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Three patients with ophthalmoplegia associated with Campylobacter jejuni
Three Patients With Ophthalmoplegia Associated With Campylobacter jejuni Shigekazu Kuroki, MD*, Takahiko Saida, MD†, Masafumi Nukina, DVM‡, Mieko Yoshioka, MD*, and Junko Seino, MD*
Cranial polyneuropathy is idiopathic in most patients. Idiopathic cranial polyneuropathy is an acute postinfectious syndrome, along with Guillain-Barre´ syndrome and Miller Fisher syndrome, in which the common preceding pathogen is Campylobacter jejuni. Serum anti-GQ1b antibodies are elevated in Miller Fisher syndrome and Guillain-Barre´ syndrome with ophthalmoplegia. Three patients with idiopathic cranial polyneuropathy with predominant ocular involvement are presented. C. jejuni isolated from stool specimens belonged to Penner serotypes O:4, O:23, and O:33. Serum anti-GQ1b antibodies were elevated in all patients but demonstrated rapid reduction concomitant with clinical recovery. All patients recovered completely. Because both preceding C. jejuni infection and elevated anti-GQ1b antibodies decreasing with time were seen in all patients, the pathogenesis of idiopathic cranial polyneuropathy with ophthalmoplegia may be similar to that of Miller Fisher syndrome. © 2001 by Elsevier Science Inc. All rights reserved. Kuroki S, Saida T, Nukina M, Yoshioka M, Seino J. Three patients with ophthalmoplegia associated with Campylobacter jejuni. Pediatr Neurol 2001;25:71-74.
From the *Department of Pediatrics; Kobe City General Hospital; Kobe, Japan; †Department of Center for Neurological Diseases; Utano National Hospital; Kyoto, Japan; and ‡Public Health Research Institute of Kobe City; Kobe, Japan.
© 2001 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00281-8 ● 0887-8994/01/$—see front matter
Introduction Although cranial polyneuropathy is a relatively rare disorder sometimes caused by tumors of the brainstem and systemic disorders, such as sarcoidosis and diabetes mellitus, its etiology is unknown in most patients [1]. Idiopathic cranial polyneuropathy in childhood is mostly a postinfectious syndrome. Guillain-Barre´ syndrome (GBS) and Miller Fisher syndrome (MFS), which display the clinical triad of ophthalmoplegia, ataxia, and areflexia, are also acute postinfectious autoimmune syndromes that follow preceding infections, such as upper respiratory tract infection and gastroenteritis. Campylobacter jejuni is the most common antecedent infectious agent in GBS and MFS [2,3]. In more than 90% of MFS patients, serum anti-GQ1b antibody is elevated [4]. Serum anti-GQ1b antibody is closely associated with ophthalmoplegia in MFS and GBS [5]. The pathogenesis is believed, at least in some instances, to involve molecular mimicry between surface epitopes on C. jejuni lipopolysaccharides and neural GQ1b ganglioside in MFS [6,7]. Although idiopathic cranial polyneuropathy with ophthalmoplegia is suggested to be a clinical variant of MFS [8], the significance of preceding C. jejuni infection and the pathogenesis remain unclear in idiopathic cranial polyneuropathy. Three patients with idiopathic cranial polyneuropathy involving oculomotor, trochlear, or abducens nerves with elevated serum anti-GQ1b antibodies and preceding C. jejuni enteritis are presented.
Methods Enzyme-Linked Immunosorbent Assay for Antibodies to C. Jejuni The presence of serum IgG, IgM, and IgA antibodies specific for C. jejuni was determined by enzyme-linked immunosorbent assay (ELISA), described previously [9]. C. jejuni strains of Penner types O:1, O:2, O:4, and O:5-1 originating from the serotyping scheme of Penner and Hennessy [10] were used as antigen. With this method, positive serum antibody titers are the following: IgG more than 1:320, IgM more than 1:80, and IgA more than 1:80. A patient was regarded as demonstrating evidence of recent C. jejuni infection if one of the following two criteria was satisfied: (1) two or more classes of antibody were in the positive range or (2) IgM more than 1:160 or IgA more than 1:160.
Communications should be addressed to: Dr. Kuroki; Department of Pediatrics; Kobe City General Hospital; 4-6 Minatojima-Nakamachi; Chuo-ku; Kobe 650-0046, Japan. Received December 20, 2000; accepted March 6, 2001.
Kuroki et al: Ophthalmoplegia and C. Jejuni 71
Stool Culture for C. Jejuni
Patient 2
Stool cultures for C. jejuni were performed as previously described [2]. Stool specimens were cultured for C. jejuni on Preston agar. The cultures were incubated in a microaerophilic atmosphere (Campylopack; Synteck, Osaka, Japan) at 42°C for 48 hours. Identity of C. jejuni was verified by positive tests for oxidase, motility, and sensitivity to nalidixic acid. The hippurate hydrolysis test was used to differentiate between C. jejuni and C. coli. Cultures for Salmonella, Shigella, Yersinia, and vibrios were also performed.
A 14-year-old male experienced fever, abdominal pain, vomiting, and diarrhea. Eight days later he started to have diplopia. On admission, 2 days after the onset of diplopia, he was afebrile and conscious. Mild bilateral abducens palsy was present. Physical examination and routine blood study were otherwise normal. The cerebrospinal fluid (CSF) examination revealed one mononuclear cell/mm3 and a protein concentration of 33 mg/dL. The CT scan was normal. Stool culture yielded C. jejuni, which belonged to Penner type O:33. IgG, IgM, and IgA antibodies to C. jejuni were 1:80, less than 1:40, and less than 1:40, respectively. Anti-GQ1b IgG, anti-GQ1b IgM, anti-GM1 IgM, antiGD1a IgM, and anti-GD1b IgM antibody titers were 1:1280, 1:640, 1:1280, 1:160, and 1:320, respectively. Abducens palsy disappeared completely within 2 months.
Serotyping of Isolated C. Jejuni Described previously by Kuroki et al. [9], serotyping of C. jejuni was performed by the method of Penner and Hennessy [10] and is based on the passive hemagglutination technique to detect soluble heat-stable antigens that have been identified as lipopolysaccharide antigens.
ELISA for Antibodies to Glycolipids The antigens used were GM1, GM2, GD1a, GD1b, GT1b, GQ1b gangliosides, and galactocerebroside. Described previously by Hao et al. [11], 500 ng of each antigen in 50-L methanol was added to each well of microtiter plates and then allowed to dry. An uncoated well for each sample was used as the control. A serum sample diluted 1:160 was added in duplicate to antigen-coated and antigen-uncoated wells after blocking with 1% bovine serum albumin in phosphate-buffered saline (PBS) pH 7.4. The plates were incubated overnight at 4°C. After washing four times with ELISA solution, 100-L peroxidase-conjugated rabbit antibodies to human IgG or IgM diluted 1:1000 in ELISA solution were added and incubated for 2 hours at room temperature. After washing four times with PBS, color was developed by adding 100-L substrate solution (phosphate-citrate buffer, pH 5.0 with 0.04% o-phenylenediamine and 0.05% H2O2). The reaction was stopped after 20 minutes by addition of 50-L 2N-H2SO4, and the optical density value was measured at 492 nm. Each optical density value was corrected by subtracting the values for the antigen-uncoated wells that had been processed the same way. Antibody activity was considered positive when the optical density of a sample exceeded the mean value ⫹ 3 S.D. for the normal controls. The antibody titer of each positive sample was expressed as the maximum dilution factor, which yielded a corrected OD value exceeding 0.1.
Case Reports Patient 1 An 11-year-old male was admitted to our hospital because of diplopia, which was noted 2 days before admission. Nine days before admission he had had abdominal pain along with nausea, diarrhea, and headache. On admission, he was afebrile and fully conscious. There was slight limitation of upgaze with partially dilated and sluggishly reactive pupils. Deep tendon reflexes were normal, and no ataxia was observed. Pathologic reflexes were absent. Results of routine laboratory studies of blood and urine were normal. Lumbar puncture revealed one mononuclear cell/mm3 and a protein concentration of 34 mg/dL. Cranial computed tomography (CT) and nerve conduction study were both normal. C. jejuni, which was serotyped as Penner type O:4, was isolated from stool culture. IgG, IgM, and IgA antibodies to C. jejuni were 1:160, 1:160, and 1:320, respectively. Anti-GQ1b IgG antibody titer was 1:320. Nine days later, moderate limitation of whole direction movement of both eyes was observed. Improvement began 20 days after admission. External ophthalmoplegia disappeared 4 months after the onset. Internal ophthalmoplegia also disappeared 8 months after onset of symptoms.
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Patient 3 A 3-year-old male was admitted to our hospital because of ophthalmoplegia and right blepharoptosis, which appeared 6 days before admission. Sixteen days before admission he had suffered from fever and diarrhea. On admission, he was afebrile and conscious. There were moderate bilateral oculomotor, trochlear, and abducens nerve palsies with normal pupillary function. He did not have ataxia or areflexia. Results of routine laboratory studies of blood and urine were normal. Lumbar puncture revealed 2 cells/mm3 and a protein concentration of 37 mg/dL. Magnetic resonance imaging revealed no abnormality in the orbits or brain. Nerve conduction study was normal. C. jejuni, belonging to Penner type O:23, was isolated from his stool. IgG, IgM, and IgA antibodies to C. jejuni were less than 1:40, 1:80, and less than 1:40, respectively. Anti-GQ1b IgM antibody titer was 1:640. He recovered completely within 1 month. Table 1 summarizes clinical and laboratory findings. Serial serum anti-GQ1b antibody titers are depicted in Figure 1. Titers are at their peak at clinical presentation and decline rapidly concomitant with clinical recovery.
Discussion Three patients with cranial polyneuropathy who exhibited pedominant ocular involvement and elevated antiGQ1b antibodies after C. jejuni infection are presented. All patients had diarrhea 7-10 days before developing cranial polyneuropathy. In all patients, stool cultures yielded C. jejuni. However, antibodies to C. jejuni were positive in only one patient. In our ELISA system for detecting antibodies to C. jejuni the specificity and sensitivity were 98% and 67%, respectively, by our criteria for the diagnosis of recent C. jejuni infection described above. Because of the relatively low sensitivity of our ELISA system, antibodies to C. jejuni were probably not detected despite the isolation of C. jejuni from stool specimens in Patient 2 and Patient 3. Two patients with cranial polyneuropathy after C. jejuni infection have been reported previously [12,13], but other reports of preceding infections are rare. C. jejuni may be the most common pathogen preceding idiopathic cranial polyneuropathy, as well as GBS and MFS. We previously reported that O:19 was the most common serotype of C. jejuni isolated from GBS patients [2], which was confirmed by another study [3]. The frequency of positive anti-GM1 antibody titers in GBS patients with
Table 1.
Clinical and laboratory findings in the three patients with idiopathic cranial polyneuropathy
Characteristics Age (years)/Sex Antecedent events Bilateral ocular palsies Pupillary reflex Elevated antiganglioside antibodies CSF cells/protein C. jejuni Penner serotype
Patient 1
Patient 2
Patient 3
11/M Abdominal pain, diarrhea, nausea, headache III, IV, VI Sluggish GQ1b IgG
14/M Fever, abdominal pain, diarrhea, vomiting VI Prompt GQ1b IgG, IgM, GM1 IgM GD1a IgM, GD1b IgM
3/M Fever, diarrhea
N/N 0:4
N/N 0:33
III, IV, VI Prompt GQ1b IgM
N/N 0:23
Abbreviations: C. jejuni ⫽ Campylobacter jejuni CSF ⫽ Cerebrospinal fluid M ⫽ Male N ⫽ Normal
O:19 isolates was higher than that in GBS patients without O:19 isolates [3]. Yuki et al. [3] also reported that five of seven C. jejuni isolates from MFS patients belonged to serotype O:2. C. jejuni isolated from our patients in this study did not belong to either of these serotypes, but anti-GQ1b antibodies were detected in all three patients. Because C. jejuni serotypes O:4 and O:23 have been isolated from a GBS patient with elevated anti-GQ1b IgG antibody and from a MFS patient with elevated anti-GQ1b IgG antibody, respectively [7,14], C. jejuni strains belonging to these serotypes may have GQ1b-like structures. A close association was found between the presence of serum anti-GQ1b antibody and both MFS and GBS with
Figure 1. Longitudinal study of anti-GQ1b antibodies in three patients with idiopathic cranial polyneuropathy. Antibody titer more than 1:160 was regarded to be positive.
ophthalmoplegia [4]. An immunohistochemical study revealed that monoclonal antibody to GQ1b gangliosides strongly stained the paranodal regions of the extramedullary portion of the human oculomotor, trochlear, and abducens nerves. These results suggest the close relationship between anti-GQ1b antibody and ophthalmoplegia [5]. Histochemical studies revealed the crossreactivity of anti-GQ1b antibodies with surface epitopes on all C. jejuni strains isolated from five MFS patients [6,7]. Therefore it is believed that there is molecular mimicry between GQ1b ganglioside and surface epitopes on MFS-associated C. jejuni strains. Because both preceding C. jejuni infection and elevated anti-GQ1b antibodies declining with time after onset were exhibited by all three patients, the pathogenesis of idiopathic cranial polyneuropathy with ophthalomoplegia may be similar to that of MFS. Although there is albuminocytologic dissociation in most patients with GBS and MFS, protein concentrations in CSF were normal in our patients. In previous reports, CSF protein was normal in eight of 11 patients with idiopathic cranial polyneuropathy with ophthalmoplegia [1] and in all eight patients with idiopathic cranial polyneuropathy with predominant ocular involvement [15]. Albuminocytologic dissociation may be less frequent in idiopathic cranial polyneuropathy, especially in association with predominant ocular involvement than in GBS and MFS, probably resulting from restricted inflammatory changes in nerve roots. The three patients received supportive care only and improved spontaneously without specific treatment with intravenous immunoglobulin or plasmapheresis. However, these treatment modalities may be beneficial in patients with complete ophthalmoplegia because they seem to shorten the clinical course [15].
The authors thank Etsuko Nishiguchi for her technical assistance.
Kuroki et al: Ophthalmoplegia and C. Jejuni 73
References [1] Juncos JL, Beal MF. Idiopathic cranial polyneuropathy. A fifteen-year experience. Brain 1987;110:197-211. [2] Kuroki S, Saida T, Nukina M, et al. Campylobacter jejuni strains from patients with Guillain-Barre´ syndrome belong mostly to Penner serogroup 19 and contain beta-N-acetylglucosamine residues. Ann Neurol 1993;33:243-7. [3] Yuki N, Takahashi M, Tagawa Y, Kashiwase K, Tadokoro K, Saito K. Association of Campylobacter jejuni serotype with antiganglioside antibody in Guillain-Barre´ syndrome and Fisher’s syndrome. Ann Neurol 1997;42:28-33. [4] Chiba A, Kusunoki S, Shimizu T, Kanazawa I. Serum IgG antibody to ganglioside GQ1b is a possible marker of Miller Fisher syndrome. Ann Neurol 1992;31:677-9. [5] Chiba A, Kusunoki S, Obata H, Machinami R, Kanazawa I. Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain-Barre´ syndrome. Clinical and immunohistochemical studies. Neurology 1993;43:1911-7. [6] Yuki N, Taki T, Takahashi M, et al. Molecular mimicry between GQ1b ganglioside and lipopolysaccharides of Campylobacter jejuni isolated from patients with Fisher’s syndrome. Ann Neurol 1994;36: 791-3. [7] Jacobs BC, Endtz HPh, van der Meche FGA, Hazenberg M, Achtereekte HAM, van Doorn PA. Serum anti-GQ1b IgG antibodies
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recognize surface epitopes on Campylobacter jejuni from patients with Miller Fisher syndrome. Ann Neurol 1995;37:260-4. [8] Fisher M. An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia). N Engl J Med 1956;255:57-65. [9] Kuroki S, Haruta T, Yoshioka M, Kobayashi Y, Nukina M, Nakanishi H. Guillain-Barre´ syndrome associated with Campylobacter infection. Pediatr Infect Dis J 1991;10:149-51. [10] Penner JL, Hennessy JN. Passive hemagglutination technique for serotyping Campylobacter fetus subsp. jejuni on the basis of soluble heat-stable antigens. J Clin Microbiol 1980;12:732-7. [11] Hao Q, Saida T, Kuroki S, Nishimura M, Nukina M, Obayashi H, Saida K. Antibodies to gangliosides and galactocerebroside in patients with Guillain-Barre´ syndrome with preceding Campylobacter jejuni and other identified infections. J Neuroimmunol 1998;81:116-26. [12] v.d. Kruijk RA, Lampe AS, Endtz HPh. Bilateral abducens paresis following Campylobacter jejuni enteritis. J Infect 1992;24:215-6. [13] Matsubara K, Nigami H., Harigaya H, Baba K. Cranial polyneuropathy with elevated serum antiganglioside antibody. Pediatr Neurol 1997;16:149-51. [14] Saida T, Kuroki S, Hao Q, Nishitani H, Nukina M, Obayashi H. Campylobacter jejuni isolates from Japanese patients with Guillain-Barre´ syndrome. J Infect Dis 1997;176(Suppl 2):S129-34. [15] Yuki N. Acute paresis of extraocular muscles associated with IgG anti-GQ1b antibody. Ann Neurol 1996;39:668-72.
Cranial polyneuropathy is idiopathic in most patients. Idiopathic cranial polyneuropathy is an acute postinfectious syndrome, along with Guillain-Barre´ syndrome and Miller Fisher syndrome, in which the common preceding pathogen is Campylobacter jejuni. Serum anti-GQ1b antibodies are elevated in Miller Fisher syndrome and Guillain-Barre´ syndrome with ophthalmoplegia. Three patients with idiopathic cranial polyneuropathy with predominant ocular involvement are presented. C. jejuni isolated from stool specimens belonged to Penner serotypes O:4, O:23, and O:33. Serum anti-GQ1b antibodies were elevated in all patients but demonstrated rapid reduction concomitant with clinical recovery. All patients recovered completely. Because both preceding C. jejuni infection and elevated anti-GQ1b antibodies decreasing with time were seen in all patients, the pathogenesis of idiopathic cranial polyneuropathy with ophthalmoplegia may be similar to that of Miller Fisher syndrome. © 2001 by Elsevier Science Inc. All rights reserved. Kuroki S, Saida T, Nukina M, Yoshioka M, Seino J. Three patients with ophthalmoplegia associated with Campylobacter jejuni. Pediatr Neurol 2001;25:71-74.
From the *Department of Pediatrics; Kobe City General Hospital; Kobe, Japan; †Department of Center for Neurological Diseases; Utano National Hospital; Kyoto, Japan; and ‡Public Health Research Institute of Kobe City; Kobe, Japan.
© 2001 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00281-8 ● 0887-8994/01/$—see front matter
Introduction Although cranial polyneuropathy is a relatively rare disorder sometimes caused by tumors of the brainstem and systemic disorders, such as sarcoidosis and diabetes mellitus, its etiology is unknown in most patients [1]. Idiopathic cranial polyneuropathy in childhood is mostly a postinfectious syndrome. Guillain-Barre´ syndrome (GBS) and Miller Fisher syndrome (MFS), which display the clinical triad of ophthalmoplegia, ataxia, and areflexia, are also acute postinfectious autoimmune syndromes that follow preceding infections, such as upper respiratory tract infection and gastroenteritis. Campylobacter jejuni is the most common antecedent infectious agent in GBS and MFS [2,3]. In more than 90% of MFS patients, serum anti-GQ1b antibody is elevated [4]. Serum anti-GQ1b antibody is closely associated with ophthalmoplegia in MFS and GBS [5]. The pathogenesis is believed, at least in some instances, to involve molecular mimicry between surface epitopes on C. jejuni lipopolysaccharides and neural GQ1b ganglioside in MFS [6,7]. Although idiopathic cranial polyneuropathy with ophthalmoplegia is suggested to be a clinical variant of MFS [8], the significance of preceding C. jejuni infection and the pathogenesis remain unclear in idiopathic cranial polyneuropathy. Three patients with idiopathic cranial polyneuropathy involving oculomotor, trochlear, or abducens nerves with elevated serum anti-GQ1b antibodies and preceding C. jejuni enteritis are presented.
Methods Enzyme-Linked Immunosorbent Assay for Antibodies to C. Jejuni The presence of serum IgG, IgM, and IgA antibodies specific for C. jejuni was determined by enzyme-linked immunosorbent assay (ELISA), described previously [9]. C. jejuni strains of Penner types O:1, O:2, O:4, and O:5-1 originating from the serotyping scheme of Penner and Hennessy [10] were used as antigen. With this method, positive serum antibody titers are the following: IgG more than 1:320, IgM more than 1:80, and IgA more than 1:80. A patient was regarded as demonstrating evidence of recent C. jejuni infection if one of the following two criteria was satisfied: (1) two or more classes of antibody were in the positive range or (2) IgM more than 1:160 or IgA more than 1:160.
Communications should be addressed to: Dr. Kuroki; Department of Pediatrics; Kobe City General Hospital; 4-6 Minatojima-Nakamachi; Chuo-ku; Kobe 650-0046, Japan. Received December 20, 2000; accepted March 6, 2001.
Kuroki et al: Ophthalmoplegia and C. Jejuni 71
Stool Culture for C. Jejuni
Patient 2
Stool cultures for C. jejuni were performed as previously described [2]. Stool specimens were cultured for C. jejuni on Preston agar. The cultures were incubated in a microaerophilic atmosphere (Campylopack; Synteck, Osaka, Japan) at 42°C for 48 hours. Identity of C. jejuni was verified by positive tests for oxidase, motility, and sensitivity to nalidixic acid. The hippurate hydrolysis test was used to differentiate between C. jejuni and C. coli. Cultures for Salmonella, Shigella, Yersinia, and vibrios were also performed.
A 14-year-old male experienced fever, abdominal pain, vomiting, and diarrhea. Eight days later he started to have diplopia. On admission, 2 days after the onset of diplopia, he was afebrile and conscious. Mild bilateral abducens palsy was present. Physical examination and routine blood study were otherwise normal. The cerebrospinal fluid (CSF) examination revealed one mononuclear cell/mm3 and a protein concentration of 33 mg/dL. The CT scan was normal. Stool culture yielded C. jejuni, which belonged to Penner type O:33. IgG, IgM, and IgA antibodies to C. jejuni were 1:80, less than 1:40, and less than 1:40, respectively. Anti-GQ1b IgG, anti-GQ1b IgM, anti-GM1 IgM, antiGD1a IgM, and anti-GD1b IgM antibody titers were 1:1280, 1:640, 1:1280, 1:160, and 1:320, respectively. Abducens palsy disappeared completely within 2 months.
Serotyping of Isolated C. Jejuni Described previously by Kuroki et al. [9], serotyping of C. jejuni was performed by the method of Penner and Hennessy [10] and is based on the passive hemagglutination technique to detect soluble heat-stable antigens that have been identified as lipopolysaccharide antigens.
ELISA for Antibodies to Glycolipids The antigens used were GM1, GM2, GD1a, GD1b, GT1b, GQ1b gangliosides, and galactocerebroside. Described previously by Hao et al. [11], 500 ng of each antigen in 50-L methanol was added to each well of microtiter plates and then allowed to dry. An uncoated well for each sample was used as the control. A serum sample diluted 1:160 was added in duplicate to antigen-coated and antigen-uncoated wells after blocking with 1% bovine serum albumin in phosphate-buffered saline (PBS) pH 7.4. The plates were incubated overnight at 4°C. After washing four times with ELISA solution, 100-L peroxidase-conjugated rabbit antibodies to human IgG or IgM diluted 1:1000 in ELISA solution were added and incubated for 2 hours at room temperature. After washing four times with PBS, color was developed by adding 100-L substrate solution (phosphate-citrate buffer, pH 5.0 with 0.04% o-phenylenediamine and 0.05% H2O2). The reaction was stopped after 20 minutes by addition of 50-L 2N-H2SO4, and the optical density value was measured at 492 nm. Each optical density value was corrected by subtracting the values for the antigen-uncoated wells that had been processed the same way. Antibody activity was considered positive when the optical density of a sample exceeded the mean value ⫹ 3 S.D. for the normal controls. The antibody titer of each positive sample was expressed as the maximum dilution factor, which yielded a corrected OD value exceeding 0.1.
Case Reports Patient 1 An 11-year-old male was admitted to our hospital because of diplopia, which was noted 2 days before admission. Nine days before admission he had had abdominal pain along with nausea, diarrhea, and headache. On admission, he was afebrile and fully conscious. There was slight limitation of upgaze with partially dilated and sluggishly reactive pupils. Deep tendon reflexes were normal, and no ataxia was observed. Pathologic reflexes were absent. Results of routine laboratory studies of blood and urine were normal. Lumbar puncture revealed one mononuclear cell/mm3 and a protein concentration of 34 mg/dL. Cranial computed tomography (CT) and nerve conduction study were both normal. C. jejuni, which was serotyped as Penner type O:4, was isolated from stool culture. IgG, IgM, and IgA antibodies to C. jejuni were 1:160, 1:160, and 1:320, respectively. Anti-GQ1b IgG antibody titer was 1:320. Nine days later, moderate limitation of whole direction movement of both eyes was observed. Improvement began 20 days after admission. External ophthalmoplegia disappeared 4 months after the onset. Internal ophthalmoplegia also disappeared 8 months after onset of symptoms.
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Patient 3 A 3-year-old male was admitted to our hospital because of ophthalmoplegia and right blepharoptosis, which appeared 6 days before admission. Sixteen days before admission he had suffered from fever and diarrhea. On admission, he was afebrile and conscious. There were moderate bilateral oculomotor, trochlear, and abducens nerve palsies with normal pupillary function. He did not have ataxia or areflexia. Results of routine laboratory studies of blood and urine were normal. Lumbar puncture revealed 2 cells/mm3 and a protein concentration of 37 mg/dL. Magnetic resonance imaging revealed no abnormality in the orbits or brain. Nerve conduction study was normal. C. jejuni, belonging to Penner type O:23, was isolated from his stool. IgG, IgM, and IgA antibodies to C. jejuni were less than 1:40, 1:80, and less than 1:40, respectively. Anti-GQ1b IgM antibody titer was 1:640. He recovered completely within 1 month. Table 1 summarizes clinical and laboratory findings. Serial serum anti-GQ1b antibody titers are depicted in Figure 1. Titers are at their peak at clinical presentation and decline rapidly concomitant with clinical recovery.
Discussion Three patients with cranial polyneuropathy who exhibited pedominant ocular involvement and elevated antiGQ1b antibodies after C. jejuni infection are presented. All patients had diarrhea 7-10 days before developing cranial polyneuropathy. In all patients, stool cultures yielded C. jejuni. However, antibodies to C. jejuni were positive in only one patient. In our ELISA system for detecting antibodies to C. jejuni the specificity and sensitivity were 98% and 67%, respectively, by our criteria for the diagnosis of recent C. jejuni infection described above. Because of the relatively low sensitivity of our ELISA system, antibodies to C. jejuni were probably not detected despite the isolation of C. jejuni from stool specimens in Patient 2 and Patient 3. Two patients with cranial polyneuropathy after C. jejuni infection have been reported previously [12,13], but other reports of preceding infections are rare. C. jejuni may be the most common pathogen preceding idiopathic cranial polyneuropathy, as well as GBS and MFS. We previously reported that O:19 was the most common serotype of C. jejuni isolated from GBS patients [2], which was confirmed by another study [3]. The frequency of positive anti-GM1 antibody titers in GBS patients with
Table 1.
Clinical and laboratory findings in the three patients with idiopathic cranial polyneuropathy
Characteristics Age (years)/Sex Antecedent events Bilateral ocular palsies Pupillary reflex Elevated antiganglioside antibodies CSF cells/protein C. jejuni Penner serotype
Patient 1
Patient 2
Patient 3
11/M Abdominal pain, diarrhea, nausea, headache III, IV, VI Sluggish GQ1b IgG
14/M Fever, abdominal pain, diarrhea, vomiting VI Prompt GQ1b IgG, IgM, GM1 IgM GD1a IgM, GD1b IgM
3/M Fever, diarrhea
N/N 0:4
N/N 0:33
III, IV, VI Prompt GQ1b IgM
N/N 0:23
Abbreviations: C. jejuni ⫽ Campylobacter jejuni CSF ⫽ Cerebrospinal fluid M ⫽ Male N ⫽ Normal
O:19 isolates was higher than that in GBS patients without O:19 isolates [3]. Yuki et al. [3] also reported that five of seven C. jejuni isolates from MFS patients belonged to serotype O:2. C. jejuni isolated from our patients in this study did not belong to either of these serotypes, but anti-GQ1b antibodies were detected in all three patients. Because C. jejuni serotypes O:4 and O:23 have been isolated from a GBS patient with elevated anti-GQ1b IgG antibody and from a MFS patient with elevated anti-GQ1b IgG antibody, respectively [7,14], C. jejuni strains belonging to these serotypes may have GQ1b-like structures. A close association was found between the presence of serum anti-GQ1b antibody and both MFS and GBS with
Figure 1. Longitudinal study of anti-GQ1b antibodies in three patients with idiopathic cranial polyneuropathy. Antibody titer more than 1:160 was regarded to be positive.
ophthalmoplegia [4]. An immunohistochemical study revealed that monoclonal antibody to GQ1b gangliosides strongly stained the paranodal regions of the extramedullary portion of the human oculomotor, trochlear, and abducens nerves. These results suggest the close relationship between anti-GQ1b antibody and ophthalmoplegia [5]. Histochemical studies revealed the crossreactivity of anti-GQ1b antibodies with surface epitopes on all C. jejuni strains isolated from five MFS patients [6,7]. Therefore it is believed that there is molecular mimicry between GQ1b ganglioside and surface epitopes on MFS-associated C. jejuni strains. Because both preceding C. jejuni infection and elevated anti-GQ1b antibodies declining with time after onset were exhibited by all three patients, the pathogenesis of idiopathic cranial polyneuropathy with ophthalomoplegia may be similar to that of MFS. Although there is albuminocytologic dissociation in most patients with GBS and MFS, protein concentrations in CSF were normal in our patients. In previous reports, CSF protein was normal in eight of 11 patients with idiopathic cranial polyneuropathy with ophthalmoplegia [1] and in all eight patients with idiopathic cranial polyneuropathy with predominant ocular involvement [15]. Albuminocytologic dissociation may be less frequent in idiopathic cranial polyneuropathy, especially in association with predominant ocular involvement than in GBS and MFS, probably resulting from restricted inflammatory changes in nerve roots. The three patients received supportive care only and improved spontaneously without specific treatment with intravenous immunoglobulin or plasmapheresis. However, these treatment modalities may be beneficial in patients with complete ophthalmoplegia because they seem to shorten the clinical course [15].
The authors thank Etsuko Nishiguchi for her technical assistance.
Kuroki et al: Ophthalmoplegia and C. Jejuni 73
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