Sachiko Irie

Association of anti-GM2 antibodies in Guillain-Barré syndrome with acute cytomegalovirus infection

We examined serum anti-cytomegalovirus (CMV) and anti-ganglioside antibodies by ELISA in 51 patients with Guillain-Barré syndrome (GBS), and titers were compared with those from 47 normal and 74 disease controls. Three GBS patients with IgM anti-CMV antibodies had high titers of IgM and IgG anti-GM2 antibodies. The other GBS patients without IgM anti-CMV antibodies, and the normal and disease controls except one of 6 non-GBS patients with acute CMV infections had no anti-GM2 antibodies. The titers of anti-GM2 antibodies decreased on absorption with CMV-infected cells. These findings suggest that anti-GM2 antibodies are associated with acute CMV infections in GBS patients.

Tryptophan-immobilized Column-based Immunoadsorption as the Choice Method for Plasmapheresis in Guillain–Barré Syndrome

Abstract:  Plasmapheresis is widely performed as treatment for patients with Guillain–Barré syndrome (GBS) in the acute phase. As tryptophan‐immobilized column‐based immunoadsorption (Tr‐IA) is a safer method than either double‐filtration plasmapheresis (DFPP) or plasma exchange (PE), we investigated whether or not Tr‐IA is as effective as other methods, and should be selected as the procedure of choice in patients with GBS. We retrospectively compared clinical outcomes, using Hughes grading, in GBS patients treated with Tr‐IA, DFPP or PE. The outcome in the Tr‐IA group was also compared historically with patients treated by PE in seven previous studies. We studied 34 patients with GBS: 20 were treated with Tr‐IA, 11 with DFPP, and 3 with PE. The age, sex, duration from onset to initiation of treatment, and Hughes grade at entry did not differ among the Tr‐IA, DFPP and PE groups. There was no significant difference in outcomes among these three groups, nor was there a significant difference between the outcomes in the Tr‐IA and DFPP groups with respect to subgroups of Hughes grade at entry. Also, our Tr‐IA group did not show a different outcome from the previously reported patients treated with PE. The frequency of complications in our Tr‐IA group is significantly lower than that in both our DFPP group, and in the previously reported cases of patients treated with PE. Tr‐IA, DFPP and PE have almost the same efficacy in patients with GBS, but Tr‐IA is recommended as the plasmapheresis method of choice because of its safety.

A case of parkinsonism and dopa-induced severe dyskinesia associated with novel mutation in the GTP cyclohydrolase I gene.

Autosomal dominant hereditary dystonia with the guanosine triphosphate (GTP) cyclohydrase I (GCH1) gene abnormality is currently known as Segawa disease or DYT 5 [1,2], which is also known as dopa-responsive dystonia. GCH1 is an enzyme involved in the biosynthesis of tetrahydrobiopterin (BH4), which is an essential cofactor for tyrosine hydroxylase (TH). More than 100 mutations have been reported in the GCH1 gene (BIOMDB Database, online at http://www.bh4.org/BH4_databases_biomdb2.asp). We report here a novel splicing mutation in intron 3 of GCH1 gene (IVS3 þ1G > A) in a male patient with middle-age-onset Segawa disease with parkinsonism. A 66-year-old man had suffered from parkinsonism for 19 years and developed severe dyskinesia after 5-years’ treatment with Ldopa. At age 47 years, he had noticed difficulty in writing and handling objects due to coarse tremor in the upper limbs and small steps. Neurological examination elsewhere at age 48 years showed postural tremor of the right hand and mild rigidity in all four limbs, predominantly on the right. He was tentatively diagnosed with Parkinson’s disease and began treatment with L-dopa/ carbidopa. His condition improved markedly with 100 mg/day of L-dopa/carbidopa; however, he soon complained of gait disturbance due to difficulty initiating gait. There was no improvement following an increase in L-dopa/carbidopa to 300 mg/day. After treatment with L-dopa for 5 years, he had developed dyskinesia and wearing-off phenomena. By the time he was referred to us at age 57 years, he showed mild rigidity and chorea-like severe dyskinesia in all four limbs, associated with mild dystonic posturing of the hands and feet when he walked. He had severe peak-dose dyskinesia, which only disappeared when he was ‘off’. There was no improvement with pergolide at a dose of 1000 mg/day. His difficulty walking was relatively well controlled following an increase in L-dopa/carbidopa to 500 mg/day, while dyskinesia increased. The patient suffered frequent falls, some resulting in injury. The patient’s 42-year-old niece had dopa-responsive limb dystonia and cervical dystonia of 29and 26-year duration, which

No cytomegalovirus DNA in sera from patients with anti-MAG/SGPG antibody-associated neuropathy.

with Anti-MAG/SGPG Antibody–Associated Neuropathy Sachiko Irie, MD, PhD,* Naomi Kanazawa, BS,† Mieko Ogino, MD, PhD,* Toyokazu Saito, MD, PhD,* and Tadao Funato, PhD‡ In a recent study by Yuki and colleagues, cytomegalovirus (CMV) DNA was detected in sera from 23 of 26 patients (88%) with IgM anti-myelin–associated glycoprotein (antiMAG)/sulfated glucuronyl paragloboside (SGPG) antibody– associated neuropathy. Anti-MAG/SGPG antibody–associated neuropathy is a slowly progressive neuropathy and generally occurs in elderly patients with IgM M proteinemia. It has been experimentally confirmed that immunization with MAG and transfer of anti-MAG/SGPG antibodies cause demyelinating neuropathy. Yuki and colleagues suggested that CMV infections induce IgM anti-MAG/SGPG antibodies based on the results of their study. We also examined serum CMV DNA by means of the polymerase chain reaction (PCR) assay in 13 patients with IgM M proteinemia and anti-MAG/SGPG antibody–associated neuropathy. Serum IgM anti-MAG antibodies were detected by immunoblotting, and serum IgM anti-SGPG antibodies were detected by thin-layer chromatography immunostaining. For the PCR, primers were synthesized from genomic CMV DNA sequences based on the major immediate early gene of the Towne strain, which were confirmed not to cross-react with other herpes viruses. The PCR was also performed in all of these patients using primers derived from the early gene corresponding to the DNA polymerase of CMV. In the PCR for both genes, serum CMV DNA was negative in all patients, in 1 of whom it was examined at another point during the course of the study. CMV DNA was also negative in blood cells from 3 patients. CMV usually causes latent infections throughout life. Ninety-five percent of the Japanese population has latent CMV infections. In compromised hosts, including fetuses, transplant patients, and acquired immunodeficiency syndrome patients, CMV causes pantropic organic disturbances. A CMV infection is confirmed by the detection of CMV DNA in samples of organs or tissues obtained by biopsy. CMV DNA detection in serum or blood cells should indicate the activation or reactivation of CMV. Therefore, primary infections or reinfections could occur in patients with CMV DNAemia. Yuki and co-workers did not mention whether their patients showed symptoms caused by direct CMV infections or whether they had high titers of serum IgG anti-CMV antibodies representing continuous CMV infections. In conclusion, we could not find any correlation between anti-MAG/SGPG antibody–associated neuropathy and serum CMV DNA. Further investigations are necessary to clarify whether patients with anti-MAG/SGPG antibody–associated neuropathy have CMV DNAemia or not.

The relation of clinical symptoms and anti-ganglioside antibodies to MEPPs frequency increase in 8 cases of variant type Guillain-Barré syndrome

Abstract Many patients with variant forms of Guillain‐Barré syndrome (vGBS) associated with anti‐ganglioside antibodies, including Miller Fisher syndrome (MFS), sometimes exhibit miniature endplate potential (MEPP) frequency increases (MFI, described as α‐latrotoxin‐like effects in a previous report) and the factor to produce this effect is present in their sera. MFI‐positive sera increase the frequency of MEPPs, then block neuromuscular transmission at the mouse neuromuscular junction. A connection between this effect at the neuromuscular junction and some vGBS symptoms is suspected. We measured MFI directly at several points during the clinical course of 8 vGBS patients who had various symptoms and courses. Six patients had confirmed MFI and this activity decreased with convalescence. In 3 clinically mild cases, we were able to elicit MFI using normal serum to supply complement after exposure to the patients serum. The anti‐GQ1b/GT1a IgG titer, the extent of ophthalmoplegia and the extent of MFI were significantly correlated. They did not correlate with the severity of limb weakness or the occurrence of respiratory failure. These results support the hypothesis that MFI caused by anti‐ganglioside antibodies is the pathogenic mechanism responsible for ophthalmoplegia in vGBS; different mechanisms or antibodies may explain limb weakness and respiratory failure. Furthermore, MFI may be an important indicator of how serum injures the nerve terminals. The symptoms of vGBS may result from multiple pathogenic factors.