European Journal of N e u r o l o ~ (1994), 1, 21-27 I RESEARCH 1

Guillain-Barre syndrome with severe persistent disability: relationship to hyperacute Guillain-Barre syndrome J.A. Palace and R.A.C. Hughes

Department of Neurology, UMDS, Guy’s Hospital, London SEl 9RT; UK

Correspondence to: R.A. C. Hughes as above address

Guillain-Bard syndrome (GBS) is a heterogeneous condition with a variable prognosis. We studied nine patients who were unable to walk unaided 12 months after the onset of their illness to discover whether they belonged to a more homogeneous subgroup. Six of the nine patients had symptoms of gastroenteritis shortly before the onset of their neuropathic symptoms and a hyperacute onset of weakness so that they were bed-bound within 24 h. These patients had predominantly motor rather than sensory involvement. We compared these nine poor outcome patients with 66 patients with lesser degrees of persistent disability of whom only three had both a history of prodromal gastroenteritis and a hyperacute onset (p < 0.0001). The poor and better outcome groups did not differ significantly in the severity of disability or other clinical or neurophysiological features in the acute stage. Patients with previous gastroenteritis and hyperacute onset of weakness may represent a relatively homogeneous subgroup of “hyperacute GB” in which severe axonal damage is caused by an aberrant immune response to a gastrointestinal pathogen such as Campylobocrer jejuni.

Keywords: Disability - Guillain-Bard syndrome

INTRODUCTION

Guillain-Bad syndrome (GBS) has been defined clini- cally to include the features of an acute motor polyradi- culoneuropathy (Asbury et al., 1978; Asbury and Comblath, 1990) with weakness progressing for a period not usually exceeding 4 weeks. Patients fulfilling this definition have a very variable prognosis ranging from complete recovery within a few weeks to severe perma- nent wasting and paralysis (Winer et al., 1988a). This variability might be due to one pathogenetic mechanism of variable severity or to heterogeneous pathogenetic processes. We have previously described a subgroup of patients with a subacute onset with a good prognosis: their illness reached its nadir within 4-8 weeks, and we have suggested that this be called subacute idiopathic demyelinating polyradiculoneuropathy (Hughes e? al., 1992). We now describe a subgroup of patients with GBS who were left with severe wasting and weakness. We have compared these patients with our other patients fulfilling the diagnostic criteria for GBS but having no or only mild or moderate persistent disability. A distinguish- ing feature of most of the patients with severe residual disability was an acute illness which had an explosive onset so that they were bed-bound within 24 h, and which was preceded by gastroenteritis. These patients

may represent a relatively homogeneous subgroup of “hyperacute GBS”.

METHODS

We collected data from all patients hlfilling standard clinical criteria for GBS encountered by one of US (R.A.C.H.) between January 1985 and February 1991 and followed prospectively for at least 1 year. These patients included 47 patients who had been admitted to OUT hospital during the acute stage of their illness and studied prospectively, and four patients who were referred later because of persistent severe disability.

The patients were divided into three groups according to their fimctional disability grade at 12 months (Hughes et al., 1978): good outcome was defined as grades 011- normal or minor residual symptoms or signs; moderate outcome as grade 2-able to walk 5 m without aid but unable to do manual work, including housework; poor outcome as grades 3/4-able’to waIk 5 m only with aid of unable to walk. Forty-seven patients had good, 15 mod- erate and 11 poor outcomes. TWO of these 11 patients were excluded from the study: one had a pre-existing

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J.A. PALACE AND R.A.C. HUGHES

paraparesis from spina bifida and one reached grade 2 at nine months but unfortunately fractured her fennur at 11 months. Thus nine patients had a poor outcome exclu- sively due to GBS. Of these nine patients, five were seen by us at the time of the acute illness. Four patients were only seen by us at a later stage, after 2 (Case 3), 3 (Case 2), 4 (Case 5) and 14 (Case 4) years, and information about the acute illness was obtained from the recollec- tions of the patient and relatives, which were vivid, and the contemporary medical records. At 12 months six were chair- or bed-bound and three were able to walk with aid. No patient was still being ventilated (grade 5) at 12 months.

Two patients who died were excluded from the analysis of prognostic variables on the ground that factors causing death might be different from factors causing prolonged disability. One was a 71 year old man with GBS who had been discharged home with a disability score of grade 1. He then developed cholestatic jaundice and died from biliary peritonitis. The second was a 73 year old man with severe chronic obstructive airways disease who had been weaned from artificial ventilation and discharged from our care: because of his poor general condition resuscitation was considered inappropriate when he de- veloped respiratory failure again 3 months later.

We reviewed the clinical, electrophysiological and lab- oratory features of the acute illness in all three groups of patients. The involvement of the arms was scored on a scale from 0 = normal, 1 = minor symptoms or signs, 2 = moderate weakness, 3 = severe weakness to 4 = complete paralysis, as used in a recent trial (Guillain-Bank Syn-

TABLE I. Comparison of patients with poor, moderate and good outcomes

drome Steroid Trial Group, 1993). Sensory, facial and bulbar muscle involvement was graded on a scale 0 = no, 1 = mild, 2 = moderate and 3 = severe involvement. Neurophysiological tests were performed using standard techniques usually in the intensive care until within 9- 19 days after the onset in our five cases. Anti-ganglioside and anti-Campylobacter jejuni ELISAs were performed on available sera using our previous methods (Gregson et al., 1991, 1993). Chi-square tests with a continuity cor- rection or, when appropriate, Fisher's exact tests were used to compare differences in proportions. Differences between groups of ordinal variables were tested with the Mann-Whitney U-test: where the number of observations exceeded 20, U was converted to the normal distribution value Z. Two-tailed significance values have been used throughout.

RESULTS

Poor outcome patients Clinical features. There were five women and four men in the poor outcome group having severe persistent disability at least 12 months after the onset of GBS (Table I). Their ages ranged from 35 to 66 years. Seven had a prodromal gastrointestinal illness, one had an upper respiratory tract infection and one had no symp- toms of a preceding illness. The maximum disability was requirement for artificial ventilatory support in four (lasting 45 - 146 days), inability to walk unaided in four, and need for support to walk in one. Of the eight patients who became bed-bound, seven became unable to walk

Case Sex Age Prodrome Days Worst grade Days 1 year

Dis Arm Sens Face Bulbar O(0-73) grade bed-bound ventilated disability

Poor outcome 1 F 35 G1 < I 5 4 0 1 2 90 3 2 F 61 G1 <1 4 4 2 1 0 - 4 3 F 65 GI <1 5 4 0 0 0 72 4 4 M 62 GI <1 4 4 1 1 0 0 4 5 M 38 GI <1 4 4 0 0 1 0 4 6 F 53 GI <1 4 3 1 0 0 0 4 7 F 54 GI <2 5 3 1 3 3 45 3 8 M 66 RTI <1 5 4 3 2 0 146 4 9 M 62 None Never 3 2 3 2 2 0 3 Mean (S.D.) 55 (12) 78% GI < l (<1-2) 4.3 (0.7) 3.6 (0.7) 1.2 (1.2) 1.1 (1.1) 0.89 (1.2) 0 (0-146)' 314

Moderate outcome

Good outcome (n = 15) 12M, 3F 51 (14) 20% GI 4.0(<1-20) 4.5 (0.5) 3.1 (1.2) 2.2 (1.1) 1.9 (1.0) 1.2 (1.1) 0 (0-73') 2

(n = 47) 26M, 42 (22) 13% GI 2.5 (11-18) 4.1 (0.8) 2.5 (1.1) 2.0 (1.3) 1.5 (1.1) 1.0 (1.6) 0 (0-46)' 011 21 F

*Median (range).

22 European Journal of Neurology . vol 1 . 1994

HYPERACUTE GUILLAIN-BA& SYNDROME

even with aid within 24 h of the initial neurological symptoms and one within 48 h.

The upper limbs had been completely paralysed or severely involved in all the poor outcome patients but sensory, facial and bulbar involvement was variable and often absent. The two patients with severe sensory in- volvement were the two without a prodromal diarrhoeal illness, one of whom never became bed-bound. All the ventilated patients had been catheterized for convenience of nursing which prevented adequate assessment of this aspect of autonomic involvement. One other patient was catheterized secondary to retention and two had hesitancy of micturition. Seven out of nine patients had no tendon reflexes at their worst while two had lost some but not all tendon reflexes.

Improvement began between 10 and 182 days after the onset in the seven patients in whom the time of improve- ment had been documented. One patient had a minor fluctuation 2 months after the onset but no patient re- lapsed.

Typical patient with prodromal gastroenteritis, hyper- acute onset and poor outco me. A 35 year old woman developed vomiting and diarrhoea lasting 24 h within days of returning from Morocco. Six days later she de- veloped weakness in all four limbs and became unable to stand within 24 h. She had no sensory symptoms or signs and moderate bulbar involvement. She had to be venti- lated within 24 h because of respiratory involvement. The CSF at 24 h contained no cells and protein 0.6 g/l. She had antibodies to C. jejuni and ganglioside GMl. She underwent plasma exchange. After 3 months she started to improve and was extubated. She was able to walk with aid by 8 months but was still unable to walk unaided at 12 months.

TABLE II. Neurophysiological data of poor outcome patients

Laboratory data. The details of the CSF were available from eight patients and the time of collection ranged from 0 to 10 days after the onset of the illness. The CSF protein concentration was raised in one patient to 1.86 g/l on Day 10 (Case 9). In the remaining patients the protein was 5 0.6 g/l. Only one CSF sample (from Case 4) contained cells (4 lymphocytes) and this specimen had a normal protein content.

Neurophysiological studies were available from the acute stage of the illness in only four of the poor out- come patients (Table 11). In Patients 1 and 6 who had a preceding gastrointestinal illness and whose neuropathy had an explosively rapid onset, the distally evoked com- pound muscle action potentials CMAPs were very small and conduction velocities relatively preserved consistent with axonal degeneration being the main underlying pa- thophysiological process. In Patient l who had no sen- sory symptoms the sensory action potentials SAPS were preserved whereas in Patient 6 who had distal paraesthe- siae, the radial SAP was reduced. In Patient 7 who also had gastroenteritis but a more prolonged onset phase of the neuropathy, the only neurophysiological abnormality was a slightly reduced CMAP and absent F wave. In Patient 9 there was conduction block and slowed conduc- tion, consistent with demyelination.

Anti-ganglioside GMl antibodies were present in acute sera available for testing from each of two patients who had also had a preceding diarrhoeal illness (Cases 1 and 6) and absent in one patient (Case 8) who had a prodro- ma1 respiratory tract infection. Antibodies to C. jejuni were detected by ELISA in both sera with anti-ganglio- side GMI antibodies tested.

Treatment. Only the five patients (Cases 1 and 6-9) seen in our own department during the acute phase had re-

Case Days Ulnar or median nerve Radial nerve from onset Distal Proximal Distal motor MCV F wave SAP scv

CMAP CMAP latency (m/s) latency (PV) (mv) (mv) (ms) (ms)

1 12 0.16 0.16 3.5 54 Absent 40 57 2 3 4 5 6 27 0.1 0.1 5.4 37 Absent 4 ND 7 9 3 2.5 3.0 56 Absent 7 67 9 19 3 0.4 7.3 29 Absent 7 67 Normal >4.0 <lo% (4.0 >50 1 3 2 >20 >50

decrement

velocity; ND, not determined.

European Journal of Neurology . Vol . 1994 23

J.A. PALACE AND R.A.C. HUGHES

U 5 15- 2 z 8

5 5 -

10-

a ). 0

U

ceived plasma exchange (PE; five 50 mVkg exchanges). Of the other four, Case 2 had received prednisolone and Case 3 ACTH.

0 0

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0 0 00 oooo 0.0

00000 0 MO..000 0.0 000.OM 00 o...

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0- - 'I T -

Moderate outcome group Fifteen patients had moderate persistent disability (Table I; 12 men and three women, aged from 23 to 66 years). Only three had had preceding gastroenteritis. Seven pa- tients had been ventilated (for 11-73 days). Out of 13 tested, three had abductor pollicis brevis CMAPs less than 1.0 m\! Fourteen had received plasma exchange and four had been treated with intravenous methylpred- nisolone (in a trial). Ten out of 14 CSF samples had protein concentrations greater than 0.6 gA. The time from onset until start of improvement ranged from 5 to 48 days in the 13 patients for whom this time was recorded.

Good outcome group Forty-seven patients had no or mild persistent disability (26 males and 21 females, aged 3-83 years; Table I). Only six had had preceding gastroenteritis. Fifteen had been ventilated for between 3 and 46 days. Out of 40 tested, 16 had abductor pollicis brevis CMAPs less than 1.0 m\! Thirty-nine patients had received plasma exchange and 10 intravenous methylprednisolone. Twenty-five out of 45 CSF samples had protein concen- trations greater than 0.6 g/l. The time from onset until improvement ranged from 4 to 78 days in 46 patients in whom the time was documented.

Comparison of poor with moderate and good outcome groups The clinical and laboratory data for the nine poor out- come patients were compared with those of the 15 mod- erate and 47 good outcome patients. The most notable difference was that patients in the poor outcome group were significantly more likely to have had a prodromal gastroenteritis than both the better outcome groups (sev- ere vs moderate group, p = 0.01; severe vs mild group. p = 0.0002). In addition the poor outcome group became bed-bound significantly more rapidly than either the normaVmildly affected outcome group (p < 0.05) or the moderately affected outcome group (p < 0.01). Not sur- prisingly, the poor outcome group took significantly longer to begin to improve than those in the mildly affected outcome group (JJ C 0.01). However the times to start improving were not significantly different in the poor and moderate outcome groups.

There was no significant difference in age (although the p value for the comparison of the severe vs mild outcome groups approached significance at p < 0.01), sex or worst disability score between those severely dis-

24 European Journal of Neurology . VOl 1 . 1994

abled at 12 months and the other two groups. When comparing the poor outcome with either the moderate or the good outcome groups, or with both of these groups together, there was no significant difference in the distal CMAP amplitudes, CSF protein concentra- tion, requirement for ventilation, or use of plasma ex- change.

Patients with prodromal gastroenteritis and hyperacute onset Six of the nine poor outcome patients fulfilled the two criteria of having had prodromal gastroenteritis and be- coming bed-bound within 24 h. Of the patients with better outcomes only three out of 62 fulfilled both these criteria (Fig. 1, p < 0.0001). We were unable to identify additional criteria which would have reliably distin- guished the patients who had had preceding gastroenter- itis and become bed-bound within 24 h and were destined to have a poor outcome from those who fulfilled these same criteria but eventually recovered well. However there were some differences between the two groups which might be relevant. Two out of the six poor out- come patients and none of the three better outcome pa- tients were ventilated. Sensory involvement was absent or mild in five of the six poor outcome patients (Table I), but present in all three better outcome patients (mild in one and moderate in two). All three patients tested in the poor outcome group had anti-ganglioside GMl antibodies and two had anti-C. jejuni antibodies. Neither of the better outcome patients who were tested had anti-ganglioside GM1 antibodies but both had anti-C. jejuni antibodies.

0 201 m 0

Prodromal gaslroenterilis

FIG. 1. Graph comparing the 12 month disability grade with the number of days from onset of neuropathic symptoms to becoming bed-bound. One patient (Case 9) who had a 12 month disability grade of 3 never became bed-bound and is therefore not on the graph.

HYPERACUTE G U I L L A I N - B A d SYNDROME

Finally all three good outcome patients had received plasma exchange during the acute illness compared with only two of the six poor outcome patients.

DISCUSS ION Out of 71 patients admitted to our hospital in the acute stage of GBS within the study period, only five (7.2%) had very severe persistent disability at 12 months and two (2.8%) died. These percentages may overestimate the residual disability and mortality of GBS in the popula- tion at large because many patients were referred from other hospitals for plasma exchange and those who were never severely disabled would have been excluded. How- ever the proportion of patients with very severe disability is comparable to those in previous studies: 8% of 87 surviving patients still had disability grade 3 or 4 at 12 months in a survey in south-east England in 1983-1984 (winer et al., 1988a), and 11% of 197 patients available for follow-up after 1 year in the French cooperative plasma exchange trial were either unable to walk or climb stairs or dress or cut meat or write (French Coop- erative Group on Plasma Exchange in Guillain-Bank Syndrome, 1992).

The most significant difference between the poor out- come and other two groups in this series was in the proportion of patients who had had preceding gastro- enteritis: seven out of nine (78%) in the poor outcome group and 14% in the other groups combined @= 0.0004). C. jejuni is the commonest recognized bacterial cause of diarrhoea in developed countries and the com- monest recognized precipitant of GBS. In a retrospective series of 56 patients with GBS those with serological evidence of recent C. jejuni infection were more likely to require ventilation and have prolonged severe disabil- ity (Kaldor and Speed, 1984). In a prospective study of 100 patients serological evidence of C. jejuni infection was associated with a poor outcome F i n e r et al., 1988a) although this association is not absolute and mild disease may also occur (Ropper, 1988). Vriesendorp et al. (1993) have recently reported a similar experience to our own: three of 58 patients were unable to walk after a year, two of the three had a history of diarrhoea, and all three had serological evidence of recent C. jejuni infection.

The mechanism by which C. jejuni causes GBS is the subject of intense research. There is an association between the occurrence of severe GBS with axonal de- generation, and serological evidence of recent Campylo- bacter infection (winer et al., 1988b; Walsh et al., 1991; Rees et al., 1993). This association raises the interesting possibility that C. jejuni infection induces an immune response against ganglioside GMI which damages motor axons (Yuki et al., 1990).

The only other feature that showed a significant assoc- iation with poor outcome was hyperacute onset of the neurological illness, defined as becoming &&bound within 24 h. A very rapid onset of GBS has previously been shown to be related to poor outcome (Ropper, 1986; Winer et al., 1988a; McKhann et al., 1988).

The combination of prodromal gastroenteritis and hy- peracute onset was even more closely associated with a poor prognosis than either alone, being present in six of the nine poor outcome patients and only 5% of the re- maining patients (p < 0.0001). The three patients of Vriesendorp et al. (1993) who had a poor prognosis all had serological evidence of C. jejuni and a “fdminant” onset of their neuropathy causing tetraplegia and respira- tory failure within 1-3 days.

Other clinical variables, including maximum disability, need for ventilation and duration of ventilation, were not statistically associated with outcome. However, older age (Winer et al., 1988a; McKhann et al., 1988), severe tetraparesis in the acute phase (De Jager and Minder- houd, 1991), the need for ventilation (McKhann et al., 1988; Winer et al., 1988a) and duration of ventilation (De Jager and Minderhoud, 199 1 ) have been reported in other studies to be associated with poor outcome.

The neurophysiological data, only available in the acute stage from four of our nine poor outcome pa- tients, did not give a reliable guide to prognosis, since the distally evoked CMAP amplitudes were not markedly reduced in two patients (Cases 6 and 9) who were des- tined to have a poor outcome. Conversely the distally evoked abductor pollicis brevis CMAP amplitude was less than 1.0 mV in 63% of the good or moderate out- come patients. Although small distally evoked C U P S were significant adverse prognostic factors in two pre- vious large series (Winer et al., 1988a; Cornblath et al., 1988), they were not sensitive prognostic factors in an- other (Van der Mechk et al., 1992). Reasons for the different conclusions about the prognostic value of dis- tally evoked CMAP amplitudes include differences in the threshold or method of calculating this amplitude (Rop- per 1988, Duret er al. 1991), and differences in timing of electrophysiological investigations. The amplitude of the distally evoked CMAPs falls rapidly during the first 2 weeks of the illness so that its value is critically depen- dent on the time from onset when the measurement is made. The distal CMAP may be relatively spared in the early phase of GBS despite severe axonal degeneration later (Van der Mechi et al., 1991). In addition a small or absent distally evoked CMAP amplitude may be due to severe distal demyelination, as we have demonstrated in a terminal motor nerve biopsy (Hall et al., 1992), Of to aonal degeneration (Brown and Feasby, 1984; FeaSbY et al., 1986; Brown et al., 1993), which have diametri- cally opposed prognostic significance (Tnggs al.3

25 European Journal of Neurology . VOl. 1994

J A PALACE AND R A C. HUGHES

1992). Serial recordings of CMAP amplitudes and elec- tromyographic features of denervation might be more accurate prognostic factors but they would be burden- some and would only offer guidance rather late. Electro- myographic features of denervation (Eisen and Humphreys, 1974; McLeod et al., 1976; Raman and Taori, 1976; McLeod, 1981; Brown and Feasby, 1984) have been reported to be poor prognostic indicators but were not routinely studied by us.

The normal CSF protein in most of the poor outcome patients might be explained by the timing of lumbar puncture which was undertaken very early, within 2 days of the onset in all cases except Case 9. In previous studies no relationship was found between CSF protein concen- tration and prognosis (Eisen and Humphreys, 1974; Mckod et al., 1976; Winer et al., 1988a; De Jager and Minderhoud, 199 1 ; De Jager and Sluiter, 199 1).

In conclusion the majority of patients with severe persistent disability 1 year after the onset of GBS had had a prodromal gastroenteritis and an explosively rapid onset of their neuropathy rendering them bed-bound within 24 h. These features identify a relatively homo- geneous clinical condition in which the underlying patho- physiology causes axonal degeneration predominantly of motor nerve fibres. We consider that what has been called the acute axonal form of GBS is most likely to be found in this group of patients (Brown and Feasby, 1984; Feas- by et al., 1986). More intensive physiological and patho- logical studies will be necessary to determine whether the underlying mechanism is an unusually fulminant inflammatory polpdiculoneuropathy or a severe acute motor or motor and sensory axonal neuropathy. Recogni- tion of this poor prognosis subgroup at an early stage by these simple clinical criteria should focus our search for improved treatment on those patients who need it.

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(Received 16 March 1994; accepted as revised 15 July 1994)

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