Fokke 2013 - Brighton Criteria GBS 2
Fokke 2013 - Brighton Criteria GBS 2
Fokke 2013 - Brighton Criteria GBS 2
BRAIN
A JOURNAL OF NEUROLOGY
1 Department of Neurology, Erasmus Medical Centre Rotterdam, Rotterdam, 3000 CA, The Netherlands
2 Department of Immunology, Erasmus Medical Centre Rotterdam, Rotterdam, 3000 CA, The Netherlands
3 Department of Neurology, University Medical Centre Groningen, Groningen, 9700 RB, The Netherlands
4 Department of Neurology, Gelre Hospitals location Apeldoorn, Apeldoorn, 7334 DZ, The Netherlands
5 Department of Neurology St. Elisabeth Hospital, Tilburg, 5022 GC, The Netherlands
6 Department of Clinical Neurophysiology, Erasmus Medical Centre Rotterdam, Rotterdam, 3000 CA, The Netherlands
Guillain-Barré syndrome is an acute polyradiculoneuropathy with a variable clinical presentation. Accurate diagnostic criteria are
essential for patient care and research, including clinical trials and vaccine safety studies. Several diagnostic criteria for Guillain-
Barré syndrome have been proposed, including the recent set by the Brighton Collaboration. In the present study we describe in
detail the key diagnostic features required to meet these Brighton criteria in a study population of 494 adult patients with
Guillain-Barré syndrome, previously included in therapeutic and observational studies. The patients had a median age of 53
years (interquartile range 36–66 years) and males slightly predominated (56%). All patients developed bilateral limb weakness
which generally involved both upper and lower extremities. The weakness remained restricted to the legs in 6% and to the arms
in 1% of the patients. Decreased reflexes in paretic arms or legs were found initially in 91% of patients and in all patients
during follow-up. Ten (2%) patients however showed persistence of normal reflexes in paretic arms. Disease nadir was reached
within 2 weeks in 80%, within 4 weeks in 97% and within 6 weeks in all patients. A monophasic disease course occurred in
95% of patients, of whom 10% had a treatment-related fluctuation. A clinical deterioration after 8 weeks of onset of weakness
occurred in 23 (5%) patients. Cerebrospinal fluid was examined in 474 (96%) patients. A mild pleocytosis (5 to 50 cells/kl) was
found in 15%, and none had more than 50 cells/kl. An increased cerebrospinal fluid protein concentration was found only in
64% of patients, highly dependent on the timing of the lumbar puncture after onset of weakness (49% at the first day to 88%
after 2 weeks). Nerve electrophysiology was compatible with the presence of a neuropathy in 99% of patients, but only 59%
fulfilled the current criteria for a distinct subtype of Guillain-Barré syndrome. Patients with a complete data set (335) were
classified according to the Brighton criteria, ranging from a high to a low level of diagnostic certainty, as level 1 in 61%, level 2
in 33%, level 3 in none, and level 4 in 6% of patients. Patients categorized in these levels did not differ with respect to
proportion of patients with preceding events, initial clinical manifestations or outcome. The observed variability in the key
diagnostic features of Guillain-Barré syndrome in the current cohort study, can be used to improve the sensitivity of the
diagnostic criteria.
Received May 22, 2013. Revised August 7, 2013. Accepted August 26, 2013. Advance Access publication October 26, 2013
ß The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
34 | Brain 2014: 137; 33–43 C. Fokke et al.
Table 1 Key diagnostic criteria and Brighton case definitions for Guillain-Barré syndrome
Belgium centres: AZ Sint-Jan Brugge-Oostende AV, Brugge (six inclusions) and Clinique Universitaire St Luc, Brussels, Belgium (10 inclusions); German centres: Medizinische Fakultät Charité, Berlin (13 inclusions) and Ruprecht-
Exclusion criteria in the therapeutic studies (1–3) were previous episodes of Guillain-Barré syndrome, allergic reactions to matched blood products, selective IgA deficiency, pregnancy, severe concurrent diseases, or expected
Stroke (NINDS) from 1990 (Asbury and Cornblath, 1990). Patients
36 other diagnosis
Excluded cases
participating in the therapeutic studies were unable to walk independ-
Five children
diagnosis
diagnosis
10 children
16 children
ently and were included within 2 weeks after onset of weakness. In
Four other
One other
One child
the observational study, patients with mild weakness at admission and
clinical variants were also included. For the purpose of this study, we
focused on adult patients with Guillain-Barré syndrome and limb
Week 1 and 4 weakness. We excluded patients 518 years of age (n = 32), because
Study entry,
53 weeks
Week 4 differ from adults (Bradshaw and Jones, 1992; Korinthenberg et al.,
Week 2
2007; Roodbol et al., 2011). In addition, we excluded patients with
NCS
Weekly during admission (n = 1), spinal disc herniation (n = 1), vasculitis (n = 1), sacral tumour
Week: 1–4: 1 /week
(or contraindications)
steroid treatment
steroid treatment
disability scale (Table 3), a widely accepted scale of disability for pa-
Age 5 16 year
Age 5 12 year
Age 5 4 year
Age 5 6 year
Inclusion criteria for all patients were fulfillment of diagnostic criteria for Guillain-Barré syndrome according to the NINDS.
sided versus the right-sided muscle groups. Nadir was defined as the
Inclusion criteriaa
55 Dutch centres
8 Dutch centres
1990–1992
1994–2000
2005–2008
(Pilot study)
IVIg and MP
the clinic where the patients were included. For 335 patients all ne-
147
225
170
25
Brighton criteria. Patients with missing data that could not be obtained
Observational
were left out of analysis regarding that particular part of data. Data
Open label
Table 2 Patient cohorts
RCT
RCT
Guillain-Barré
et al., 2004
c
36 | Brain 2014: 137; 33–43 C. Fokke et al.
Table 3 Guillain-Barré syndrome disability scale, adapted Table 4 Description of patients with Guillain-Barré
from Hughes et al. (1978) syndrome (n = 494)
Results
The demographic and general clinical characteristics of the 494
patients with Guillain-Barré syndrome are provided in Table 4.
Weakness restricted to the arms was found in three (1%) patients. recovery phase, secondary deteriorations were seen in 73 (15%)
Only one of these patients developed leg weakness later; the patients. In 50 (68%) of these patients the deterioration was re-
other two patients were diagnosed as a pharyngeal-cervical- garded to be a ‘treatment-related fluctuation’, which by definition
brachial variant of Guillain-Barré syndrome. In patients with a occurred within 8 weeks of start of treatment (Ruts et al., 2010a).
tetraparesis, the MRC sum scores expressing the weakness of Patients with a treatment-related fluctuation were considered to
severity in arms and legs were correlated (rs = 0.66, P = 0.01). have a monophasic disease course that was influenced by a tran-
sient effect of treatment. Therefore, in total 472 (95%) patients
had a monophasic disease course during the 6 months of follow-
Reflexes
up. The remaining 23 (5%) patients had clinical fluctuations more
Reflexes and strength were described in detail in 395 (80%) than 8 weeks after start of treatment. In those patients the time
patients for the arms and in 410 (83%) patients for the legs. At interval between onset of weakness and the relapse of muscle
study entry, normal reflexes in paretic limbs were observed in 36 weakness was highly variable with a median of 18 weeks (IQR
erythrocyte cell counts caused by a traumatic puncture was not Nerve conduction studies
recorded systematically. There was no relation between the cell
count and the timing of the lumbar puncture. Results of routine nerve conduction studies were available from
The classic ‘cytoalbuminologic dissociation’, defined as the com- 440 (89%) patients. The median time between onset of weakness
bination of an increased protein concentration and a cell count and these examinations was 13 days (IQR 8–18 days). Only four
550 cells/ml, was observed only in 290 (64%) of these 455 (1%) patients had a normal nerve electrophysiology (conducted at
patients. The proportion of patients with cytoalbuminologic dis- 2, 18, 19 and 30 days after onset of weakness). Patients with a
sociation was fully dependent on the protein concentration and normal EMG had significantly milder weakness at nadir (median
thereby timing of the lumbar puncture (Fig. 3), as no patient had a MRC sum score of 51, range 43–53) compared to patients with an
pleocytosis 450 cells/ml. abnormal nerve conduction study (P = 0.04). Acute inflammatory
Diagnosis of Guillain-Barré syndrome Brain 2014: 137; 33–43 | 39
demyelinating polyneuropathy was the predominant subtype, but and CSF and reflexes (n = 1). The remaining 335 patients were
only 213 (48%) patients fulfilled the specific diagnostic criteria for classified in four levels of diagnostic certainty according to the
a demyelinating polyneuropathy. An axonal polyneuropathy was Brighton criteria. Criteria for level 1 were met by 205 (61%) pa-
found in 27 (6%) patients and 16 (4%) patients had inexcitable tients, for level 2 by 111 (33%) as a result of the normal protein
nerves (Hadden et al., 1998). A subgroup of 180 (41%) patients concentration, for level 3 by none and for level 4 by 19 (6%)
showed an abnormal nerve electrophysiology compatible with per- patients because of a prolonged progressive phase (n = 6) or late
ipheral nerve (root) involvement, but did not fulfil the criteria for fluctuations that deviate from a monophasic disease course
one of the distinct subtypes (demyelinating, axonal, or inexcita- (n = 13) (Table 6). The patient groups in these various diagnostic
ble). The proportion of patients with these equivocal electrophysi- levels did not differ regarding: age, sex, severity of disease, pro-
ology findings decreased after 3 weeks of weakness onset (Fig. 4). portion of ventilator dependency or outcome at 6 months (defined
In the first two studies (between 1986 and 1992), serial nerve by Guillain-Barré syndrome disability score). Preceding upper re-
conduction studies were performed as part of the study protocol spiratory tract infections were seen in 68/203 (34%) of patients in
Figure 4 Classification of nerve electrophysiology subtypes in relation to timing of nerve conduction study after onset of weakness. The
proportions of patients with an equivocal result are given in percentages, indicating abnormal nerve conduction but not fulfilling the
criteria for one of the specific subtypes of Guillain-Barré syndrome. NCS = nerve conduction studies.
40 | Brain 2014: 137; 33–43 C. Fokke et al.
Table 6 Classification of patients with Guillain-Barré presentation not meeting the NINDS criteria may not have entered
syndrome according to the Brighton criteria the trials. The primary aim of the NINDS was to develop diagnos-
tic criteria for research purposes with a high specificity, not to
Brighton level Data All
complete patients capture all cases in clinical practice. On the other hand, the
(n = 335) (n = 494) NINDS criteria are not very strict in the sense that predefined
clinical features are categorized as ‘supporting the diagnosis’ or
Level 1 61% (205) 41% (205)
AIDP, axonal, inexitable 36% (120) 24% (120) ‘casting doubt on the diagnosis’ without specifying the decision
Equivocal NCS 25% (85) 17% (85) rules for inclusion or exclusion of individual patients. This explains
Level 2 33% (111) 36% (177) why a cohort with such a variety of clinical symptoms was
Normal NCS 0% (1) 0% (1) included.
Normal CSF protein concentration 33% (110) 25% (123) Since 1990 many studies showed the high variability of Guillain-
NCS missing 5% (24) Barré syndrome, including variants, ‘formes frustes’ and overlap
electrophysiological and CSF examination may be difficult, imprac- represent a ‘subacute’ variant of Guillain-Barré syndrome (Hughes
tical, or unavailable. This study emphasizes the fact that accurate et al., 1992). The duration of the plateau phase was equally vari-
and thorough documentation of clinical signs should allow for able: most patients start recovering within less than a week after
better classification of Guillain-Barré syndrome in both developed, reaching nadir, but 6 months follow-up without clear signs of
and in developing countries. In The Netherlands additional inves- recovery is still compatible with the diagnosis of Guillain-Barré
tigations such as CSF examination or serial nerve physiology may syndrome. All patients recovered at some stage, yet secondary
not be conducted routinely in clinical practice if alternative diag- deteriorations during the follow-up period were seen in 15% of
noses are not suspected. patients. Two-thirds of these patients (10%) had a typical treat-
The current study identified subgroups of patients with charac- ment related fluctuation, in which the secondary progression may
teristics that may be considered atypical for Guillain-Barré syn- be attributed to a transient effect of treatment that lasted shorter
drome, and may cause initial diagnostic confusion. One than the active disease phase (Kleyweg and van der Meché,
subgroup of 8% presented with a paraparesis of the legs, which 1991). One-third of deteriorations (5%), however, occurred 48
have prognostic relevance (Cornblath et al., 1988). Importantly, at Koningsveld, Liselotte Ruts, Nikki van Leeuwen, Carina
present there are no definite agreed-upon diagnostic electro- Bunschoten, and the patients participating in the studies. We
physiological criteria for the diagnosis of Guillain-Barré syndrome. also thank David C. Cornblath and James J. Sejvar for their valu-
All current electrophysiological criteria focus on the discrimination able comments on previous versions of the manuscript.
between axonal and demyelinating subtypes of Guillain-Barré syn-
drome. The subtyping of Guillain-Barré syndrome is complex as
(i) the electrophysiology examination requires high standards and
skills; (ii) various classification systems have been developed; and
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