatric symptoms; AND 2) at least one of the following: a. New focal CNS findings b. Seizures not explained by previously known seizure disorder c. CSF pleocytosis (white cell count of more than 5 cells per mm3) d. MRI features suggestive if encephalitis 3) absence of well characterised autoantibody in serum or CSF
Paraneoplastic encephalitis	Clinically diagnosed encephalitis; AND Cancer diagnosed within 5 years of neurological symptoms development; AND No antineuronal antibody detected.
Hashimoto’s encephalitis	All 6 of the following criteria: • encephalopathy with seizures, myoclonus, hallucinations or stroke like episodes; • subclinical or mild overt thyroid disease (usually hypothyroidism); • brain MRI normal or with non-specific abnormalities; • presence of serum thyroid antibodies (thyroid peroxidase, thyroglobulin); • absence of well characterized neuronal antibodies in serum and CSF; • reasonable exclusion of alternative cause

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There were two primary analyses; one looked for an association between baseline variables and HSV encephalitis, the other between baseline variables and autoimmune encephalitis. Univariate analysis was performed initially on each variable to look for associations using unpaired t-tests, Mann- Whitney U test, chi-square test and Fisher’s exact test where appropriate. Clinical variables that had potential for significance were selected using the lasso variable selection approach to perform a multiple logistic regression model. The stepBIC approach to multiple logistic regression model was used to identify variables significantly associated with encephalitis. Data were analysed using R [23].

Results

Between 2012 and 2015, 341 patients with suspected encephalitis were enrolled, of whom 233 (68%) met the case definition of clinically diagnosed encephalitis (Fig 1); 108 (32%) did not have encephalitis, but a range of mimicking conditions, most commonly septic encephalopathy 18 (17%). Of the 233 patients with encephalitis, 108 (46%) had an infectious cause including 65 (28%) with HSV type 1 or 2, 32 (14%) with other viruses and 11 (5%) with bacterial or fungi. Autoimmune encephalitis was diagnosed in 38 (16%) patients, of whom 35 (15%) had a confirmed diagnosis with autoantibodies and 3 (1%) had probable; in addition, 23 (10%) had possible autoimmune encephalitis making 61 in total. Sixty-four (27%) patients with encephalitis had no cause identified, despite further testing for infectious and autoimmune causes. Clinical features of the study population are shown in Table 3.

Table 3. Presenting clinical features and outcomes for 233 patients with encephalitis.

	Infective encephalitis 108					All Autoimmune 61
	HSV 65	P value¹	Other viruses 32	Other organisms 11	All infectious causes 108	Autoimmune Confirmed & probable 38	p value³	Autoimmune possible 23	All autoimmune 61	p value⁴	Unknown enceph 87	All Enceph 233
Age (med. IQR)	60 (47,71)	0.004	47 (33, 64)	62 (47, 62)	56.5(39, 69)	38 (24, 59)	0.004	57(38, 64)	50 (26, 62)	0.019	54 (36, 67)	54 (34, 68)
Female	38 (59%)	0.113	14 (44%)	2 (20%)	54(50%)	23 (61%)	0.136	13 (57%)	36 (59%)	0.108	38 (43%)	115 (49%)
White	64(99%)	0.020	26 (81%)	9 (90%)	99(92%)	33 (87%)	1.000	21 (91%)	54(89%)	0.716	78 (90%)	210 (91%)
Co-morbidities (1 or more)	21 (32%)	0.757	10 (31%)	5 (50%)	36(33%)	7 (18%)	0.107	9 (39%)	16 (26%)	0.553	36 (41%)	70 (30%)
Immunocompromise	5 (8%)	0.299	9 (28%)	2 (20%)	16(15%)	1 (3%)	0.056	2 (9%)	3(5%)	0.402	9 (10%)	27 (12%)
Symptoms
History of Fever	46 (71%)	0.003	16(50%)	9 (90%)	71(66%)	13 (34%)	0.017	9 (39%)	22(36%)	0.001	43(49%)	127(54.5%)
Flu like symptoms	13 (20%)	1.000	4 (13%)	5 (50%)	22 (20%)	5 (13%)	0.597	6 (26%)	11 (18%)	0.839	14 (16%)	46(19.7%)
History of Rash	4 (6%)	0.166	10 (31%)	0 (0%)	14 (13%)	3 (8%)	0.585	3 (13%)	6 (10%)	0.791	10 (11%)	27 (11.6%)
Severe/worst ever headache	19 (31%)	0.635	6(19%)	4 (40%)	29 (27%)	3 (8%)	0.004	8 (35%)	11 (18%)	0.075	31 (36%)	63 (28.0%)
Seizures	29 (44%)	0.123	6 (19%)	4 (40%)	39 (36%)	21 (55%)	0.007	8 (35%)	29 (48%)	0.043	24 (28%)	84 (36.1%)
Altered personality/ behaviour	41 (63%)	0.370	11 (34%)	0 (0%)	52 (48%)	30 (79%)	0.143	17 (17%)	47 (77%)	0.119	32 (37%)	159 (68.2%)
Agitation	13 (20%)	<0.001	7 (22%)	5 (50%)	25 (23%)	19 (50%)	0.096	13 (57%)	32 (52%)	0.012	45 (52%)	89 (38.2%)
Lethargy/ increased sleeping	28 (43%)	0.111	9 (28%)	1 (10%)	38 (35%)	15 (39%)	0.682	7 (30%)	22 (36%)	0.862	27 (31%)	80 (34.3%)
Psychosis	1 (2%)	0.187	1 (3%)	0 (0%)	2 (2%)	6 (16%)	0.006	1 (4%)	7 (12%)	0.024	4 (5%)	12 (5.2%)
Confusion/ disorientation	52 (80%)	0.588	20 (63%)	7 (70%)	79 (73%)	27 (71%)	0.543	20 (87%)	47 (77%)	1.000	73 (84%)	179 (76.8%)
Language/ speech problems	28 (43%)	0.753	13 (41%)	3 (30%)	44 (41%)	17 (45%)	0.932	12 (52%)	29 (48%)	0.823	45 (52%)	106 (45.5%)
Memory problem	28 (43%)	0.527	9 (28%)	2 (20%)	39 (36%)	19 (50%)	0.125	9 (39%)	28 (46%)	0.262	33 (38%)	91 (39.1%)
Hallucinations	8 (13%)	1.000	3 (9%)	0 (0%)	11 (10%)	6 (16%)	0.616	4 (17%)	10 (16%)	0.333	12 (14%)	29 (12.7%)
Examination findings
Fever	47 (75%)	<0.001	11 (34%)	7 (70%)	65 (60%)	7 (18%)	0.001	7 (30%)	14 (23%)	<0.001	30 (34%)	102 (44.7%)
Rash	4 (6%)	0.049	12 (38%)	1 (10%)	17 (16%)	7 (18%)	0.623	2 (9%)	9 (15%)	1.000	9 (10%)	33 (14.2%)
GCS ≤12	44 (66%)	0.846	18 (56%)	2 (20%)	64 (59%)	11 (29%)	1.000	8 (35%)	18 (30%)	1.000	20 (23%)	152 (64%)
Abnormal movements	10 (15%)	0.160	3 (9%)	1 (10%)	14 (13%)	15 (39%)	<0.001	9 (39%)	28 (48%)	<0.001	18 (21%)	52 (22.3%)
Focal weakness	23 (35%)	0.128	8 (25%)	3 (30%)	34 (31%)	5 (13%)	0.634	3 (13%)	8 (13%)	0.675	18 (21%)	64 (27.5%)
Investigation findings
Median CSF WCC (IQR)	74 (17, 200)	<0.01	22 (4, 93)	1480 (117, 3778)	55 (10, 194)	8 (1, 32)	<0.01	6 (0, 16)	6 (0, 30)	0.031	21 (4, 116)	28 (5, 133)
Median blood sodium (IQR)	133 (130, 137)	<0.01	138 (133, 140)	138 (135, 140)	134 (131, 139)	139 (138, 142)	0.910	136 (134, 138)	139 (136, 141)	0.517	138 (134, 141)	137 (133, 140)
Hyponatraemia	39 (60%)	<0.01	11 (34%)	3 (30%)	53 (49%)	5 (13%)	0.603	8 (35%)	13 (21%)	0.558	23 (26%)	80/231 (35%)
Abnormal initial CT head	24/58 (41%)	<0.001	4/25 (16%)	2/10 (20%)	30/103 (29%)	2 (5%)	0.041	6 (26%)	8 (13%)	0.250	11/83 (13%)	43/213 (20%)
Abnormal initial MRI head~	48/51 (94%)	<0.001	10/29 (34%)	4/8 (50%)	62/ 88 (71%)	14 (37%)	0.096	16 (70%)	30 (49%)	1.000	31/78 (40%)	105/200 (53%)
Abnormal EEG	23/29 (79%)	0.363	7/8 (88%)	4/4 (100%)	34/41 (83%)	23/31 (74%)	0.422	13/13 (100%)	36/44 (82%)	0.485	26/29 (90%)	83/101 (82%)
Inpatient progress & outcome
ICU admission	23 (35%)	1.000	7 (22%)	9 (90%)	39 (36%)	20 (53%)	0.022	9 (39%)	29 (48%)	0.063	46 (53%)	87 (37%)
Hosp LOS Median (IQR)	34 (21–65)	0.054	16 (10–27)	39 (15–72)	26 (16, 55)	36 (16, 113)	0.810	22 (14, 40)	26 (15, 80)	0.987	14 (10–25)	22 (13–49)
Mortality admission	3 (5%)	0.879	1 (3%)	1 (10%)	5 (5%)	3 (8%)	0.472	1 (4%)	4 (7%)	0.753	4 (5%)	12 (5%)
GOS at discharge	4 (3, 4.2)	0.449	4 (3, 5)	5 (3, 5)	4 (3, 5)	4 (3, 4.8)	0.096	4 (4, 5)	4 (3, 5)	0.324	5 (4, 5)	4 (3,5)
Outcomes at 12 months
Mortality at 12 months	5 (8%)	0.576	3 (9%)	1 (10%)	9 (8%)	5/30 (17%)	0.790	4/20 (20%)	9/50 (18%)	0.674	12/84 (14%)	26 (11%)
Median GOS at 12 months	4 (3, 5)	0.838	5 (4, 5)	5 (5, 5)	5 (4, 5)	5 (3, 5)	0.515	4 (2.5, 5)	4 (3, 5)	0.162	5 (4, 5)	5 (3, 5)

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Note: P-value calculated from Chi-square test for categorical variables with >5 individuals in each cell (group combination), Fisher’s exact test for categorical variables with <5 individuals in at least one cell (group combination) and one-way ANOVA for continuous variables. P value ¹HSV vs non HSV encephalitis; p value² all infective vs not infective encephalitis; p value ³ proven & probable autoimmune vs all other encephalitis; p value⁴ all autoimmune vs not autoimmune encephalitis. *>10% missingness of this variable ~In keeping with encephalitis

The median age of the 233 patients with encephalitis was 54 years (IQR 34–68) and 115 (59%) were female. 70 (30%) had at least one comorbidity. 27 (12%) patients had immunocompromise, which was significantly more likely in those with viruses other than HSV detected (9 [28%] of 32, versus 18 (9%] of 201, p<0.0001).

HSV encephalitis

Patients with HSV encephalitis typically presented with a brief febrile illness (2 days [IQR 1–2]) and altered cognitive function, particularly confusion/disorientation or altered personality/behaviour. Compared with the 168 other encephalitis patients, the 65 with HSV encephalitis were significantly older (median 60 years [IQR 47–71] versus 52 [32–66] years, p = 0.004) and more likely to have a fever on examination (47 [75%] of 65 versus 55 [33%] of 168, p = 0.001), but less likely to have a history of agitation (13 [20%] versus 76 [45%], p = 0.001), or a rash (4 [6%] versus 29 [17%], p = 0.04). Investigations showed the HSV encephalitis patients were more likely to by hyponatraemic than other patients (39 [60%] versus 42 [25%], p<0.01; they also had a higher median CSF white cell count (74 [17–200] versus 18 [0–7680] x10⁶ cells per L, p<0.01). On imaging HSV encephalitis patients were more likely to have abnormal CT scans than those with other forms of encephalitis (24 [41%] of 58 versus 19 [11%] of 166, p<0.001;) and to have abnormal MRI scans (48 [94%] of 51 versus 59 [39%] of 153, p<0.001).

In a multivariate logistic regression analysis having a fever on examination, not having a rash on examination, and lower serum sodium were associated with HSV encephalitis compared to other causes of encephalitis (Table 4). For validity, a sensitivity analysis was performed using imputed data which found minimal difference in the associations found; multivariate analysis demonstrated the same associations. The combined presence of fever, lack of rash, and presence of hyponatremia had a sensitivity of 86% for diagnosis of HSV encephalitis and specificity of 42%, with a positive predictive value (PPV) of 0.36 and negative predictive value of 0.88.

Table 4. Multivariate logistic regression model with selected variables for HSV encephalitis vs other forms of encephalitis.

Selected variables from the model	Parameter estimate	Standard error	Odds ratio	95% CI of OR	p-value
Intercept	-0.69	0.78	0.50	0.11, 2.30	0.37
Fever on examination	1.84	0.38	6.29	3.00,13.18	<0.01
Rash on examination	-1.54	0.68	0.21	0.06,0.81	0.02
Presence of Hyponatraemia	1.11	0.37	3.04	1.48, 6.26	<0.01

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Multivariate analysis was performed using 18 clinical and laboratory variables at presentation that were significant from the univariate analysis. The results were fitted by step Bayesian information criterion using backward selection.

Autoimmune encephalitis

The 38 patients with confirmed or probable autoimmune encephalitis typically presented with a few weeks’ history (median 30 days [IQR 25–34]) of altered personality and/or confusion, often with agitation and seizures; the most commonly identified antibodies were against VGKC complex and NMDAR (Fig 1). Of note 7 of the 10 VGKC complex positive individuals were tested for LGI1 of which 1 was positive in CSF (serum was not available for retrospective testing). LGI1 testing was not in routine practice at the time of patient recruitment. Patients with confirmed or probable autoimmune encephalitis were younger than the 195 with other forms of encephalitis (median age 38 [IQR 24–59] versus 55 [IQR 37–69] years, p = 0.004) and more likely to be female (23 [61%] versus 90 [46%], p = 0.04). They were more likely to have abnormal movements (15 [39%] versus 27[14%], p<0.01), have seizures (22 [56%] versus 62 [32%], p<0.01), and have a psychosis (6 [15%] versus 6 [3%], p<0.01), but less likely to have a severe headache (3 [8%] versus 60 [32%], p<0.01) than those with other forms of encephalitis. They were also less likely to be hyponatraemic, and had a lower median CSF white cell count (8 [IQR 1–32] versus 42 [8–168] x10⁶ cells per L, p<0.01) than those with other causes (Table 3).

In a multiple logistic regression, female sex, abnormal movements, lack of hyponatremia and a CSF white cell count <20 x10⁶/L were associated with confirmed or probable autoimmune encephalitis, compared to other causes (Table 5). The presence of all these features gave a sensitivity of 97%, specificity 12%, with positive predictive value (PPV) of 0.18 and negative predictive value (NPV) of 0.96.

Table 5. Multivariate logistic regression model with selected variables for autoimmune encephalitis (confirmed or probable) versus other forms of encephalitis.

Selected variables from the model	Parameter estimate	Standard error	Odds ratio	95% CI of OR	p-value
Intercept	-2.06	0.78	0.13	0.03,0.59	<0.01
Gender (Male)	-1.26	0.49	0.29	0.11,0.75	0.01
Abnormal movement	1.71	0.49	5.50	2.11,14.37	<0.01
Hyponatraemia	-1.20	0.52	0.30	0.11,0.84	0.02
CSF WCC ≥20	-1.31	0.45	0.27	0.11,0.65	<0.01

Open in a new tab

Multivariate analysis was performed using 19 clinical and laboratory variables at presentation that were significant selected from the univariate analysis. The results were fitted using step Bayesian information criterion using backward selection

Because new diagnostic guidelines have been introduced which include case definitions for possible, as well as probable and confirmed autoimmune encephalitis, we repeated the analysis including 23 such patients. This showed that the 61 patients with confirmed, probable or possible autoimmune encephalitis were likely to be younger and have seizures, psychosis, abnormal movements, and a lower CSF white cell count, than those with other forms of encephalitis (Table 3); in addition, they were more likely to have agitation.

In a multivariate logistic regression analysis, a lack of fever on examination, the presence of abnormal movements, and a CSF white cell count of <20 cells x10⁶/L were associated with a diagnosis of confirmed, probable or possible autoimmune encephalitis, compared to other causes (S1 Table). For validity, a sensitivity analysis was performed using imputed data which found minimal difference in the associations found; multivariate analysis demonstrated the same associations. The combined absence of fever, presence of abnormal movements and CSF white cell count <20 cells x10⁶/L had a sensitivity of 95% for diagnosis of confirmed, probable or possible autoimmune encephalitis and specificity of 37%, with a PPV of 0.35 and NPV of 0.95.

Treatment and outcomes

276 patients with suspected encephalitis had aciclovir initiated a median 15 hours (IQR 5–44) after hospital admission; this included the 61 patients with HSV encephalitis whose time to treatment was 14 hours (IQR 5–50). Time to treatment with aciclovir improved during the course of the study from 23 hours (IQR 10–56) in the first year, to 12 hours (IQR 4–28) in the 2^nd and 10 hours (IQR 3–34) in the 3^rd year. Among the 38 patients treated for autoimmune encephalitis the median time to first immunosuppressant drug (corticosteroids in 28, intravenous immunoglobulin in 6) was 125 hours (IQR, 45–250). This did not change significantly across the course of the study.

Overall, 87 (37%) of the 233 patients were admitted to intensive care; those with confirmed or probable autoimmune encephalitis were more likely to be admitted than those with other diagnoses (20 [53%] of 38 verses 67 [34%] of 195, p = 0.022). 12 (5%) of 233 patients died in hospital and 86 (37%) made a full recovery; the median Glasgow Outcome Scale score at discharge was 4; these outcomes did not differ significantly between groups (Fig 2). By 12 months the mortality had increased to 26 (11%) and the number with full recovery to 92 (54%) of 171 with the information available, so that the median Glasgow Outcome Scale score had increased to 5.

Discussion

This is one of the largest prospective studies on unselected encephalitis patients from any western industrialised nation, recruiting more patients with HSV encephalitis than any previous prospective report. We found just under half the patients had an infectious cause, approximately one quarter had a confirmed, probable or possible autoimmune encephalitis, and one quarter had no aetiology identified. Over the last 20 years the epidemiology of encephalitis has changed considerably. Whilst HSV continues to be the most important sporadic cause, patients with autoimmune aetiologies are being recognised increasingly. Encephalitis remains relatively rare overall, with an incidence of 2–5 per 100,000 per year; [24] however, it causes a disproportionately high disease burden because of the devastating impact of this acquired brain injury on those affected, particularly if there are delays in recognition, diagnosis and treatment.

For HSV encephalitis, the link between worse outcome and delays in treatment, particularly beyond 48 hours after hospital admission, has been recognised for some years [10, 25]. National guidelines for viral encephalitis were developed in the UK in 2012 [17]. Their introduction through an NIHR programme grant in applied research was associated with a reduction in the time to aciclovir treatment for those with HSV encephalitis. The programme examined where delays occur, introduced innovative measures such as a lumbar puncture pack to streamline management [15, 26], and included intense efforts to raise awareness of encephalitis and the national guidelines, in conjunction with The Encephalitis Society, our partner in patient and public involvement and engagement [27].

Across the three years of our study, we found the median time from admission to treatment reduced from 23 hours to ten hours, which is still longer than the 6 hours recommended by the national guidelines. Our findings that fever on examination, absence of a rash, and hyponatremia were associated with a diagnosis of HSV encephalitis may help improve things. A small retrospective study from Argentina suggested fever, headache, and higher CSF white cell count and protein were more likely in infectious than non-infectious encephalitis [28]; in a study from Turkey hyponatremia was associated with HSV encephalitis [29].

A retrospective comparison of 95 patients from China found involuntary movements and memory deficits were more common in autoimmune than infectious encephalitis patients [30]. A similar retrospective study in Australia evaluated retrospectively 84 patients evaluated over a ten-year period and found headache, fevers, altered consciousness, psychiatric symptoms, and a CSF pleocytosis were more common in infectious encephalitis, whereas seizures were more common in autoimmune [31].

In practice, the typical management for patients with suspected encephalitis is to perform a lumbar puncture and neuroimaging whist starting intravenous aciclovir and antibiotics. If an infectious cause is confirmed by PCR or culture of the cerebrospinal fluid, the antimicrobials are adjusted accordingly. The dilemma clinicians face currently is what to do when the investigations for infectious causes are negative. The results of tests for antibodies associated with autoimmune encephalitis, such as NMDAR, LGI-1, and GAD, often take several days to come back, and may not be helpful in seronegative autoimmune cases, which are being recognised increasingly [22, 32]. In our study the median time from hospital admission to immunosuppressive therapy was 5 days.

Our study found female sex, abnormal movements, a lack of hyponatremia and a CSF white cell count <20 x10⁶/L were associated with confirmed or probable autoimmune encephalitis. These features have also been reported in studies of individual causes of autoimmune encephalitis: female sex, abnormal movements and a moderate pleocytosis are reported for NMDAR [33], a moderate pleocytosis for LGI-1 [34], and female sex for GAD-associated encephalitis [9]. Interestingly, other features reported frequently for individual forms of autoimmune encephalitis, such as abnormal mental status and seizures, were not helpful in distinguishing autoimmune from other causes of encephalitis in our study. Although neurologists focus on the clinical features which can distinguish between different causes of autoimmune encephalitis, for the general and infectious disease clinician, the critical thing is to identify patients who may have any form of autoimmune encephalitis, and thus benefit from prompt initiation of presumptive treatment with immunosuppressive drugs. We thus analysed all patients with probable or confirmed autoimmune encephalitis as a single group, whatever the underlying aetiology. There are very few such prospective studies of non-selected patients with encephalitis of all causes. A retrospective comparison of 95 patients from China found involuntary movements and memory deficits were more common in autoimmune than infectious encephalitis patients [30]. A similar retrospective study evaluated 84 encephalitis patients in Austria admitted over a ten-year period, including 34 with confirmed infection and 17 with confirmed autoimmune disease; headache, fevers, altered consciousness, psychiatric symptoms, and a CSF pleocytosis were more common in infectious encephalitis, whereas seizures were more common in autoimmune patients [31].

An expert review concluded that we are too reliant on antibody testing, and need syndrome-based diagnostics of possible, probable and confirmed encephalitis to allow prompt initiation of therapy [22]. Our study preceded these guidelines, but we modified our classification to include patients with possible autoimmune encephalitis, and repeated our analysis including such patients. This confirmed the importance of abnormal movements and a moderate pleocytosis in identifying patients with autoimmune disease. Although there are data to suggest earlier treatment is beneficial in patients with proven autoimmune encephalitis, at what stage to start treatment in patients with suspected autoimmune encephalitis is less clear, and there are no randomised trials [22].

The diagnosis of antibody-associated encephalitis for most of our patients was based on antibody detection in the serum, rather than CSF. For GAD encephalitis in particular this may be important, because GAD antibodies occur at 1% of healthy people and in 80% of those with type 1 diabetes; there is not yet convincing evidence that GAD antibodies are pathogenic, rather than an epiphenomenon [9]. However, none of GAD positive patients in our study had diabetes, and all were felt to need immunosuppressive drugs, as judged by neurologists.

The presence of female sex, abnormal movements, lack of hyponatremia plus a CSF white cell count <20 x10⁶/L had a sensitivity of 95% for diagnosis of autoimmune encephalitis and specificity of 37%, with a PPV of 0.35 and NPV of 0.95. The high sensitivity and high negative predictive value are what is required to minimise the chance of overlooking patients with the condition. Such indicators should raise a strong suspicion, and might be used to guide clinicians to start presumptive corticosteroid treatment for patients, as encouraged by the recent guidelines [22]. A prospective study is needed to evaluate them fully.

With increasing recognition of autoimmune encephalitis, and the wider availability of antibody testing, the time to initiation of treatment is likely to have improved since our study was completed. Corticosteroids are the first line therapy for autoimmune encephalitis, and additional immunosuppressive treatment is recommended for some forms, but there have been few randomised trials. A prospective placebo-controlled trial of intravenous immunoglobulin in autoimmune encephalitis is currently recruiting in the UK.

Our study had several limitations. Firstly, although ours was one of the largest prospective studies of unselected patients with encephalitis, the size was limited, especially in terms of numbers with specific autoimmune diagnoses and also inherently biased towards those autoimmune causes that would present acutely or subacutely whereas some forms are known to take more insidious and longer presentation courses. Secondly, because it was performed some years ago, the number of patients with some of the rarer antibodies, was limited. We re-evaluated samples as newer antibody tests became available, but applying tests retrospectively to samples which may have been frozen and thawed many times is never ideal. There may also have been a bias towards identifying well recognised forms of encephalitis, such as HSV, rather than newer emerging forms of autoimmune disease. The time to initiation of treatment for autoimmune encephalitis may have reduced since our study, due to increasing recognition of the condition. We were also reliant on testing of serum for the most part rather than CSF. We now know that antibody testing of CSF has greater specificity. Although our primary purpose was identifying patients with any form of autoimmune encephalitis, there is heterogeneity among different types of autoimmune encephalitis, and grouping them together will have blunted these differences.

In summary, we have shown that among adults admitted to hospital with a diagnosis of encephalitis, clinical features can be used to identify those with HSV and those with autoimmune disease to guide presumptive treatment. Currently, the initiation of treatment for patients with HSV is significantly quicker than for those with autoimmune disease. The presence of female sex, abnormal movements, lack of hyponatremia and a CSF white cell count <20 x10⁶/L predicted autoimmune encephalitis with high sensitivity and high negative predictive value and may be used to guide presumptive treatment, but this requires further evaluation in a prospective study.

Supporting information

S1 Table. Multivariate logistic regression model with selected variables for autoimmune encephalitis (confirmed, probable and possible) versus other forms of encephalitis.

(DOCX)

Click here for additional data file.^{(14.2KB, docx)}

S2 Table. Presenting clinical features and outcomes of the autoantibody mediated forms of autoimmune encephalitis.

(DOCX)

Click here for additional data file.^{(19.4KB, docx)}

S1 Data

(XLSX)

Click here for additional data file.^{(108.5KB, xlsx)}

Acknowledgments

The authors would like to thank all the participants who gave their time to help with this study, and the research nurses and principal investigators at the hospital sites for their help with recruitment. We would also like to thank Chloe Smith, Greg Gibson, Rebecca Spencer, Mike Scully, Kieran Crabtree, Katy Smith and Chris Jecks for ensuring data collection was entered from the sites.

ENCEPH-UK Study group lead author Tom Solomon¹

Contact email for group lead: tsolomon@liverpool.ac.uk.

ENCEPH-UK study group members; Ruth Backman¹, Gus Baker², Nicholas J Beeching^3,4, Rachel Breen⁵, David Brown⁶, Chris Cheyne⁷, Enitan D Carrol^1,8, Nicholas W S Davies⁹, Sylviane Defres^1,3,4, Ava Easton¹⁰, Martin Eccles¹¹, Robbie Foy¹², Marta Garcia-Finana⁷, Julia Granerod⁶, Julia Griem¹³, Michael Griffiths^1,8, Alison Gummery¹, Lara Harris¹³, Helen Hickey⁵, Helen Hill⁵, Ann Jacoby², Hayley Hardwick¹, Ciara Kierans¹⁴, Michael Kopelman¹³, Rachel Kneen^1,8, Gill Lancaster¹⁵, Michael Levin¹⁶, Rebecca McDonald¹⁷, Antonieta Medina-Lara¹⁸, Esse Menson¹⁹, Benedict Michael¹, Natalie Martin²⁰, Andrew Pennington¹⁷, Andrew Pollard²⁰, Julie Riley¹⁷, Manish Sadarangani²⁰ Anne Salter²¹, Kukatharmini Tharmaratnam⁷ Maria Thornton¹⁷, Angela Vincent²², Charles Warlow²³.

1. Department of Clinical Infection Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK

2. Department of Clinical Neuropsychology, The Walton Centre NHS Foundation Trust, Liverpool, UK

3. Tropical and Infectious Disease Unit, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK

4. Clinical Trials Unit, Liverpool, UK

5. Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK

6. Public Health England (formerly Health Protection Agency) Colindale, London, UK

7. The Department of Biostatistics, Institute of translational medicine, University of Liverpool, Liverpool, UK

8. Alder Hey Hospital Children’s NHS Foundation Trust, Liverpool, UK

9. Department of Neurology, Chelsea and Westminster NHS Trust, London, UK

10. Encephalitis Society, Malton, UK

11. Faculty of Medical Sciences, Institute of Health and Society, Newcastle University, Newcastle, UK

12. Faculty of Medicine and Health, Institute of Health Sciences, Leeds University, Leeds, UK

13. Institute of Psychiatry, Kings College, London, UK

14. Public Health and Policy, Institute of psychology Health and Society, University of Liverpool, Liverpool, UK

15. Mathematics and Statistics, Lancaster University, Lancaster, UK

16. Paediatrics and International Child Health, Imperial College, London, UK

17. Research and Development Department, The Walton Centre NHS Foundation Trust, Liverpool, UK

18. Health Economics Group, University of Exeter medical School, Exeter, UK

19. Infectious diseases and Immunology team, Evelina London Children’s Hospital, London, UK

20. Oxford Vaccine Group, University of Oxford, Oxford, UK

21. Patient representative, Encephalitis Society, Malton, UK

22. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

23. Department of Neurosciences, Western General Hospital, University of Edinburgh, Edinburgh, UK

Hospitals sites involved in recruitment into ENCEPH UK

Principal Investigators

Gavin Barlow¹, Nicholas J Beeching², Thomas Blanchard³, Richard Body⁴, Gavin Boyd⁵, Lucia Cebria-Prejan⁶, David Chadwick⁷, Richard Cooke⁸ Pamela Crawford⁹, Brendan Davies¹⁰, Nicholas W S Davies¹¹, Sam Douthwaite¹², Hedley Emsley¹³, Simon Goldenberg¹², Clive Graham¹⁴, Steve Green¹⁵, Clive Hawkins¹⁰, Dianne Irish¹⁶, Kate Jeffrey¹⁷, Matt Jones¹⁸, Liza Keating¹⁹, Jeff Keep²⁰, Susan Larkin⁸, Maria Leita¹⁷, Derek Macallan²¹, Jane Minton²², Kavya Mohandas²³, Ed Moran²⁴, David Muir²⁵, Monicka Pasztor²⁶, Matthew Reed²⁷, Tom Solomon²⁸, Philip Stanley²⁹, Julian Sutton³⁰, Peter Thomas³¹, Guy Thwaites¹², John Weir¹⁹, Mark Zuckerman²⁰.

1. Hull and East Yorkshire Hospitals NHS Trust, Hull.

2. Liverpool University Hospitals NHS Foundation Trust Liverpool

3. North Manchester General Hospital, Manchester

4. Manchester Royal Infirmary, Manchester

5. Calderdale and Huddersfield NHS Foundation Trust, Huddersfield

6. Mid Yorkshire Hospitals NHS Trust, Pinderfields

7. South Tees Hospitals NHS Foundation Trust, Middlesbrough

8. Aintree University Hospital NHS Foundation Trust, Liverpool

9. York Teaching Hospital NHS Foundation Trust, York

10. University Hospitals North Midlands, Stoke on Trent

11. Chelsea and Westminster Hospital NHS Foundation Trust, London

12. Guy’s and St Thomas’ NHS Foundation Trust, London

13. Lancashire Teaching Hospitals NHS Foundation Trust, Royal Preston Hospital, Preston

14. North Cumbria University Hospitals NHS Trust, Carlisle

15. Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield

16. Royal Free London NHS Foundation Trust, London

17. Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford

18. Salford Royal NHS Foundation trust, Salford

19. Royal Berkshire NHS Foundation Trust, Reading

20. Kings College Hospital NHS Foundation Trust, London

21. St George’s University Hospitals NHS Foundation Trust, London

22. Leeds Teaching Hospitals NHS Trust, St James’ University Hospital, Leeds

23. Wirral University Teaching Hospital NHS Foundation Trust–Arrowe Park Hospital, Upton

24. University Hospitals Birmingham NHS Foundation Trust, Birmingham Heartlands Hospital, Birmingham

25. Imperial College Healthcare NHS Trust, St Mary’s Hospital, London

26. University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster

27. NHS Lothian, Royal Infirmary Edinburgh, Edinburgh

28. The Walton Centre NHS Foundation Trust, Liverpool

29. Bradford Teaching Hospitals NHS Foundation Trust, Bradford

30. University Hospital Southampton NHS Foundation Trust, Southampton

31. Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This study was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (grant number RP-PG-0108-10048) awarded to TS. The funders of the study had no role in study design, data collection, analysis or interpretation or writing of the report.

References

1.Venkatesan A, Michael BD, Probasco JC, Geocadin RG, Solomon T. Acute encephalitis in immunocompetent adults. Lancet 2019; 393: 702–16. doi: 10.1016/S0140-6736(18)32526-1 [DOI] [PubMed] [Google Scholar]
2.Glaser CA, Honarmand S, Anderson LJ, et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clin Infect Dis 2006; 43: 1565–77. doi: 10.1086/509330 [DOI] [PubMed] [Google Scholar]
3.Koskiniemi M, Rantalaiho T, Piiparinen H, et al. Infections of the central nervous system of suspected viral origin: a collaborative study from Finland. J Neurovirol 2001; 7: 400–8. doi: 10.1080/135502801753170255 [DOI] [PubMed] [Google Scholar]
4.Mailles A, Stahl JP. Infectious encephalitis in france in 2007: a national prospective study. Clin Infect Dis 2009; 49: 1838–47. doi: 10.1086/648419 [DOI] [PubMed] [Google Scholar]
5.Granerod J, Ambrose HE, Davies NW, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infectious Diseases 2010; 10: 835–44. doi: 10.1016/S1473-3099(10)70222-X [DOI] [PubMed] [Google Scholar]
6.Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 2010; 133: 1655–67. doi: 10.1093/brain/awq113 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Irani SR, Fukushima K, Yazaki M, Vincent A. Limbic encephalitis: under-recognition of voltage-gated potassium channel antibodies. Eur Neurol 2007; 58: 184. doi: 10.1159/000104722 [DOI] [PubMed] [Google Scholar]
8.Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti NMDAR encephalitis. Lancet Neurology 2011; 10: 63–74. doi: 10.1016/S1474-4422(10)70253-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Graus F, Saiz A, Dalmau J. GAD antibodies in neurological disorders—insights and challenges. Nat Rev Neurol 2020; 16: 353–65. doi: 10.1038/s41582-020-0359-x [DOI] [PubMed] [Google Scholar]
10.Raschilas F, Wolff M, Delatour F, et al. Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 2002; 35: 254–60. doi: 10.1086/341405 [DOI] [PubMed] [Google Scholar]
11.Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12: 157–65. doi: 10.1016/S1474-4422(12)70310-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.de Ory F, Avellon A, Echevarria JE, et al. Viral infections of the central nervous system in Spain: a prospective study. J Med Virol 2013; 85: 554–62. doi: 10.1002/jmv.23470 [DOI] [PubMed] [Google Scholar]
13.Hamid JS, Meaney C, Crowcroft NS, Granerod J, Beyene J. Cluster analysis for identifying sub-groups and selecting potential discriminatory variables in human encephalitis. BMC Infect Dis 2010; 10: 364. doi: 10.1186/1471-2334-10-364 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Lee TC, Tsai CP, Yuan CL, et al. Encephalitis in Taiwan: a prospective hospital-based study. Jpn J Infect Dis 2003; 56: 193–9. [PubMed] [Google Scholar]
15.Cooper J, Kierans C, Defres S, Easton A, Kneen R, Solomon T. Diagnostic Pathways as Social and Participatory Practices: The Case of Herpes Simplex Encephalitis. PLoS One 2016; 11: e0151145. doi: 10.1371/journal.pone.0151145 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Michael BD, Sidhu M, Stoeter D, et al. Acute central nervous system infections in adults—a retrospective cohort study in the NHS North West region. Qjm 2010; 103: 749–58. doi: 10.1093/qjmed/hcq121 [DOI] [PubMed] [Google Scholar]
17.Solomon T, Michael BD, Smith PE, et al. Management of suspected viral encephalitis in adults—Association of British Neurologists and British Infection Association National Guidelines. J Infect 2012; 64: 347–73. doi: 10.1016/j.jinf.2011.11.014 [DOI] [PubMed] [Google Scholar]
18.Public Health England. UK Standards for Microbiology Investigations: Investigation of Viral Encephalitis and Meningitis. Public Health England: UK Standards for Microbiology Investigations: Investigation of Viral Encephalitis and Meningitis, 2014. (accessed. [Google Scholar]
19.Irani SR, Gelfand JM, Al-Diwani A, Vincent A. Cell-surface central nervous system autoantibodies: clinical relevance and emerging paradigms. Ann Neurol 2014; 76: 168–84. doi: 10.1002/ana.24200 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 2013; 80: 1430–8. doi: 10.1212/WNL.0b013e31828c2fa1 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis 2013; 57: 1114–28. doi: 10.1093/cid/cit458 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15: 391–404. doi: 10.1016/S1474-4422(15)00401-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Team RC. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL http://www.R-project.org/. 2013. [Google Scholar]
24.Granerod J, Cousens S, Davies NW, Crowcroft NS, Thomas SL. New estimates of incidence of encephalitis in England. Emerg Infect Dis 2013; 19. doi: 10.3201/eid1909.130064 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.McGrath N, Anderson NE, Croxson MC, Powell KF. Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome. J Neurol Neurosurg Psychiatry 1997; 63: 321–6. doi: 10.1136/jnnp.63.3.321 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Backman R, Foy R, Diggle PJ, et al. A pragmatic cluster randomised controlled trial of a tailored intervention to improve the initial management of suspected encephalitis. PLoS One 2018; 13: e0202257. doi: 10.1371/journal.pone.0202257 [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Easton A. Increasing understanding of encephalitis. Lancet Neurol 2018; 17: 301. doi: 10.1016/S1474-4422(18)30077-2 [DOI] [PubMed] [Google Scholar]
28.Wilken M, Ameghino L, Cammarota A, Nogues MA, Del Castillo M, Farez MF. Clinical and cerebrospinal fluid findings contribute to the early differentiation between infectious and noninfectious encephalitis. Medicina (B Aires) 2017; 77: 214–21. [PubMed] [Google Scholar]
29.Basaran S YS, Bali EA, Cagatay A, Oncul O, Ozsut H, Eraksoy H. Hyponatremia Is Predictive of HSV-1 Encephalitis among Patients with Viral Encephalitis. Tohoku J Exp Med 2019; 247: 189–95. doi: 10.1620/tjem.247.189 [DOI] [PubMed] [Google Scholar]
30.Huang CN, Tian XB, Jiang SM, et al. Comparisons Between Infectious and Autoimmune Encephalitis: Clinical Signs, Biochemistry, Blood Counts, and Imaging Findings. Neuropsychiatr Dis Treat 2020; 16: 2649–60. doi: 10.2147/NDT.S274487 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Wagner JN, Kalev O, Sonnberger M, Krehan I, von Oertzen TJ. Evaluation of Clinical and Paraclinical Findings for the Differential Diagnosis of Autoimmune and Infectious Encephalitis. Front Neurol 2018; 9: 434. doi: 10.3389/fneur.2018.00434 [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018; 83: 166–77. doi: 10.1002/ana.25131 [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Dalmau J, Armangue T, Planaguma J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol 2019; 18: 1045–57. doi: 10.1016/S1474-4422(19)30244-3 [DOI] [PubMed] [Google Scholar]
34.Montojo MT, Petit-Pedrol M, Graus F, Dalmau J. Clinical spectrum and diagnostic value of antibodies against the potassium channel related protein complex. Neurologia 2015; 30: 295–301. doi: 10.1016/j.nrl.2013.12.007 [DOI] [PMC free article] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0282645.r001

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14 Jun 2022

PONE-D-21-37215Clinical predictors of encephalitis in UK adults – a multi-centre prospective observational cohort studyPLOS ONE

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Reviewer #1: Yes

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Reviewer #1: The authors describe a large prospective, multicentric cohort of patients with suspected encephalitis between 2012 and 2015. They screened 794 patients, had to exclude 453 and recruited 341 patients with suspected encephalitis. 233 had encephalitis (according to prespecified criteria) of whom 97 were viral, 11 bacterial/fungal, 61 autoimmune and 64 unknown. Their main findings were that patients with HSV more often had fever and were older (and has less frequently rash) while patients categorized as definite or probable AE were more often female, had movement disorders and had less often fever and less pleocytosis in cSF.

In general the authors have recruited a very large cohort including infectious and autoimmune encephalitis allowing for comparative studies. The manuscript is well written and especially the discussion is nice to read. It openly discusses all obvious limitations. The main findings are well supported by their data and the figures and tables are instructive. It is a bit surprising, that the results get published only now.

My main issues are:

- Antibody studies. Indeed the authors acknowledge that their antibody studies evolved during the trial with new antibodies described… However, it appears the authors had stored serum available and it would have been possible to comprehensively reexamine the patients for common and less common antibodies. Freezing/thawing cycles usually are not a problem for serologic studies. I think it is somewhat of a missed chance to identify AE antibody frequency in this unbiased, remarkable cohort of acute encephalitis. The lack of CSF is unfortunate, the advantage of CSF testing is correctly pointed out in the discussion. On the same note, the cited Graus et al criteria emphasize that the category of probable seronegative AE should only be entertained after comprehensive testing, which the authors did not do. Finally, LGI1/VGKC is not a valid category anymore. How was the antibody tested? VGKC plus CBA or only VGKC. VGKC testing alone will be difficult to classify here.

- It would be instructive (as supplementary data) to know the features of the ab defined subgroups of AE even though numbers are small. This also holds true for outcome. E.g. In suspect that the majority of movement disorders stems from the NMDARE subgroup. Gad and Hashimoto rarely have MD.

- I would suggest to point out in the discussion, that the spectrum of AE is biased by the intial criteria chosen. Patients with rapid/subacute onset. We know that Iglon5, CAPSR2, LGI1 can have very extended and sometimes insidious onset. Therefore, the spectrum of AE is more representative of acute rapid onset AE and not AE in general.

- The findings that HSVI is associated with lack of rash. Is that mainly carried by the 9 VZV encephalitis patients? The other viruses usually do not associate with rash as far as I know.

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PLoS One. 2023 Aug 23;18(8):e0282645. doi: 10.1371/journal.pone.0282645.r002

Author response to Decision Letter 0

5 Sep 2022

all points covered in response to reviewer letter

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PLoS One. doi: 10.1371/journal.pone.0282645.r003

Decision Letter 1

Richard John Lessells

12 Oct 2022

PONE-D-21-37215R1Clinical predictors of encephalitis in UK adults – a multi-centre prospective observational cohort studyPLOS ONE

Dear Dr. Defres,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================I would appreciate you addressing the two remaining issues raised by the reviewer - if addressed satisfactorily, I would hope we could move to acceptance.==============================

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Reviewer #1: (No Response)

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Reviewer #1: Partly

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Reviewer #1: Yes

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Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

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6. Review Comments to the Author

Reviewer #1: The authors have addressed most of the issues I raised. Unfortunately, I am not fully satisfied:

1.The authors comment to the reviewer, that indeed of 10 VGKC pos patients, only 5 were tested for LGI1 and none were positive. Therefore it is clearly misleading to label this group as VGKC/LGI1 patients, which implies positivity against LGI1. Referring to PMID: 32595134 from Sophia Michaels, Paddy Waters and Sarosh Irani, LGI1/CASPR2 negative VGKC findings are “more often misleading than not.”. Yet, the authors still introduce the term VGKC complex in the introduction and include this group which is – frankly – not appropriate anymore in 2022 even though the data and testing was done several years ago. And the lack of LGI1 positivity in the group tested for it (n=5) is not clearly stated in the manuscript. Unless there is serum for retesting available, I would suggest to include that entire group (n=10) into the possible AE (if they fulfill the critertia) but not in the definite group according to the Graus et al consensus paper.

2.The authors have clarified their testing strategy. Indeed all patients had NMDAR and GAD (and VGKC) testing and eventually patients were also tested for a panel of newer cell surface antibodies. To make this clear for readers, I would add the number of patients CSF and serum only tested with core testing and the ones tested with the extended panel (either during clinical routine or during re-testing of stored samples). This would make it easier to judge the fraction of idiopathic and possible cases that might contain undetected abs like cASPR2. Also please indicate the panel of “paraneoplastic” onconeural abs that were tested.

Minor comment: In figure 1 Panel Autoimmune: Iglon5 instead of IglonS, paraneoplastic (seronegative) cases

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PLoS One. 2023 Aug 23;18(8):e0282645. doi: 10.1371/journal.pone.0282645.r004

Author response to Decision Letter 1

11 Jan 2023

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PLoS One. doi: 10.1371/journal.pone.0282645.r005

Decision Letter 2

Rizaldy Taslim Pinzon

20 Feb 2023

Clinical predictors of encephalitis in UK adults – a multi-centre prospective observational cohort study

PONE-D-21-37215R2

Dear Dr. Defres

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Additional Editor Comments (optional):

This is a good study. There is novelty in this study. Thank you for your prompt reply and responses to the reviewer.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

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6. Review Comments to the Author

Reviewer #1: The reviewers have addressed all comments. I would recommend accepting the article. It is a relevant contribution to the field.

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PLoS One. doi: 10.1371/journal.pone.0282645.r006

Acceptance letter

Rizaldy Taslim Pinzon

10 May 2023

PONE-D-21-37215R2

Clinical predictors of encephalitis in UK adults – a multi-centre prospective observational cohort study

Dear Dr. Defres:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Multivariate logistic regression model with selected variables for autoimmune encephalitis (confirmed, probable and possible) versus other forms of encephalitis.

(DOCX)

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S2 Table. Presenting clinical features and outcomes of the autoantibody mediated forms of autoimmune encephalitis.

(DOCX)

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S1 Data

(XLSX)

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Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

[pone.0282645.ref001] 1.Venkatesan A, Michael BD, Probasco JC, Geocadin RG, Solomon T. Acute encephalitis in immunocompetent adults. Lancet 2019; 393: 702–16. doi: 10.1016/S0140-6736(18)32526-1 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref002] 2.Glaser CA, Honarmand S, Anderson LJ, et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clin Infect Dis 2006; 43: 1565–77. doi: 10.1086/509330 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref003] 3.Koskiniemi M, Rantalaiho T, Piiparinen H, et al. Infections of the central nervous system of suspected viral origin: a collaborative study from Finland. J Neurovirol 2001; 7: 400–8. doi: 10.1080/135502801753170255 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref004] 4.Mailles A, Stahl JP. Infectious encephalitis in france in 2007: a national prospective study. Clin Infect Dis 2009; 49: 1838–47. doi: 10.1086/648419 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref005] 5.Granerod J, Ambrose HE, Davies NW, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infectious Diseases 2010; 10: 835–44. doi: 10.1016/S1473-3099(10)70222-X [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref006] 6.Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 2010; 133: 1655–67. doi: 10.1093/brain/awq113 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref007] 7.Irani SR, Fukushima K, Yazaki M, Vincent A. Limbic encephalitis: under-recognition of voltage-gated potassium channel antibodies. Eur Neurol 2007; 58: 184. doi: 10.1159/000104722 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref008] 8.Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti NMDAR encephalitis. Lancet Neurology 2011; 10: 63–74. doi: 10.1016/S1474-4422(10)70253-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref009] 9.Graus F, Saiz A, Dalmau J. GAD antibodies in neurological disorders—insights and challenges. Nat Rev Neurol 2020; 16: 353–65. doi: 10.1038/s41582-020-0359-x [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref010] 10.Raschilas F, Wolff M, Delatour F, et al. Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 2002; 35: 254–60. doi: 10.1086/341405 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref011] 11.Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12: 157–65. doi: 10.1016/S1474-4422(12)70310-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref012] 12.de Ory F, Avellon A, Echevarria JE, et al. Viral infections of the central nervous system in Spain: a prospective study. J Med Virol 2013; 85: 554–62. doi: 10.1002/jmv.23470 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref013] 13.Hamid JS, Meaney C, Crowcroft NS, Granerod J, Beyene J. Cluster analysis for identifying sub-groups and selecting potential discriminatory variables in human encephalitis. BMC Infect Dis 2010; 10: 364. doi: 10.1186/1471-2334-10-364 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref014] 14.Lee TC, Tsai CP, Yuan CL, et al. Encephalitis in Taiwan: a prospective hospital-based study. Jpn J Infect Dis 2003; 56: 193–9. [PubMed] [Google Scholar]

[pone.0282645.ref015] 15.Cooper J, Kierans C, Defres S, Easton A, Kneen R, Solomon T. Diagnostic Pathways as Social and Participatory Practices: The Case of Herpes Simplex Encephalitis. PLoS One 2016; 11: e0151145. doi: 10.1371/journal.pone.0151145 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref016] 16.Michael BD, Sidhu M, Stoeter D, et al. Acute central nervous system infections in adults—a retrospective cohort study in the NHS North West region. Qjm 2010; 103: 749–58. doi: 10.1093/qjmed/hcq121 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref017] 17.Solomon T, Michael BD, Smith PE, et al. Management of suspected viral encephalitis in adults—Association of British Neurologists and British Infection Association National Guidelines. J Infect 2012; 64: 347–73. doi: 10.1016/j.jinf.2011.11.014 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref018] 18.Public Health England. UK Standards for Microbiology Investigations: Investigation of Viral Encephalitis and Meningitis. Public Health England: UK Standards for Microbiology Investigations: Investigation of Viral Encephalitis and Meningitis, 2014. (accessed. [Google Scholar]

[pone.0282645.ref019] 19.Irani SR, Gelfand JM, Al-Diwani A, Vincent A. Cell-surface central nervous system autoantibodies: clinical relevance and emerging paradigms. Ann Neurol 2014; 76: 168–84. doi: 10.1002/ana.24200 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref020] 20.Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 2013; 80: 1430–8. doi: 10.1212/WNL.0b013e31828c2fa1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref021] 21.Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis 2013; 57: 1114–28. doi: 10.1093/cid/cit458 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref022] 22.Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15: 391–404. doi: 10.1016/S1474-4422(15)00401-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref023] 23.Team RC. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL http://www.R-project.org/. 2013. [Google Scholar]

[pone.0282645.ref024] 24.Granerod J, Cousens S, Davies NW, Crowcroft NS, Thomas SL. New estimates of incidence of encephalitis in England. Emerg Infect Dis 2013; 19. doi: 10.3201/eid1909.130064 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref025] 25.McGrath N, Anderson NE, Croxson MC, Powell KF. Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome. J Neurol Neurosurg Psychiatry 1997; 63: 321–6. doi: 10.1136/jnnp.63.3.321 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref026] 26.Backman R, Foy R, Diggle PJ, et al. A pragmatic cluster randomised controlled trial of a tailored intervention to improve the initial management of suspected encephalitis. PLoS One 2018; 13: e0202257. doi: 10.1371/journal.pone.0202257 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref027] 27.Easton A. Increasing understanding of encephalitis. Lancet Neurol 2018; 17: 301. doi: 10.1016/S1474-4422(18)30077-2 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref028] 28.Wilken M, Ameghino L, Cammarota A, Nogues MA, Del Castillo M, Farez MF. Clinical and cerebrospinal fluid findings contribute to the early differentiation between infectious and noninfectious encephalitis. Medicina (B Aires) 2017; 77: 214–21. [PubMed] [Google Scholar]

[pone.0282645.ref029] 29.Basaran S YS, Bali EA, Cagatay A, Oncul O, Ozsut H, Eraksoy H. Hyponatremia Is Predictive of HSV-1 Encephalitis among Patients with Viral Encephalitis. Tohoku J Exp Med 2019; 247: 189–95. doi: 10.1620/tjem.247.189 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref030] 30.Huang CN, Tian XB, Jiang SM, et al. Comparisons Between Infectious and Autoimmune Encephalitis: Clinical Signs, Biochemistry, Blood Counts, and Imaging Findings. Neuropsychiatr Dis Treat 2020; 16: 2649–60. doi: 10.2147/NDT.S274487 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref031] 31.Wagner JN, Kalev O, Sonnberger M, Krehan I, von Oertzen TJ. Evaluation of Clinical and Paraclinical Findings for the Differential Diagnosis of Autoimmune and Infectious Encephalitis. Front Neurol 2018; 9: 434. doi: 10.3389/fneur.2018.00434 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref032] 32.Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018; 83: 166–77. doi: 10.1002/ana.25131 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0282645.ref033] 33.Dalmau J, Armangue T, Planaguma J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol 2019; 18: 1045–57. doi: 10.1016/S1474-4422(19)30244-3 [DOI] [PubMed] [Google Scholar]

[pone.0282645.ref034] 34.Montojo MT, Petit-Pedrol M, Graus F, Dalmau J. Clinical spectrum and diagnostic value of antibodies against the potassium channel related protein complex. Neurologia 2015; 30: 295–301. doi: 10.1016/j.nrl.2013.12.007 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Clinical predictors of encephalitis in UK adults–A multi-centre prospective observational cohort study

Sylviane Defres

Kukatharmini Tharmaratnam

Benedict D Michael

Mark Ellul

Nicholas W S Davies

Ava Easton

Michael J Griffiths

Maneesh Bhojak

Kumar Das

Hayley Hardwick

Chris Cheyne

Rachel Kneen

Antonieta Medina-Lara

Anne Christine Salter

Nicholas J Beeching

Enitan Carrol

Angela Vincent

Marta Garcia-Finana

Tom Solomon

Roles

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Methods

Study population and design

Table 1. Inclusion and exclusion criteria for suspected encephalitis.

Aetiological testing

Methods for analysis

Table 2. Case definitions for types of encephalitis.

Results

Fig 1. Flow diagram of recruitment and classification of diagnoses.

Table 3. Presenting clinical features and outcomes for 233 patients with encephalitis.

HSV encephalitis

Table 4. Multivariate logistic regression model with selected variables for HSV encephalitis vs other forms of encephalitis.

Autoimmune encephalitis

Table 5. Multivariate logistic regression model with selected variables for autoimmune encephalitis (confirmed or probable) versus other forms of encephalitis.

Treatment and outcomes

Fig 2. Glasgow outcome scale scores at discharge and at 12 months after discharge for all 233 patients with encephalitis, 64 with HSV encephalitis and 38 with autoimmune encephalitis.

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Thomas Tischer

Roles

Author response to Decision Letter 0

Decision Letter 1

Richard John Lessells

Roles

Author response to Decision Letter 1

Decision Letter 2

Rizaldy Taslim Pinzon

Roles

Acceptance letter

Rizaldy Taslim Pinzon

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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