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Journal of the Neurological Sciences
journal homepage:www.elsevier.com/locate/jns
Electrophysiological features and prognosis of Guillain-Barré syndrome in Israel: A single-center's 20 years' experience
Gilad Kenan
a, Mark Kushnir
a, Yuval Leonov
b,1, Eduard Ilgiyaev
b, Rina Aroesty
a, Sarah Bhonkar
a, Itzhak Kimiagar
a,2, Carmel Armon
a,⁎,2aDepartments of Neurology, Tel Aviv University Sackler Faculty of Medicine and Shamir (Assaf Harofeh) Medical Center, Israel
bDepartments of Intensive Care, Tel Aviv University Sackler Faculty of Medicine and Shamir (Assaf Harofeh) Medical Center, Israel
A R T I C L E I N F O
Keywords:
GBS Axonal variant Demyelinating variant Outcomes
IVIg safety
A B S T R A C T
Introduction:We previously reported on 40 patients with Guillain-Barré syndrome (GBS) identified 1999–2005 at our center, and showed that a higher proportion had an axonal pattern, compared to Europe and North America.
Methods:Retrospective chart review of 100 adult patients with GBS between 2006 and 2018 at Shamir Medical Center.
Results:46.8% of those with an abnormal EMG had an axonal pattern. Of the 60 patients who presented with mild disease (defined as Hughes score 1–2), walking deteriorated in 35 (58%, considering any worsening of Hughes score). 20 patients (33%) lost the ability to walk independently (Hughes score 3), 8 reached a point they could not walk (Hughes 4), and 2 needed mechanical ventilation.
Ninety-four of 100 patients (94%) were treated with intravenous immunoglobulins (IVIg). Using ECG mon- itoring and DVT prophylaxis, IVIg-related adverse reactions were rare.
Conclusions:This study demonstrated a higher proportion of axonal GBS patients in Israel, compared to European and North American patients, replicating thefindings in the 1999–2005 patients. Due to the pro- gressive nature of the disease, with more than half of patients presenting with mild disease deteriorating and needing inpatient rehabilitation - we advocate initiation of treatment once a clinical diagnosis of GBS is made.
1. Introduction
Guillain-Barré syndrome (GBS) is a common cause of acute pro- gressive flaccid paralysis, with about 100,000 people developing the disorder every year worldwide [1–3]. Originally, GBS was considered a single disorder, however it is now recognized as a heterogeneous syn- drome with several variants. The main forms are acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and acute sensorimotor axonal neuropathy (AMSAN). Each form has unique clinical, pathological and pathophy- siological features [4,5].
The proportion of different forms varies by region [6]. In Europe and North America, the demyelinating form accounts for up to 90% of
cases and the axonal form accounts for less than 10% [5,7], whereas in China [8], Japan [9] and Israel [10] the frequency of the axonal sub- type ranges from 30% to 65%. The explanation for this may be differ- ences in antecedent infection (precipitating antigen) or different im- munological reactions to infectious agents, resulting in production of antibodies to different epitopes on peripheral nerve [5].
The clinical spectrum ranges from mild symptoms to severe, rapidly- progressing weakness with life threatening consequences [11]. In some reports, up to 25% of patients require mechanical ventilation, and be- tween 3.5% - 12% of patients die of complications during the acute phase [12]. Recovery takes several weeks or months. Many patients have persistent fatigue, 12% require assistance to walk one year after onset and 62% report that their lives are impacted three to six years
https://doi.org/10.1016/j.jns.2020.117074
Received 26 May 2020; Received in revised form 4 July 2020; Accepted 29 July 2020
Abbreviations:AIDP, Acute inflammatory demyelinating polyradiculoneuropathy; AMAN, Acute motor axonal neuropathy; AMSAN, Acute motor and sensory axonal neuropathy; DVT, Deep vein thrombosis; GBS, Guillain-Barré syndrome; IVIg, Intravenous immunoglobulins; NCS, Nerve conduction studies; PE, Pulmonary embolism; SMC, Shamir Medical Center
⁎Corresponding author at: Department of Neurology, Shamir (Assaf Harofeh) Medical Center, PO Beer Yaakov, Zerifin 70300, Israel.
E-mail address:[email protected](C. Armon).
1Deceased.
2Joint senior authors.
Available online 01 August 2020
0022-510X/ © 2020 Elsevier B.V. All rights reserved.
T
later [13].
Shamir (Assaf Harofeh) Medical Center (SMC) is a 900-bed tertiary teaching hospital of Tel Aviv University Sackler School of Medicine. It has a multi-ethnic catchment area with a population of about 700,000 people.
In 2008, Kushnir et al. [10] published their experience with GBS patients at SMC between 1999 and 2005. They demonstrated over-re- presentation of axonal GBS in Israel, compared to Europe and North America. In the present study, we sought to extend these observations to see if they replicated, by reviewing records of all GBS patients ad- mitted to SMC between 2006 and 2018. We compared ourfindings to the earlierfindings, and, combining the data, summarize 20 years' ex- perience with GBS in our hospital, reporting the clinical features, epi- demiology, electrophysiology and outcomes of patients, as well as temporal trends. During the 20 years covered, there was a shift in practice, towards initiating treatment earlier in the course of the dis- ease, without waiting for patients to lose the ability to ambulate in- dependently. We report the number of patients impacted by this change, who were treated with mild disease (Hughes 1–2) [13] and their outcomes. Finally we report on the safety of IVIg treatment in our hands.
2. Methods 2.1. Patients
A retrospective computerized search of patient records from 2006 to 2018 was undertaken, using the diagnostic codes of GBS or acute polyneuritis. Patient charts were reviewed, to verify the diagnosis of GBS. All patients 18 years and older, with afirst occurrence of GBS were included. Patients were included based on clinical or electro- physiological criteria (see below).
10 patients were excluded: in 8- review of the medical record led to a non-GBS diagnosis, and 2 were patients transferred to or from our hospital, and complete details were not available.
We extracted information regarding age, sex, initial presentation, treatment decisions and disposition. The original NCS reports were reviewed and analyzed, classifying the disease into demyelinating or axonal (see below).
In the former study [10] only patients with EMG abnormalities supporting a diagnosis of GBS were included and treated. During the past few years (since 2013) we have treated patients based on clinical features (see below), even in the absence of supporting NCS abnorm- alities.
2.2. Clinical diagnostic criteria
Clinical criteria for the diagnosis of GBS were based on the Brighton Criteria [14]: a natural history compatible with the disease (progressive weakness, hyporeflexia, and a monophasic illness with progression of no more than four weeks), and the exclusion of a more likely alternative diagnosis.
2.3. Clinical neurophysiological diagnostic criteria
Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) was diagnosed in patients with electrophysiological signs of demyeli- nation in at least two motor nerves, such as: prolonged distal la- tency > 125% of the upper limit of normal; motor velocity slowing <
80% of the lower limit of normal; prolonged F-wave latency > 120% of the upper limit of normal; recording of a conduction block, defined as proximal/distal CMAP amplitude ratio < 50%; or abnormal temporal dispersion, defined as increased proximal CMAP duration by more than 15%. Axonal GBS was diagnosed in patients without evidence of de- myelination who had decreased CMAP amplitudes below 80% of the lower limit of normal in at least two nerves [15,16].
2.4. Statistical analysis
We compared the periods 1999–2005 (Kushnir et al. [10]), to 2006–2018, looking for trends. We compared distributions of demo- graphic features and clinical characteristics. We usedt-tests or z-tests to compare means and proportions, and chi-square to test differences of distributions of categorical attributes.P < 0.05 was considered sig- nificant.
2.5. Ethical approval
The study was approved by the SMC Institutional Review Board.
3. Results
3.1. Clinical and electrophysiological features (2006–2018)
Overall, 100 patients with GBS were treated between 2006 and 2018 at SMC. All patients met the Brighton criteria. 53 were women.
The average age was 50 years (range 18–84 years).
The presenting symptoms were pure motor (weakness or gait ab- normality) in 35%, pure sensory in 5% and both motor and sensory in 60%. 42% reported an antecedent infection (upper respiratory or gas- trointestinal infection).
The original NCS report could be retrieved and analyzed in 77 pa- tients. 62 of 77 patients (80%) had electrophysiological findings es- tablishing a diagnosis of GBS. Of these, 33 had demyelination, and 29 were axonal.Table 1compares the features of patients with demyeli- nating and axonal GBS, patients with normal NCS whose disease was established on clinical grounds, and patients whose original NCS were unavailable. Patients with normal NCS were younger, female, had milder disease and better outcomes, but the differences did not attain statistical significance. 3 of the 15 patients with normal NCS had the studies repeated. One remained normal when repeated later in the course of the disease, and two evolved into an axonal pattern.
Table 1
Electrophysiological characteristics of patients with GBS between 2006 and 2018.
Demyelinative Axonal Normal NCS Unavailable
N= 33 N= 29 N= 15 N= 23
Age M ± SD (range) 54.7 ± 16 (23–76) 50.5 ± 19 (20–84) 37.8 ± 13 (18–68) 53.4 ± 17 (19–81)
Men/women (% men) 22/11 (67%) 13/17 (43%) 3/13 (19%) 9/12 (43%)
Antecedent infection (%) 36% 50% 44% 38%
Rehabilitation (%) 76% 87% 25% 76%
Duration of hosp. (days) M ± SD 13.5 ± 6 13.2 ± 6 9 ± 3 13.1 ± 5
Onset: Hughes 1–2 64% 67% 81% 29%
Onset: Hughes 3–4 36% 33% 19% 71%
3.2. Comparison of clinical and electrophysiological features (1999–2005 and 2006–2018)
We compared the characteristics of the 62 patients with patholo- gical NCS seen 2006–2018, to the 40 patients reported previously [10]
(Table 2). While the demographic features were similar (age and sex distribution, rate of antecedent infection), there were mild changes in clinical features. In the second group (2006–2018), more patients pre- sented with mild disease, and more sensory complaints were docu- mented. All the apparent differences did not attain statistical sig- nificance. They likely reflect a lower threshold for diagnosing and treating GBS in the second period, including the decision to diagnose and treat patients with mild clinicalfindings and normal NCS.
There was no difference between the two periods in the percentage of patients with axonal features: 15/40 (37.5%) between 1999 and 2005, and 29/62 (46.8%) between 2006 and 2018 (p = not sig- nificant). The overall percentage of patients with axonal features was 44/102 (43.1%).
3.3. Treatment (2006–2018)
94 of 100 patients (94%) were treated with intravenous im- munoglobulins (IVIg). 4 patients were treated with plasmapheresis, and 2 had a mild course and did not receive mechanism-specific treatment.
2 patients died during hospitalization. A 74 year-old patient had a fatal cardiac arrhythmia after the third day of IVIg treatment. It might be attributed to the IVIg treatment itself or to autonomic instability seen prior to the event. A 78 year-old patient succumbed to pneumonia after prolonged ventilation.
One other serious treatment-emergent event required stopping IVIg treatment: confusion (1 patient). Mild adverse effects were chest dis- comfort (3 patients) and headache (2 patients). No cases of deep vein thrombosis (DVT) or pulmonary embolism (PE) were documented.
Mild side effects (headaches, fevers, shivering) were treated symp- tomatically and by slowing the infusion rate, or resolved spontaneously.
3.4. Course and discharge outcomes (2006–2018)
Of the 100 patients– 27 were discharged home, 71 required in- patient rehabilitation, and two died.
60 of the 100 patients presented with mild disease (Hughes dis- ability grade 1 or 2,Table 3), and 40 presented with moderate disease (Hughes 3 or 4,Table 3). Of the 60 with mild disease on presentation– walking deteriorated in 35 (58%, considering any worsening of Hughes score). 20 patients (33%) lost the ability to walk independently (Hughes score 3), 8 reached a point they could not walk (Hughes 4), and 2 needed mechanical ventilation. 35 patients (58%) required inpatient rehabilitation and 25 (42%) were discharged home.
Of the 40 patients presenting with moderate disability (Hughes score 3 and 4), 8 deteriorated to the point of requiring mechanical ventilation. 36 patients (90%) required inpatient rehabilitation, 2 were discharged home and 2 died.
4. Discussion
4.1. Epidemiology and electrophysiological features
Large retrospective studies and meta-analyses demonstrate con- siderable geographical variations in GBS epidemiology. Most of these studies rely on North American and European databases and may not necessarily apply elsewhere [17]. While most studies demonstrate Table 2
Electrophysiological and epidemiological features of patients with GBS and pathological NCS: 1999 to 2018 (N= 102).
1999–2005 2006–2018 TOTAL
AIDP Axonal AIDP Axonal AIDP Axonal
25 15 33 29 58 44
Age M ± SD (range) 47 (20–77) 53 (15–84) 54 ± 16 (20–76) 50 ± 20 (20–84) 51 (20–77) 51 (15–84)
Men/women (% men) 12/13 (48%) 8/7 (53%) 22/11 (67%) 12/17 (41%) 34/24 (58%) 20/24 (45%)
Antecedent infection (%) 14 (56%) 9 (60%) 12 (36%) 12 (41%) 26 (45%) 21(48%)
Presenting Symptoms:
Paresthesia 16 (64%) 4 (27%) 19 (57%) 17 (58%) 35 (60%) 21 (48%)
Weakness 7 (28%) 11 (73%) 32 (97%) 29 (100%) 39 (67%) 40 (91%)
Other 2 (8%) 0 0 0 0 0
Duration of hosp. (days) 13.7 16.8 13.5 ± 6 12.9 ± 5 13.6 13.9
Sensory disturbances 14 (56%) 7 (47%) 25 (76%) 20 (69%) 39 (67%) 27 (61%)
Motor disability at presentation
Hughes 1–2 16 2 21 19 37 21
Hughes 3–4 9 13 12 10 21 23
Hughes 5–6 0 0 0 0 0 0
Motor disability at nadir
Hughes 1–2 7 0 8 7 15 7
Hughes 3–4 14 13 19 20 33 33
Hughes 5–6 4 2 6 2 10 4
Disposition
Home NA NA 7 4 NA NA
Rehabilitation NA NA 25 25 NA NA
Died NA NA 1 0 NA NA
Table 3
Guillain-Barré syndrome disability scalea. 0 Healthy
1 Minor symptoms or signs, capable of manual work / running 2 Able to walk without support of a stick (5 m across an open space) but
incapable of manual work/running.
3 Able to walk with a stick, appliance or support (5 m across an open space).
4 Confined to bed or chair bound.
5 Requiring assisted ventilation (for any part of the day or night).
6 Death
a Hughes RAC, Swan AV VP. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Libr 2014.
higher incidence in men, our study found similar incidence for men (47%) and women (53%). Age distribution and severity on presentation is generally similar to those reported in other large studies [2,17].
The percentage of patients with antecedent infection is lower than that reported in the literature (two thirds) [18]. This may be due in part to incomplete ascertainment of history of antecedent infections. Two patients developed GBS after a vaccination.
Our study affirms the observation made previously by Kushnir et al., that the axonal pattern is more prevalent in Israel than in Europe and North America. The rate of axonal pattern in the present study (47%) is similar to what we reported previously (38%), and is similar to the rate described in large studies in China, Japan and South America [2,17].
The geographical variations of electrophysiological patterns in GBS have several possible explanations. Considering,first, nosological fac- tors: variability in definition of AIDP may influence the diagnosis, and no consensus has been achieved regarding electrodiagnostic differ- entiation between axonal GBS and AIDP [15,16,19,20]. Some studies classify the electrophysiological pattern not only as axonal or demye- linating, but add an“equivocal”or “mixed”type [7,16]. The Italian Guillain-Barré Study Group [7] classified 45% of NCS as a“mixed”NCS pattern.
Another circumstance is the case of an abnormal NCS that does not cross the threshold of a specific subtype, or displays only mild changes implying one type, only to emerge as a distinct pattern when repeated a few days later. Some studies have shown that serial NCS of the same patient may exhibit different electrophysiological patterns [16], sug- gesting that the timing of the NCS may have considerable influence on the results, but other studies suggest otherwise [19].
A likely explanation for the over-representation of the axonal GBS pattern in our patients is that different epitopes generate different im- mune responses [1,5]. This explanation is congruent with the current theory of post-infectious molecular mimicry, and may also explain seasonal variations. According to this explanation, heterogeneity in electrophysiological phenotypes may represent diversity in the primary target of the immune response against antigens presented by different elements of the peripheral nervous system: axon, myelin, node of Ranvier or paranodal regions. The dichotomous classification of GBS into axonal or demyelinating probably is an oversimplification of a spectrum of pathological processes. Even though there are currently no therapeutic implications, a better understanding of the underlying pa- thological process is essential both for disease classification and for developing novel therapeutic strategies.
4.2. Natural history of patients with mild disease
GBS is characterized by progressive weakness, and many patients present with mild weakness and deteriorate soon after. That 60% of our patients presented with mild neurological deficit probably reflects early arrival to the emergency department (ED) of patients who eventually developed severe disease, and their early recognition by the ED staff.
Most studies of treatments of GBS included only GBS patients with severe disease, meaning patients who could not walk unaided [13].
Therefore, current guidelines, published by the American Academy of Neurology (2003) [21] and the European Federation of Neurological Societies (2008) [22] suggest immunotherapy for GBS patients with impaired walking. In practice, some neurologists restrict treatment to those with severe disease, while others treat even those with mild disease, hoping to avoid deterioration. Randomized controlled trials comparing IVIg or plasmapheresis to placebo early in the course of the disease are lacking.
Studies that have tried to characterize the group of patients with mild GBS on admission, usually found that a significant proportion of patients deteriorated subsequently [23–25]. A large prospective study done in the Netherlands of mildly affected patients, defined as patients who were able to walk unaided at nadir, showed that this mild form was associated with being female and younger than 50 years old [24].
However, in our study the characteristics of patients presenting with mild disease were similar to those who could not walk unaided.
Early initiation of treatment with either IVIg or plasmapheresis, when motor deficits are still relatively mild, is supported by the ob- servation that more than half of patients with mild disease deteriorated and needed inpatient rehabilitation. Even though proof of improved outcomes with early intervention remains elusive, withholding treat- ment until a patient deteriorates defies social expectations for rapid intervention, especially in the light of the low rate of adverse effects.
Further studies are needed to provide definitive evidence supporting this approach.
4.3. Safety of IVIg in GBS patients
Two patients died during hospitalization: one had a fatal cardiac arrhythmia on the third day of treatment, and one developed pneu- monia after prolonged ventilation. Attribution, whether to disease or treatment, is uncertain. There was only one additional instance in which treatment had to be stopped due to a severe side effect (confu- sion). Since these events were rare, no trends or population char- acteristics could be inferred. We found no documented side effects at- tributable to a hypercoagulable state. We used thromboembolism prophylaxis in all bedridden and high-risk patients, and later in all patients treated with IVIg. It is possible that some adverse effects were not documented in the medical records especially if they were mild, resolved quickly and did not cause cessation of treatment.
5. Conclusions
This study affirms our previous observations [10] of the high pre- valence of the axonal form of GBS in Israel. Extending our reported experience to a full 20 years and 100 patients provides data regarding the robustness of our original observations, temporal trends, and safety.
Comparative studies may show if thesefindings are seen in other parts of the country. Some adverse effects occur when using IVIg, but serious life-threatening manifestations are rare, especially if cardiac monitoring and DVT prophylaxis are used.
Due to the progressive nature of the disease, with more than half of patients presenting with mild disease deteriorating and needing in- patient rehabilitation – we advocate initiation of treatment once a clinical diagnosis of GBS is made, even though data to establish the benefit of early intervention are lacking. We share the observation that more than 50% of patients deteriorate after treatment is initiated to help set patient expectations. GBS continues to be a challenging con- dition.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethical publication statement
We confirm that we have read the Journal's position on issues in- volved in ethical publication and affirm that this report is consistent with those guidelines.
Declaration of Competing Interest
None of the authors has any conflict of interest to disclose.
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