Clinical presentation and outcome of Guillain–Barré and related syndromes in relation to anti-ganglioside antibodies

Journal of the Neurological Sciences 168 (1999) 78–84 www.elsevier.com / locate / jns

Clinical presentation and outcome of Guillain–Barre´ and related syndromes in relation to anti-ganglioside antibodies M. Carpo a , R. Pedotti a , S. Allaria a , F. Lolli b , S. Mata` b , G. Cavaletti c , A. Protti d , S. Pomati a , a a, G. Scarlato , E. Nobile-Orazio * a

‘ Giorgio Spagnol’ Service of Clinical Neuroimmunology, Centro Dino Ferrari, Institute of Clinical Neurology, IRCCS Ospedale Maggiore Policlinico, University of Milan, Via F. Sforza 35, 20122 Milan, Italy b Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy c Department of Neurology, ‘ San Gerardo’ Institute for Biomedical Sciences, University of Milan, Monza, Italy d Department of Neurology, Ospedale di Niguarda, Milan, Italy Received 28 July 1998; received in revised form 14 January 1999; accepted 28 January 1999

Abstract We correlated the clinical features of 78 patients with Guillain–Barre´ syndrome (GBS) or related variants, with the presence of serum antibodies to the gangliosides GM1, GM2, GD1a, GD1b and GQ1b in order to determine whether these antibodies may influence the clinical presentation or outcome of GBS. Sixty-three patients had typical GBS (81%), nine a pure motor form (11%), three a paraparetic form (4%), and three had Miller Fisher syndrome (MFS). IgG or IgM (or both) anti-ganglioside antibodies were found by ELISA in 37% of patients, including 36% with typical, 33% with pure motor and 100% with MFS. Beside the constant occurrence of anti-GQ1b antibodies in patients with MFS (P,0.00001), the other clinical forms were not associated with a specific anti-ganglioside reactivity. Anti-GM1 and anti-GD1a antibodies tended to be associated with a worse disability at 6 month than other or no reactivity and, similarly to anti-GM2 antibodies, with a more frequent respiratory impairment. Anti-GM2 and anti-GD1b antibodies were always associated with typical GBS and, in all but one patient, with a complete recovery; still they were found in only 13 and 3%, respectively, of the patients with this presentation. Anti-GQ1b antibodies, though always associated with ophthalmoplegia and ataxia in both MFS and GBS, were found in only 36 and 26%, respectively, of patients with these symptoms. Even if different anti-ganglioside antibodies tend to be associated with some clinical features possibly suggesting that they may influence the clinical presentation or outcome, with the exception of anti-GQ1b antibodies for ophthalmoplegia and ataxia, they do not permit to predict the clinical presentation or outcome in individual patients.  1999 Published by Elsevier Science B.V. All rights reserved. Keywords: Gangliosides; Antibodies; GQ1b; GM1; GM2; GD1a; Neuropathy; Guillain–Barre´ Syndrome; Miller–Fisher syndrome

1. Introduction The Guillain–Barre´ syndrome (GBS) is the most frequent cause of acute neuromuscular paralysis. Even if most affected patients have the typical presentation of an acute inflammatory demyelinating neuropathy [1], several patients have regionally or functionally restricted clinical *Corresponding author. Tel.: 139-02-5503-3836 / 4; fax: 139-02-55190392. E-mail address: [email protected] (E. Nobile-Orazio)

presentation [2] or evidence for an axonal neuropathy [3,4] broadening the boundaries of this syndrome. The pathogenesis of GBS and related syndromes is still unknown but an autoimmune-mediated mechanism, possibly triggered by an infectious agent sharing epitope / s with neural antigens (molecular mimicry), has been proposed. Antibodies against different gangliosides including GM1, GD1a, GT1a, GM2, GQ1b have been reported in a variable proportion of GBS patients and their decrease during clinical improvement supports a possible pathogenetic role in the neuropathy [5–8]. These antibodies have been often

0022-510X / 99 / $ – see front matter  1999 Published by Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00173-2

M. Carpo et al. / Journal of the Neurological Sciences 168 (1999) 78 – 84

correlated with different clinical or electrophysiological features of GBS: high anti-GM1 [5,9–15], and, though less frequently, anti-GD1a antibodies [16,17] have been associated with an antecedent Campylobacter jejuni (CJ) infection, prevalent motor and axonal impairment and poor prognosis; anti-GM2 antibodies with an antecedent cytomegalovirus (CMV) infection, severe sensory–motor impairment, frequent respiratory impairment and demyelinating features [18,19]; anti-GQ1b antibodies with ophthalmoplegia and ataxia in GBS and MFS [20–24]. These associations have not been however always confirmed and it is therefore unclear whether these antibodies may indeed influence, if not determine, the clinical presentation or outcome or both in these patients a finding that might support their pathogenetic relevance in GBS.

2. Materials and methods

2.1. Patients We studied 78 patients with GBS or related syndromes admitted from 1984 to 1996 in our Hospitals, mostly in Neurological Departments, whose sera were tested in our laboratory for anti-ganglioside antibodies. Before inclusion in the study, the clinical and electrophysiological features of all the patients were reviewed by two of us (MC and RP). Sera from all patients had been collected during the acute phase of the disease and before any treatment. The diagnosis of GBS was established according to currently accepted clinical criteria [1]. Atypical forms of GBS were classified according to the clinical diagnostic criteria proposed by Ropper [2], based on the presence of only sensory, only motor or only autonomic signs (functional variants) or weakness confined to a distinct district (regional variants). From all patients the following data were collected: name, age, sex of the patient; presence and type of antecedent infection; time and duration of maximal worsening; type and severity of neuropathy symptoms and signs. The severity of neuropathy at maximal worsening and at 6 month was graded according to the functional scale proposed by Hughes et al. [25]: 05healthy; 15minor signs or symptoms of neuropathy but capable of manual work; 25able to walk without support of a stick but incapable of manual work; 35able to walk with a stick, appliance, or support; 45confined to bed or chairbound; 55requiring assisted ventilation, and 65dead. Being a retrospective study, electrophysiological studies were not performed according to a standardized protocol or at the same time from the onset of symptoms. Nevertheless in all patients motor conduction velocities (MCV) and distal and proximal compound muscle action potentials (CMAP) amplitude were measured in the median and peroneal nerves within 4 weeks from the onset using surface electrodes.

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2.2. ELISA for anti-ganglioside antibodies Anti-GM1, -GM2, -GD1a, -GD1b, and -GQ1b IgG and IgM antibodies were measured by enzyme-linked immunosorbent assay (ELISA) following previously reported procedures [24,26,27]. Briefly, 1 mg / well of purified GM1, GM2, GD1a, GD1b, and GQ1b (Sigma, USA) in ethanol was added to microtitration plates (Costar, USA) until complete evaporation. Plates were saturated with 1% bovine serum albumin (BSA) (Sigma) in phosphate-buffered saline, pH 7.4 (PBS-saturating solution) for 4 h at 48C. Patients’ sera were added in duplicate to the wells at the initial dilution of 1 / 320 for anti-GM1, -GD1a, -GD1b and -GM2 and 1 / 100 for anti-GQ1b in saturating solution and incubated overnight. IgM and IgG binding was detected using peroxidase-conjugated goat anti-human IgM or IgG, respectively (Cappel, USA). All incubations were carried out at 48C and detergent was omitted in all solutions. Sera were considered positive when the difference between GM1-, GD1a-, GD1b-, GM2-, GQ1b-coated wells and BSA-coated wells exceeded 0.05. Positive sera were titrated by serial twofold dilutions until negative. The upper normal limit for anti-GM1 (1 / 640), GD1a (1320) and GQ1b (1 / 100) IgG and IgM antibodies and for antiGD1b IgM antibodies (1 / 320) were previously established [8,24,26,27]. The upper normal limit for anti-GM2 IgG and IgM and anti-GD1b IgM antibodies (1 / 320) were calculated in 141 control patients, including 46 with other neuropathies, 46 with other neurological diseases (motor neuron disease, multiple sclerosis, stroke, dementia, epilepsy etc.), 23 with other immunological diseases (myasthenia gravis, polymiosites, dermatomiosites, lupus, Sjogren syndrome etc.) and 26 normal subjects.

2.3. Immunostaining after high-performance thin-layer chromatography ( HPTLC) In all positive patients antibody reactivities by ELISA were confirmed by immunostaining after HPTLC [28] of the purified gangliosides (0.5 mg / lane, each) (Sigma) on aluminum-backed silica gel 60 HPTLC plates (Merck, Germany). Patients sera were tested at 1 / 100 dilution and counterstained with peroxidase-conjugated rabbit immunoglobulins to human IgG or IgM (Dako, Denmark).

2.4. Anti-Campylobacter jejuni antibodies Anti-CJ antibodies were measured in 39 patients by complement fixation assay at Fleming Laboratory (Milan, Italy) following manufacturer’s instruction (Virion, Switzerland).

2.5. Statistics All statistical analyses were performed using a computer software package (SPSS). Comparisons among groups

M. Carpo et al. / Journal of the Neurological Sciences 168 (1999) 78 – 84

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were made using chi-square analysis for categorical responses an one-way analysis of variance (ANOVA) for continuous measures. A significance value of P,0.05 was used for all comparisons.

3. Results According to previously described criteria, 63 patients (83%) fulfilled the clinical criteria for GBS (typical GBS), nine (11%) had a purely motor impairment (pure motor form), three (4%) an exclusive impairment of the lower limbs (paraparetic form) and three (4%) had MFS (Table 1). High titer of anti-gangliosides antibodies were found in 29 (37%) patients including 12 with anti-GM1 (15%) (four IgM, seven IgG and one both), eight with anti-GM2 (10%) (three IgM, two IgG and three both), five with IgG antiGQ1b (6%), and two each with IgG anti-GD1a and antiGD1b (one IgM and one IgG) (3% both) antibodies. No statistically significant difference in the demographic characteristics, antecedent events and outcome of patients (Table 1) were found in relation to the clinical presentation. Patients with the paraparetic form tended however to have an older age and worse recovery than patients in the other groups, whereas all patients with MFS, though severely impaired at nadir because of ataxia, had a complete functional recovery at 6 month. An upper respiratory infection was the most frequent antecedent event in all patients group while only six patients (7.6%),

all with typical GBS, had an antecedent gastrointestinal infection. Anti-CJ antibodies where found in 26% of the patients and, though not specifically associated with any clinical presentation, were more frequently found in patients with the purely motor or paraparetic forms (50% in both group) than with the typical form (19%). Beside the constant occurrence of anti-GQ1b antibodies in patients with MFS (P,0.00001; x 2 538.3), the other clinical forms were not associated with a specific antiganglioside reactivity (Table 1). When we analyzed however the presence of anti-ganglioside antibodies in relation to individual clinical signs (Table 2), we found that patients with ophthalmoplegia and respiratory failure had an higher frequency of anti-ganglioside antibodies (57 and 60%, respectively) than patients without these signs (25 and 34%) (Table 2). These differences were mainly related to the increased frequency of anti-GQ1b antibodies in ophthalmoplegia (36 vs. 0% in those without it) and of anti-GM1, GM2 and GD1a antibodies in those with respiratory failure. On the other hand the frequency of anti-ganglioside antibodies in patients with dysautonomia (20%) was approximately one half of that in patients without it (39.7%). None of these difference reached however a level of significance. In Table 3 are summarized the demographic and clinical features of the patients in relation to anti-ganglioside antibodies. Patients with anti-GM1 and GD1a antibodies tended to have a worse median disability at 6 month than patients with other or no reactivity, with only one third of

Table 1 Demographic characteristics, antecedent events and immunological findings in relation to clinical presentation Total patients

Typical GBS

Pure motor

Paraparetic

MFS

No. of patients Mean age (range) Sex ( M /F)

78 49 (16–80) 48 / 30

63 48 (17–80) 38 / 25

9 52 (17–74) 6/3

3 63 (60–67) 2/1

3 44 (26–56) 2/1

Antecedent events URTI b Gastroenteritis Other Anti-CJ antibodies

55% 31 6 6 26% (10 / 39)

55% 25 6 4 19% (6 / 31)

55% 4 – 1 50% (3 / 6)

67% 1 – 1 50% (1 / 2)

33% 1 – – nd

Total anti-ganglioside antibodies Anti-GM1 Anti-GM2 Anti-GD1a Anti-GD1b Anti-GQ1b

37% (29) 15% (12) 10% (8) 3% (2) 3% (2) 6% (5)

37% (23) 16% (10) 13% (8) 2% (1) 3% (2) 3% (2)

33% (3) 22% (2) – 11% (1) – –

– – – – – –

100% (3) – – – – 100% (3)a

4 1.5 64% (45 / 70)

3 1 66% (37 / 56)

4 1 50% (4 / 8)

3 2 33% (1 / 3)

4 1 100% (3 / 3)

Disability At nadir (median) At 6 months (median) Grade #1 a b

x 2 538.3; P,0.00001. Upper respiratory tract infection.

M. Carpo et al. / Journal of the Neurological Sciences 168 (1999) 78 – 84

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Table 2 Frequency and type of anti-ganglioside antibodies in relation to clinical signs a Total patients

Limb weakness

Ophthalmoplegia

Other cranial nerve inv.

Deep sensory loss

Ataxia

Dysautonomia

Respiratory failure

No. of patients

78 (100%)

75 (96%)

14 (18%)

36 (46%)

23 / 72 (32%)

19 / 59 (32%)

10 (13%)

10 (13%)

% with anti-ganglioside antibodies Anti-GM2 Anti-GM1 Anti-GD1a Anti-GD1b Anti-GQ1b

37

35

57

36

39

42

20

60

10 15 3 3 6

11 16 3 3 3

7 7 7 36

11 11 3 3 8

4 17 4 – 13

10 5 – – 26

– 10 – 10 –

20 30 10 – –

Negatives (%)

63

65

43

64

61

58

80

40

a

–

No significant difference found by x 2 -test, for each clinical sign.

Table 3 Clinical and prognostic features in patients with GBS and related syndromes in relation to anti-ganglioside antibodies Anti-GM1 $1 / 1280

Anti-GM2 $1 / 1280

Anti-GD1a $1 / 1280

Anti-GD1b $1 / 1280

Anti-GQ1b $1 / 200

Negatives

Total patients Age (mean) Sex ( M /F)

12 49.8 9/3

8 36.8 3/5

2 56.5 0/2

2 27 2/0

5 43 4/1

49 52.3 29 / 20

Antecedent events URTI c Gastroenteritis Other CJ antibodies

5 (42%) 1 2 2 (parenteral gangliosides) 5 / 7 (71%)

4 / 7 (57%) 1 1 2 0/4

2 (100%) 2 – – 1 / 2 (50%)

1 (50%) 1 – – 0/1

3 (60%) 3 – – n.d.

29 (59%) 23 3 3 4 / 25 (16%)

GBS forms Typical Pure motor Paraparetic Miller Fisher

10 (83%) 2 (17%) – –

8 (100%) – – –

1 (50%) 1 (50%) – –

2 (100%) – – –

2 (40%) – – 3 (60%)

40 (82%) 6 (12%) 3 (6%) –

Clinical signs Weakness Pain / paresthesias Ophthalmoplegia Other cranial nerves Deep sensory loss Ataxia Dysautonomia Respiratory failure

12 (100%) 9 (75%) – 4 (33%) 4 (33%) 1 / 9 (11%) 1 (8%) 3 (25%)

8 (100%) 7 (100%)* 1 (12%) 4 (50%) 1 / 7 (14%) 2 / 6 (33%) – 2 (25%)

2 (100%) – 1 (50%) 1 (50%) 1 (50%) 0/1 – 1 (50%)

2 2 1 1 – – 1 –

2 3 5 3 3 5 – –

49 (100%) 35 (71%) 6 (12%) 23 (47%) 14 / 44 (31%) 11 / 36 (31%) 8 (16%) 4 (8%)

Disability At nadir (median) At 6 months (median) Grade #1 a

4 2 4 (33%)

4 1 5 (63%)

4 2.5 1 (50%)

3 0 2 (100%)

4 1 4 (80%)

3 1 25 / 41 (61%)

56.4 6.2 4 / 11 (36%) 3 / 11 (27%)

42.9 6.8 2 / 7 (29%) 1 / 7 (14%)

41.9 4.8 1 (50%) –

52 4.7 – –

55.3 10.7 – –

44.9 5.4 18 (41%) 1 (2%)

36.9 3.7 4 / 11 (36%) 2 / 11 (18%)

34.7 3.1 2.8 (25%) 1 / 8 (13%)

39.7 2.4 – –

40.4 1.6 1 (50%) –

46.5 5.4 – –

34.9 3.4 17 (36%) 5 (11%)

Motor conduction studies Median nerve Mean MCV (m / s) Mean CMAP (amp mV) (No. with ,4 mV) (No response) Peroneal nerve Mean MCV (m / s) Mean CMAP (amp mV) (No. with ,2 mV) (No response) a

x 2 529.51 (P,0.00005). x 2 513.29 (P,0.05); (GQ1b1 vs. GQ1b2). c Upper respiratory tract infection. b

(100%) (100%) (50%) (50%)

(50%)

(40%) (60%) (100%)a (60%) (60%) (100%)b

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patients with anti-GM1 antibodies reaching a complete autonomy (grade #1) at 6 months as compared to approximately one half of those with anti-GM2, GD1a or no antibodies and all but one patient with anti-GD1b or GQ1b antibodies (Table 3). Anti-GM2 and anti-GD1b antibodies were always associated with typical GBS (Table 3) although they were only found in 13 and 3%, respectively, of the patients with this presentation. Anti-GQ1b antibodies were always associated with ophthalmoplegia and ataxia (P,0.00005 and P,0.05, respectively) both in MFS and GBS (Table 3). Still, only 36% of those with ophthalmoplegia and 26% with ataxia had these antibodies (Table 2).

4. Discussion We reviewed the clinical, immunological and prognostic features of 78 patients with GBS and related variants in relation to anti-ganglioside antibodies. Similarly to two previously reported series [29,30] even if typical GBS was the most frequent clinical presentation in our population, almost 20% of patients had a functionally or regionally restricted variant including the purely motor or paraparetic form of GBS or MFS (Table 4). Beside the lower incidence of respiratory impairment in our patients (13 vs. 30 and 24%), probably reflecting the referral of most of them from Neurology Departments and only few from Intensive Care Units, the frequency of other symptoms and signs in our series was similar to that of previously reported series indicating that our population was representative of a ‘neurological’ GBS population. Similarly, the overall frequency of anti-gangliosides antibodies in our population (37%) was similar to previously reported series [7,8,12,15,31–33] with anti-GM1 IgG being the most frequently found antibodies (15%), followed by anti-GM2

(10%), anti-GQ1b (6%), and anti-GD1a and anti-GD1b (3% each) antibodies. As in most previous series [13,14,33–35], anti-CJ antibodies were detected in 26% of our tested patients (50% of total). This reactivity only occasionally correlated with an antecedent gastrointestinal infection. Since however stool cultures were not available to confirm CJ infection, it is not possible to exclude that, at least in some patients, these antibodies merely reflected a cross-reactivity between anti-CJ and anti-GM1 antibodies [11], possibly explaining their higher frequency in patients with anti-GM1 than with other or no anti-ganglioside antibodies (Table 3). For this reason we decided not to perform any correlation with this reactivity. When we analyzed the clinical presentation and signs of our patients in relation to anti-ganglioside antibodies, we found that only MFS, ophtalmoplegia and ataxia were significantly associated with anti-GQ1b confirming the previously reported data on these associations. High titers of anti-GQ1b IgG antibodies were indeed reported in 80 to 100% of patients with MFS [20–23] as well as in some patients with GBS with ophthalmoplegia [21], Bickerstaff’s brain stem encephalitis [36] or acute ophthalmoparesis [37]. The frequent association of these antibodies with diseases characterized by oculomotor impairment was correlated with the abundant expression of GQ1b in the paranodal regions of the extramedullary portion of the oculomotor nerves [21], while ataxia in MFS and GBS was related to a selective staining of the cerebellar molecular layer by IgG from patients with high anti-GQ1b IgG [38]. If however anti-GQ1b antibodies in our series were always associated with ophthalmoplegia and ataxia in either MFS and GBS, these antibodies were only found in 36 and 26%, respectively, of patients with these signs, so that in the majority of patients these signs could not be attributed to anti-GQ1b antibodies, leaving it unclear the mechanisms underlying these signs in most of them.

Table 4 Frequency of clinical features and variants in different series of GBS patients Our series

Ropper [29]

Beghi et al. [30]

No. of patients

78

a

109

Symptoms and signs (%) Paresthesias Ophthalmoparesis Other cranial nerves Sensory loss Ataxia Respiratory failure Dysautonomic signs

72 18 46 46 (36) 32 13 13

85 15 nm b 75 15 30 5

– nm b nm b 49 – 24 14

GBS forms Typical Pure motor Paraparetic Miller Fisher

81 11 4 4

85 3 2 5

87 0 1 5

a b

Figures derived from previous large series and personal experience. nm, not mentioned.

M. Carpo et al. / Journal of the Neurological Sciences 168 (1999) 78 – 84

None of the other anti-ganglioside reactivities was significantly associated with any clinical presentation or, vice versa, none of the clinical presentation of GBS or clinical sign correlated with a specific anti-ganglioside reactivity. There were however some associations that, though not significant, are consistent with previously reported correlations. Anti-GM1 and anti-GD1a antibodies tended to be associated with a worse prognosis compared to other or no reactivity and, together with anti-GM2 antibodies, with an higher frequency of respiratory impairment. Even if we did not find an association between anti-GM1 or anti-GD1a antibodies and a pure motor form, these antibodies tended to be more frequent in patients with this presentation We also did not find an association between these reactivities and electrophysiological findings consistent with an axonal impairment. Since however this was a retrospective study, no conclusion can be drawn due to the lack of uniformly and serially performed studies in these patients. It is possible however that the worse recovery observed in patients with anti-GM1 antibodies, after a similar maximal impairment, reflects the presence of an axonal impairment. Similarly to recent reports, anti-GM2 antibodies were always associated with a typical GBS, possibly with more frequent sensory symptoms and respiratory impairment then observed in negative patients, but with superimposable electrophysiological studies. Also in this case however, anti-GM2 antibodies, though always associated with typical GBS, were only found in a minority of them suggesting that these antibodies may at the most influence this clinical presentation in a minority of patients. Even if we did not investigate the association with an antecedent CMV infection, only one of these patients had a clinically manifest antecedent event possibly related with CMV infection. The small number of patients with anti-GD1a and GD1b antibodies do not permit to draw any conclusion on the clinical correlate of these reactivities even if they tended to be similar to those of anti-GM1 and anti GM2 antibodies, respectively. From a prognostic point of view, even if this study seems to confirm previously reported associations, with MFS, high anti-GQ1b or anti-GD1b antibodies associated with a better prognosis and the paraparetic form and anti-GM1 antibodies with a poorer prognosis with respect to patients not having these features, none of these association was either invariably present or statistically significant. We therefore think that at the present time these antibodies may not be used to predict the outcome of the patients on a individual basis. In conclusion anti-ganglioside antibodies tended to be more frequently associated with some clinical features, suggesting that they may influence, if not determine, the clinical presentation or outcome and possibly have pathogenetic relevance in GBS. Beside however the constant association of anti-GQ1b antibodies with ophthalmoplegia and ataxia, these associations were not invariably ob-

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served, indicating that these antibodies do not permit to predict the clinical presentation or outcome in individual patients.

Acknowledgements This work was made possible by the financial support of Associazione Amici Centro Dino Ferrari and by grants from Telethon, Italy (grants no. 674), Associazione Italiana Sclerosi Multipla, and IRCCS Ospedale Maggiore Policlinico, Milan, Italy.

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