coli in patients with multifocal motor neuropathy

Serological evidence for infection with Campylobacter jejuni/coli in patients with multifocal motor neuropathy

B. V. Taylor 1, B. A. Phillips 2, B. R. Speed 3, J. Kaldor 3, IN. M. CarrolP, F. L. M a s t a g l i a ~ 1Department of Neurology, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia 2Australian Neuromuscular Research Institute, QEII Medical Centre, Nedlands, Western Australia 6009, Australia SFairfield Infectious Diseases Hospital, Melbourne, Victoria 3078, Australia

Campylobacterjejuni/coli (CJC) infection has been implicated in the immunopathogenesis of

Guillain-Barr6 syndrome (GBS), acute motor axonal neuropathy (AMAN), and Miller Fisher syndrome (MFS). However, its role in chronic immune mediated neuropathies such as multifocal motor neuropathy (MMN) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is less clear. Anti-ganglioside antibodies are associated with chronic motor neuropathies such as MMN and IgM anti-GM1, and IgM anti-asialo GM1 antibodies have been shown to cross-react with CJC lipopolysaccharides. Molecular mimicry between CJC and IgG anti-GM1 antibodies has also been suggested. Therefore we have performed a retrospective assessment of anti-cJC-specific IgG, IgM, and IgA antibodies in a cohort of seven patients with clinical and electrophysiologicaily definite MMN. The control group consisted of 140 healthy blood donors with no history of enteric illnesses. We found elevated titres of anti-CJC-speciflc IgG in 5 of 7 patients, IgM in 3 of 7 and IgA in 1 of 7. At least 1 anti-CJC antibody was elevated in 6 of 7 patients, and 3 patients had elevations of both IgG and IgM antibodies. Three patients had significantly elevated titres of anti-ganglioside antibodies without a clear relationship to the anti-CJC titres. Therefore antibodies specific for CJC were found more frequently than expected in patients with MMN. Prior or ongoing infection with CJC may play a role in the aetiopathogenesis of MMN.

Journal of Clinical Neuroscience 1998, 5(1): 33-35

© Harcourt Brace & Co. Ltd 1998

Keywords: multifocal motor neuropathy, conduction block, campylobacter

Introduction Infection with Campylobacter jejuni/coli (CJC) has b e e n implicated in the aetiopathogenesis of inflammatory demyelinating polyneuropathies such as the GuillainBarr4 syndrome (GBS)) -3 the Miller-Fisher syndrome (MFS) 4-7 and acute m o t o r axonal neuropathy (AMAN).8-10 Cross-reactivity between CJC epitopes and h u m a n sciatic nerve epitopes has also been shown) 1 O n e case report has d o c u m e n t e d an acute m o t o r neuropathy with conduction block following proven CJC enteritis) 2 However, the relationship between previous CJC infection and m o r e chronic forms of immune-mediated demyelinating polyneuropathies is not clear. Monoclonal IgM anti-GM1 and IgM anti-asialo GM1 antibodies from patients with chronic m o t o r neuropathies have been shown to crossreact with CJC epitopes, particularly CJC lipopolysaccharides) 3 However, IgM anti-monosialo GM1 antibodies in high titres have been found in only 63% of patients with mnltifocal m o t o r neuropathy (MMN)?4IgG, IgA and IgM anti-GM1 antibodies have been associated with GBS. 2 The MFS has been associated with IgG anti-GQlb antibodies and cross-reactivity between IgG anti-GQlb antibodies and CJC epitopes has been demonstrated. 6 Cross-reactivity and

molecular mimicry between IgG anti-GM1 antibodies and Campylobacter bacteria in GBS has been shown. 15,16High titre GM1 antibodies and Campylobacter infection have also b e e n strongly associated with AMAN and the acute m o t o r neuropathy f o r m of GBS. 8-1° MMN is a recently recognized f o r m of chronic predominantly m o t o r n e u r o p a t h y which is characterized by slowly progressive asymmetrical muscle wasting and weakness, particularly in the u p p e r limbs, with multiple sites of conduction block in m o t o r nerve fibres) 7 Although sensory symptoms are generally absent or minor, subclinical changes of demyelination and axonal d e g e n e r a t i o n may also be f o u n d in sensory nerves such as the sural n e r v e ? 8 The cause of MMN is unknown but it has b e e n suggested that it is a variant of chronic inflamm a t o r y demyelinating polyradiculoneuropathy. 17 An association with anti-ganglioside antibodies has b e e n suggested; however, these are not f o u n d in all cases) 4 It is i m p o r t a n t to distinguish MMN f r o m m o t o r n e u r o n disease as t r e a t m e n t with intravenous i m m u n o g l o b u l i n ( M G ) may be useful in MMN. a9 M G may prevent the binding of anti-GM1 antibodies to their targets. 2°

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Clinical studies

Table 1 Case 1 2 3 4 5 6 7

Campylobacter and multifocal motor neuropathy

Clinicaland electrophysiological findings in seven MMN patients Age

Sex

Duration of symptoms

Site of initial symptoms

51 54 53 56 50 45 48

M M F M M M M

3 years 13 years 16 years 3 years 5 years 7 years 4 years

L Hand L Hand Both Hands L Hand L Hand L Hand L Hand

Nerves with conduction block (L) M U (R) M (L) M U P (L) M U (R) M U (L) M MC (L) U (R) M (L) M U R R

M = median nerve, U = ulnar nerve, R = radial nerve, MC = musculocutaneous nerve and P = peroneal nerve, L = left, R = right.

Table 2 Case 1 2 3 4 5 6 7

Immunological characteristics of seven MMN patients

AnIi-CJC IgG titre

Anti-CJC IgM titre

Anti-CJC IgA titre

IVIG courses

Time since last IVIG

Anti-GM1 titre

1578 566 878 918 1077 695 460

207 257 233 332 890 631 207

105 494 210 162 220 217 67

3 1 3 25 3 3 0

2 years 2 years 2 years 1 month 18 months 1 month -

460 10500 1800 < 400 1800 < 400 < 400

Positive titres for anti-CJC IgG > 640, anti-CJC IgM > 320, anti-CJC IgA > 240 and anti-GM1 > 400. IVIG = intravenous immunoglobulin.

Methods

Seven patients, 6 males and 1 female, aged from 45 to 56 years, who met the clinical and electrophysiological criteria for MMN, were investigated. The duration of symptoms ranged from 2 to 16 years (mean 6.8). Six patients had received immunoglobulin therapy (IGT) in varying amounts (Table 1). All patients demonstrated persistent m o t o r conduction block on nerve conduction studies; the principal site of involvement was the non-dominant u p p e r limb which was the initially involved site in all 6 male patients. No patient r e p o r t e d an episode of enteritis preceding the onset of their neuropathy or their antibody assay. MMN was defined as a slowly progressive motor predominant neuropathy with evidence of conduction block on nerve conduction studies, in m o t o r but not sensory fibres and not at c o m m o n sites of entrapment. Conduction block was defined as a greater than 50% reduction in the amplitude of the c o m p o u n d muscle action potential when stimulating at proximal than distal sites along the same nerve, without significant dispersion. An inching technique was used to more accurately define the site of conduction block where possible. The clinical and electrophysiological findings of the patients are shown in Table 1. Class-specific antibodies to Campylobacterjejuni/coli were measured using a previously developed enzyme immunoassay. 1 Cut-offs for each class were based on 140 serum samples from healthy individuals and calculated as two standard deviations (SD) above the healthy population mean. This m e t h o d is able to detect one or more classes of anti-CJC antibodies in up to 90% of individuals with confirmed CJC enteritis 21 and 38% of GBS cases. 1

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Anti-ganglioside antibodies were measured for each patient using an ELISA technique; IgM anti-GM1 and IgM anti-asialo GM1 antibodies were assayed (Courtesy of Dr A. Pestronk, Washington University School of Medicine.)

Results

Six of the seven patients with MMN had levels of anti-CJC antibodies above the 2 SD cut-off for one or more antibody classes. Anti-CJC IgG was elevated in five cases, IgA in 1 and IgM in three. T h r e e patients had elevation of both IgG and IgM CJC antibodies. Four of the seven cases also had elevated titres of anti-ganglioside antibodies (Table 2). In three of these cases the elevations were significant; however, there was no clear correlation with CJC antibody titres. In the fourth case the anti-GM1 titre was only marginally elevated. T h e patient with the highest titre of IgM anti-GM1 antibodies had elevation of only IgA-specific CJC antibodies. The only patient without elevation of CJC antibodies was also negative for anti-GM1 antibodies. All patients except one had previously received 1VIG therapy at varying intervals prior to the time of antibody assessment (Table 1), with one patient (case 4) currently receiving monthly infusions of immunoglobulin, and three other cases having not received IVIG for more than 2 years (cases 1, 2 and 3).

Discussion

The hypothesis that infection with CJC may trigger an immune response directed at myelin or axons is supported by the evidence of molecular mimicry and cross-reactivity

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Campylobacter and multifocal motor neuropathy

Clinical studies

between CJC and ganglioside epitopes in acute inflammatory neuropathies such as GBS, MFS and AMAN. '-1°'15,:6 Cross-reactivity between anti-ganglioside antibodies from patients with chronic m o t o r neuropathies and CJC epitopes has also b e e n demonstrated 13 however, the role of CJC in chronic neuropathies is not clear as this would require persistent antigenic stimulation to continue the i m m u n e process. This may be provided by molecular mimicry as has been shown between ganglioside epitopes and CJC lipopolysaccharides. :3 Whether the excess c J c specific antibodies in our cases also have anti-ganglioside actMty is unclear. Although o u r results are suggestive of infection with CJC, and a possible role for CJC infection in the aetiopathogenesis of MMN, other possibilities n e e d to be addressed. Passive transference of CJC antibodies was considered as all patients positive for CJC antibodies had previously, or are currently, receiving M G with I n t r a g a m ( C o m m o n w e a l t h S e r u m Laboratories Australia) o r Sandoglobulin (Sandoz), b o t h of which are p r o d u c e d f r o m p o o l e d h u m a n serum. However, the use of these products would not explain the presence of IgA or IgM antibodies in 4 of the 6 seropositive individuals, as b o t h products consist almost exclusively of IgG. 22 T h e possible transference of CJC-specific IgG is less clear as this was detected at a level of 1 . 3 0 D units in Intragam. However, this figure is still less than that of two of the MMN cases and there would be considerable dilution after infusion. F u r t h e r m o r e , the patient with the highest level of CJCspecific IgG has not received I G T for 2 years (case 1), the r e p o r t e d half-life of IgG being 21 days 2s and a patient who has had m o n t h l y I G T for 3 years (case 4) has a low level of CJC-specific IgG. Persistence of class-specific anti-CJC antibodies is not readily explained as our own experience shows that IgM and IgA fall steadily over 4-6 weeks following CJC enteritis although IgG can persist for up to 6 months; longer follow-up information is not available. The persistence of antibody would suggest continued antigenic stimulation either f r o m chronic infection, or persisting CJC crossreacting antigens, possibly neural in origin. W h e t h e r cross-reaction with neural antigens such as gangliosides could p r o d u c e a serological response mimicking CJC infection is unclear. Although preliminary, these findings suggest a possible role for infection with CJC in the aetiopathogenesis of MMN and warrant further investigation. Received29 November 1995; Accepted 1 February 1997

Correspondence and offprint requests: P r o f e s s o r

E L.

Mastaglia, Department of Neurology, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia, Tel: 61 8 9346 2098, Fax: 61 8 9346 2816

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