| Background Herpes zoster(HZ)is an acute skin infection caused by the reactivation of the varicella-zoster virus(VZV)which is latent in the dorsal root ganglion or the geniculate ganglion.The incidence of HZ is about 4-4.5 per 1000 person-years,which is characterized by vesicular rash and burning pain.Postherpetic neuralgia(PHN)is the most common neurologic complication of HZ,accounting for 20-40%;whereas segmental zoster paresis of limbs(SZP)is a relatively rare complication,characterized by focal weakness of upper or lower extremity.The affected muscle groups were distributed by nerve roots,nerve plexuses or single nerve.The motor involvement was observed in 0.5-5%patients with HZ.The focal motor weakness appeared in the same segments where the skin eruptions occured,and occasionally the involved myotome was inconsistent with the dermatome in the literature.The upper limb weakness may occur if cervical spinal nerves were involved;while the lower limb weakness occured if lumbosacral spinal nerves were involved.Weakness involving cranial nerve muscles caused by HZ is common,accounting for about half,and the most common is Bell's paralysis.However,SZP is rare,and it is still under-recognized by clinicians.Misdiagnosis as cervical spondylosis or lumbar spondylosis and a delay in treatment may occur.The exact mechanism of SZP is not clear,although the spread of virus along the nerve to the adjacent anterior horns,anterior roots and peripheral nerve motor fibers is presumed.The existing literature mainly includes case reports.Comparatively,only few studies have described case series of SZP based on electrophysiological,imaging characteristics and prognosis data.Moreover,there are few neuroimaging data about SZP.In addition,antiviral medications and corticosteroids are the most commonly applied drugs for treating SZP.The prognosis for patients with SZP is generally favorable;however,in some extreme cases it can lead to permanent disability.Here,we investigated clinical,electrophysiological and imaging evidence in a case series of 8 patients with SZP,as well as possible factors influencing prognosis,in order to attract the attention of clinicians.Purpose 1.Analyze the clinical characteristics of SZP patients;2.Analyze the electrophysiological characteristics of SZP patients;3.Analyze the imaging characteristics of SZP patients;4.Analyze the factors that may affect the prognosis of SZP.Methods 1.Case collection and clinical evaluation The patient database in Shandong Provincial Qianfoshan Hospital was reviewed for coded diagnoses of HZ from June 2015 to July 2017.Patients who met the SZP diagnostic criteria were collected to analyze their clinical characteristics.According to the Medical Research Council scale,the degree of weakness and recovery of the affected muscle was assessed.All patients were followed up and evaluated for prognosis.The retrospective study was approved by the ethics committee at Shandong Provincial Qianfoshan Hospital.2.Electrophysiology Electromyograph was used to evaluate nerve injury.Surface electrodes were used to perform nerve conduction studies,including motor and sensory nerve conduction velocity(NCV),distal motor latency(DML),amplitudes of compound muscle action potentials(CMAPs)and sensory nerve action potentials(SNAPs).The needle Electromyography(EMG)was used to evaluate the amount of abnormal spontaneous potentials and the firing pattern of motor unit action potentials(MUAPs).A comparison with contralateral(asymptomatic)sides or normal values helped to determine the degree of damage.Demyelination was determined by NCV and DML.Axonal damage was determined by SNAPs,CMAPs and needle EMG.According to SNAPs and spontaneous activities in paraspinal muscles,associated limb was characterized as preganglionic,postganglionic lesions or combined pre-and postganglionic lesions,and then further identified as radiculopathy,plexopathy,radiculoplexopathy and peripheral neuropathy.3.Imaging The MRI results were reviewed by an experienced radiologist.All studies included both T1-and T2-weighted images in coronal planes,without gadolinium-enhanced T1-weighted images.Brachial plexus had a short time inversion recovery sequence.Nerve root,plexus,or peripheral nerve images were identified as abnormal if prolonged nerve T2 or nerve enlargement was shown based on comparison with contralateral neural structures within the imaging field.Results 1.Clinical characteristics Eight out of 1393 patients with HZ fulfilled the diagnostic criteria for SZP,accounting for 0.57%,which was confirmed by neurologic examination and electrodiagnostic evaluation.Rash distribution in all patients corresponded to weakness distribution.The right upper limb was involved in 5 patients,the right lower limb in 2 patients and left upper limb in 1 patient.There were 5 patients with PHN.Antiviral drugs were administered to 8 patients orally or intravenously.In addition,4 patients received short term use of oral corticosteroids.The prognosis was quite different.One patient recovered completely 3 months after symptoms onset two patients recovered partially and the remaining five patients did not recover until 0.5-2.0 years of follow-up.2.Electrophysiological characteristics The SNAPs and CMAPs amplitudes of affected nerves decreased significantly or were absent.NCV of the affected nerve was normal or slightly reduced,and DML was shorter than 130%of the upper limit of normal.All of these showed axonal lesions,not demyelinating lesions.All the patients showed different grades of spontaneous potentials in affected muscles.The average grade was 2+.There was a pattern of decreased recruitment of motor unit action potentials(MUAPs)in weak muscles.The abnormal spontaneous potentials in affected myotomes and the decreased recruitment of MUAPs suggested ongoing axonal lesions.According to spontaneous activities in paraspinal muscles and SNAPs amplitudes,2among 8 were diagnosed with radiculopathy;2/8 were characterized as having brachial plexopathy;and 4 out of 8 were recognized as radiculoplexopathy and peripheral neuropathy.3.Imaging characteristics The MRI examination was performed in 4 out of 8 patients no more than 1 week after electrophysiological testing.Scans of affected brachial plexus nerves and corresponding spine segments showed nerve enlargement and increased T2 signal.Two patients demonstrated nerve roots enlargement and increased T2 signal,one patient showed peripheral nerves hyperintensity,and one patient demonstrated hyperintensity in the dorsal horn.Conclusion1.SZP is a rare complication of HZ with a low incidence.2.SZP involved motor nerves and caused obvious limb weakness.The involved myotome was consistent with the involved dermatome;the affected muscle groups were distributed by nerve root,nerve plexus or single nerve.Electrophysiological examination confirmed the axonal damage of the affected nerves.3.MRI showed nerve enlargement and increased T2 signals of affected nerves.4.The prognosis of SZP varied greatly.In this study,some patients recovered completely or partially within a short time(3/8),while some patients(5/8)did not recover during 0.5-2.0 years of follow-up.5.The clinicians should pay enough attention to SZP to avoid misdiagnosis and delayed treatments.Background Myasthenia gravis(MG)is a T-cell-dependent,B-cell immediated autoimmune disease affecting the neuromuscular junction.It is caused by an immunologic attack on muscle acetylcholine receptor(AChR),muscle-specific tyrosine kinase(MuSK),or lipoprotein receptor-related peptide 4(LRP4)of the postsynaptic membrane due to antibodies.It presents with painless fluctuating weakness of muscle groups and the aggravation of weakness after exercise.At present,patients are mainly treated by taking cholinesterase inhibitors,immunosuppressants and adrenal corticosteroids.However,there are still some patients with poor condition,so it is urgent to explore new treatment strategies.Experimental autoimmune myasthenia gravis(EAMG)is a standard animal model of MG induced with AchR antigen or synthetic peptide corresponding to the region 97-116 of the rat AChR a subunit(R97-116 peptide).Its clinical manifestations and immunological changes are very similar to MG.Follicular helper T cells(Tfh)are a subgroup of T cells that specialize in B cell antibody production and are involved in many autoimmune diseases.They are characterized with B cell lymphoma factor 6(bcl-6),CXC chemokine receptor 5(CXCR5),inducible costimulator(ICOS)and programmed cell death protein 1(PD-1),and secrete IL-21.In peripheral blood of MG patients,the proportion of Tfh was significantly increased and positively correlated with the level of anti-AChR antibody in serum.In generalized MG patients without thymus abnormality,Tfh ratio is highly consistent with plasma cell level in peripheral blood,which may activate autoreactive B cells and contribute to MG.In addition,intrathymic Tfh may play a role in the pathogenesis of MG with thymoma.Germinal center(GC)B cells are crucial for antibody production.Tfh cells are pivotal for GC formation and maintenance,and for B cell differentiation into plasma cells and memory B cells.Dendritic cells(DCs)are important antigen presenting cells and play an important role in initiating the immune response.DCs may induce the development of Tfh.The humoral response from Tfh is involved in the development of MG and EAMG,along with GC B cells and DCs.Fingolimod(2-amino-2[2-(4-octylphenyl)ethy]-1,3-propanediol,FTY720)is a unique novel immunomodulatory that possesses a strong immunomodulator function.FTY720 is a sphingosine 1-phosphate(SIP)receptor antagonist,and plays an immunosuppressive role by binding to SIP receptor SIP1 to induce receptor downregulation.Since SIP1 is crucial for lymphocyte trafficking,the downregulation of SIP1 redistributes T and B cells from peripheral blood to secondary lymphatic tissues such as peripheral and mesenteric lymph nodes.It also induces medullary thymocyte phenotypic maturation and inhibits thymocyte emigration.Thus,FTY720 causes peripheral lymphopenia,reduces the numbers of lymphocytes reaching lesions,and decreases local infiltration.The main immunomodulatory effect of FTY720 is based on acceleration of lymphocyte homing.FTY720 has been studied in a variety of clinical conditions,including kidney transplantation and stroke,and approved as a treatment for patients with relapse-remitting multiple sclerosis.In addition to this,FTY720 inhibits T-dependent antibody responses and suppresses GC reaction in secondary lymphoid organs,leading to a diminished production of high-affinity,isotype-switched specific antibodies.It has been found that preventive administration of FTY720 can prevent the development of EAMG.Nevertheless,the exact mechanisms remain unclear,and the effect of FTY720 on Tfh cells remains unknown.Objective The aim of the present study was to examine the effect of a preventive administration of FTY720 on EAMG rats and the effect on Tfli cells and their subsets,GC B cells,memory B cells,DCs,and spleen and bone marrow antibody secreting cells(ASCs).Methods1.EAMG induction and clinical score Rats were immunized with synthetic R97-116 peptide,corresponding to the ? 97-116 region(DGDFAIVKFTKVLLDYTGHI)of the rat AChRa subunit at the base of the tail on day 0,and with a boost immunization on day 30 post immunization(p.i.).According to Lennon scoring standards,EAMG rats were clinically graded every other day.2.Administration of FTY720 EAMG rats were randomly divided into two groups: the control group and the FTY720 group.FTY720 was administered at 1 mg/kg(dissolved in distilled water)orally every other day from day 0 to day 46 p.i..The control group was given distilled water.3.Detection of T and B cells in peripheral blood by FACS The Cardiac blood from EAMG rats was obtained at the peak of the disease,and the absolute number of T,B,CD3+CD4+ and CD3+CD4- T cells in each microliter of blood was detected.4.Detection of thymocytes by FACS The thymus of EAMG rats was removed at the peak of the disease,and the proportion of CD4+CD8-,CD4-CD8+,CD62L+CD4+CD8-and CD62L+CD4-CD8+ thymocytes was detected.5.Detection of T,B,DCs and ASCs in spleen mononuclear cells(MNCs)by FACS Spleen was removed from EAMG rats at the peak of the disease,and the total number of spleen MNCs,CD3+ T,CD4+T,Th1(CD4+IFN-?+),Th2(CD4+IL-4+),Th17(CD4+IL-17+),Tfh(CD4+CXCR5+ or CD4+CXCR5+ICOS+)and its subtypes,Tfh1(CD4+CXCR5+IFN-?+ or CD4+CXCR5+ICOS+IFN-?+),Tfh2(CD4+CXCR5+IL-4+ or CD4+CXCR5+ICOS+IL-4+),Tfh17(CD4+CXCR5+IL-17+or CD4+CXCR5+ICOS+IL-17+).The percentage and absolute number of B220+,GC B and memory B cells were detected,as well as DCs,B220-IgG+ ASCs,B220+IgG+ ASCs,B220-Igkappa+ ASCs and B220+Igkappa+ ASCs.6.Detection of ASCs in bone marrow MNCs by FACS The rat femur was removed at the peak of the disease,bone marrow MNCs were prepared,and B220-IgG+ and B220-Igkappa+ ASCs were detected.7.Detection of serum anti-R97-116 antibodies and isotypes by ELISA EAMG rat serum was obtained on day 15,30 and 46 p.i.respectively to detect antiR97-116 IgG and isotypes IgG1,IgG2a and IgG2b.8.Detection of the effect of FTY720 on Tfh differentiation by FACS in vitro Splenic MNCs of EAMG rats were prepared.The percentage of Tfh was detected in the absence or presence of different concentrations of FTY720.9.Data processing and statistical analysis Data were analyzed and processed by Graphpad prism 6.0 and SPSS 22.0 software.A two-tailed unpaired Student's t-test with a 95% confidence interval or a nonparametric two-tailed Mann-Whitney test was used to calculate the P values.Comparisons among more than two groups were carried out using one-factor analysis of variance(ANOVA)followed by the least significant difference(LSD)post-hoc test.P values < 0.05 were considered statistically significant.The absolute counts of various T,B cells,DCs and ASCs were obtained by multiplying total spleen or bone marrow MNCs counts by their respective frequency.Results1.FTY720 prevents the development of EAMG Administration of FTY720 alleviated EAMG rats.Compared with the control group,the rats in FTY720 group presented milder clinical symptoms and lower clinical scores on day 32,34,40,42and 46 p.i.,with statistically significant differences.2.FTY720 reduces anti-R97-116 IgG antibodies productionWith the progression of disease,anti-R97-116 IgG antibodies in the control group increased steadily from day 15 to 46 p.i.,while the increase was significantly less important in the FTY720 group(P < 0.05 for both comparison).On day 30 p.i.,the protective antibody IgG1 and destructive antibody IgG2b both decreased,but the IgG1/IgG2b ratio increased.At day 46 p.i.,IgG2b decreased in the FTY720 group.3.FTY720 causes lymphopenia in peripheral blood of EAMG rats Compared with the EAMG control group,the number of lymphocytes in peripheral blood of FTY720 group was significantly reduced.FTY720 lowered the absolute number of T,B,CD3+CD4+ T,and CD3+CD4- T cells per microliter blood,with a statistical significance.4.FTY720 inhibits thymocytes emigration in EAMG rats FTY720 inhibited emigration of single positive thymocytes(CD4+CD8- and CD4-CD8+)and mature thymocytes(CD62L+CD4+CD8- and CD62L+CD4-CD8+).5.FTY720 reduces the absolute number of splenic MNCs,CD3+ T,CD4+ T,Th1,Th2,Th17,Tfh and subtypes Tfh1,Tfh2,and Tfh17 Compared with the EAMG control group,FTY720 reduced the total number of spleenMNCs,CD3+T,CD4+T,Th1(CD4+IFN-?+),Th2(CD4+IL-4-),Th17(CD4+IL-17+),Tfh(CD4+CXCR5+ and CD4+CXCR5+ICOS+)and its subtypes,Tfh1(CD4+CXCR5+IFN-?+ and CD4+CXCR5+ICOS+IFN-?+),Tfh2(CD4+CXCR5+IL-4+ and CD4+CXCR5+ICOS+IL-4+),Tfh17(CD4+CXCR5+IL-17+ and CD4+CXCR5+ICOS+IL-17+).6.FTY720 reduces the absolute number of DCs in spleen Compared with the EAMG control group,FTY720 reduced the absolute amount of OX62+MHCII+ DCs in the spleen.7.FTY720 changes the number of B cells in the spleen FTY720 reduced the total number of B220+ B in the spleen,but did not affect the absolute number of GC B and memory B cells.8.FTY720 reduces the number of ASCs in the spleen FTY720 reduced the absolute number of B220-IgG+,B220+IgG+,B220-Igkappa+ and B220+Igkappa+ ASCs in the spleen.9.FTY720 at different concentrations has no effect on Tfh differentiation in vitro The spleen MNCs of EAMG rats were cultured for 48 hours in the absence or presence of different concentrations of FTY720,and the proportion of Tfh was detected by FACS.There was no difference between the groups,suggesting that FTY720 had no effect on the differentiation of Tfh in vitro.Conclusion In conclusion,administration of FTY720 inhibited emigration of thymocytes,decreased the numbers of spleen CD3+T,CD4+T and Th1,Th2,Th17,Tfh(including Tfh1,Tfh2,and Tfh 17),decreased spleen DCs,decreased spleen and bone marrow ASCs,and thereby reduced serum antibody levels,which prevented the clinical progression of EAMG in rats. |
PDF Full Text Request