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The clinical features of combined central and peripheral demyelination in Chinese patients
Journal of Neuroimmunology 317 (2018) 32–36
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The clinical features of combined central and peripheral demyelination in Chinese patients Yan-Qin Wanga, Han Chena, Wu-Ping Zhuanga, Hong-Lei Lib,
T
⁎
a
Fuqing Hospital of Fujian Province, The Affiliated Fuqing Hospital to Fujian Health College, China Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Medical Neurobiology, Zhejiang Province, Hangzhou, China b
A R T I C L E I N F O
A B S T R A C T
Keywords: Combined central and peripheral demyelination (CCPD) Multiple sclerosis (MS) Neuromyelitis optical spectrum disorders (NMOSD) Chronic inflammatory demyelinating polyneuropathy (CIDP) Guillain-Barre syndrome (GBS)
Background: Combined central and peripheral demyelination (CCPD) is rare and has never been reported as a spectrum disease in Han Chinese population. Objectives: To study the clinical features of CCPD in Han Chinese patients. Methods: Twenty-two CCPD patients were selected from 788 demyelination cases. We reviewed and compared the clinical manifestation, laboratory data, electrophysiological examination, MRI and the prognosis. Results: CCPD patients presented with sensory disturbance (86.4%), plegia (77.3%), cranial nerve involvement (77.3%), abnormal deep tendon reflexes (72.7%). CSF data showed increased CSF protein in 81% patients. Oligoclonal IgG bands (OB) were negative. Cortical or juxtacortical, periventricular, infratentorial lesions, thoracic and cervical spinal cord were mostly affected. Visual evoked potentials indicated optic nerves demyelinating in 50% cases. 21 CCPD patients were treated with intravenous immunoglobulin or steroids or both of them, and the efficacy was 33.3%, 54.5%, 71.4%, respectively. One case that showed no response to steroids plus intravenous immunoglobulin treatment was improved significantly after using cyclophosphamide. Conclusions: CCPD is a spectrum disease that can't be regarded as a simple combination of MS and CIDP. A suspected CCPD should receive brain and spinal MRI as well as electrophysiological examination to obtain a precise diagnosis.
1. Introduction In the common concept, inflammatory demyelinating disorders selectively affect either the central or peripheral nervous system, such as multiple sclerosis (MS) or chronic inflammatory demyelinating polyneuropathy (CIDP). But concurrent central and peripheral demyelination is a real-world phenomenon. Forrester and Lascelles firstly reported 2 cases of MS and polyneuritis in 1979 (Forrester and Lascelles, 1979). In 1987 a series of 6 cases were reported firstly proposing the name of combined central and peripheral demyelination (CCPD), which was not widely appreciated at that time (Thomas et al., 1987). Since then some case reports or case series have been reported about CCPD but using different diagnostic names such as MS with peripheral neuropathy, CIDP with central demyelination or Guillain-Barre syndrome (GBS) and acquired central nervous system (CNS) demyelinating, etc. (Falcone et al., 2006; Krivickas et al., 2006; Mao and Hu, 2014; Mehndiratta and Gulati, 2014). But combined central and peripheral demyelination (CCPD) has never been reported as a spectrum disease in Han Chinese population. ⁎
In this study, in order to investigate CCPD as a spectrum disease to gain a better understanding and avoid misdiagnosis, we reviewed and compared the clinical manifestation, laboratory data, results of the nerve conduction study (NCS), magnetic resonance imaging (MRI) and the prognosis of 22 CCPD patients enrolled in our department. To our understanding, this is the first study on CCPD in Chinese population. 2. Methods 2.1. Study subjects This is a retrospective, observational analysis in the Second Affiliated Hospital of Zhejiang University School of Medicine between January 2014 and January 2017. All the study subjects were in hospital and were evaluated by at least two experienced neurologists. In our study, the criteria of CCPD are determined as follows, referring to a nationwide survey of CCPD in Japan (Ogata et al., 2016): 1) peripheral nervous system (PNS) involvement criteria:
Corresponding author at: No 88, Jiefang Road, Hangzhou, Zhejiang, China. E-mail address: [email protected] (H.-L. Li).
https://doi.org/10.1016/j.jneuroim.2018.02.006 Received 9 November 2017; Received in revised form 30 December 2017; Accepted 5 February 2018 0165-5728/ © 2018 Elsevier B.V. All rights reserved.
Journal of Neuroimmunology 317 (2018) 32–36
Y.-Q. Wang et al.
amounts of protein, anti-gangliosides, anti AQP-4 antibodies, oligoclonal IgG bands (OB). Brain and spinal MRI were performed on a 1.5 T/3.0 T MR scanner. NCS were performed at the median, ulnar, tibial, common peroneal, superficial peroneal and sural nerves. The modified Rankin Scale (mRS) was employed to measure disability and prognosis. Improvers were defined as patients who were recorded an increase of at least one point on the mRS 30 days after treatment. Variables were analyzed by descriptive statistics and expressed by the mean (standard deviation-SD) or frequency. The mean (SD) NCS parameters of the p-CNSD patients were recorded and compared with the p-PNSD patients by a two-sample of t-test: p value < 0.05 were considered to be statistically significant. We used Statistical Package of Social Science (SPSS 15.0) for all statistical analyses.
a. Supportive symptoms: lower paralysis, glove and stocking sensory disturbance, muscle atrophy, hyporeflexia (> 1 month). b. Necessary (Ogata et al., 2016): NCS indicated immediate prolonged distal latency, decreased motor conduction velocity (MCV)/sensory conduction velocity (SCV), decreased or absent compound muscle action potential (CMAP)/sensory nerve action potential (SNAP), F-Waves/H-reflex abnormalities; CSF albuminocytologic dissociation. 2) central nervous system (CNS) involvement criteria: a. Supportive symptoms: upper paralysis, sphincter disturbance, sensory level, hyperreflexia, pathological sign, decreased vision, epilepsy, mental disturbance, and unconsciousness. b. Necessary (Ogata et al., 2016): T2 high-signal intensity lesions in the brain, optic nerves or spinal cord on MRI, or abnormalities on visual-evoked potentials (VEPs). 3) exclusion criteria (Ogata et al., 2016): secondary demyelinating diseases or changes, such as infectious diseases (e.g., human T lymphocyte trophic virus type 1-associated myelopathy, syphilis, neuroborreliosis, HIV infection or progressive multifocal leucoencephalopathy), pre-existing inflammatory diseases (e.g., sarcoidosis, Behçet's disease, Sjögren's syndrome, vasculitis or other collagen diseases), mitochondrial disease, metabolic/toxic diseases (e.g. Vitamin deficiency, amyloidosis, chronic alcoholism, diabetes mellitus or subacute myelo-opticoneuropathy due to clioquinol intoxication, cervical spondylotic myelopathy, syringomyelia, spinocerebellar degeneration, multiple myeloma, other tumors, inherited diseases (e.g., leucodystrophies), cerebrovascular disease and nonspecific lesions on T2-weighted MRI (e.g., leucoaraiosis).
3. Results 3.1. Demographic data The proportion of men and women was just 1:1; and the mean onset age was 47.72 ± 13.15 years (range, 23-68 years). The number of patients with antecedent infection was 5 (22.7%). The model of onset was acute in 12 cases (54.5%), subacute in 3 (13.6%) and chronic in 7 (31.8%). Disease courses were monophasic in 15 cases (68.1%), relapsing-remitting in 3 (13.6%) and chronic-progressive in 4 (18.2%), respectively (Table 1). 3.2. Prevalence
Patients with CCPD may involve CNS and PNS simultaneously or subsequently. The duration of sequential attack was defined as two months (Ogata et al., 2016). Onset of CCPD was defined as acute (within 1 month), subacute (1–2 months) or chronic (> 2 months), and the disease course was classified as monophonic, relapsing-remitting or chronic-progressive. The target patients were divided into two groups. One was CCPD patients primarily diagnosed as CNS demyelinating patients (p-CNSD). There were 125 multiple sclerosis, 178 neuromyelitis optical spectrum disorders and 145 spinal demyelination patients. The revised 2010 McDonald Criteria (Polman et al., 2011) and the 2015 International consensus diagnostic criteria (Wingerchuk et al., 2015) were applied for the diagnosis of MS and NMOSD respectively. According to the CCPD criteria, 12 p-CNSD patients were diagnosed with CCPD, including 4 MS, 4 NMOSD and 4 Spinal demyelination patients. The other group was CCPD patients primarily diagnosed as PNS demyelinating patients (p-PNSD). There were 241 Guillain-Barre syndrome (GBS) patients and 99 CIDP patients. GBS fulfilled the new diagnostic classification in 2014 and CIDP fulfilled the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria (Van den Bergh et al., 2010; Wakerley et al., 2014). According to the CCPD criteria, 10 p-PNSD patients were diagnosed with CCPD finally, including 9 GBS patients and 1 CIDP patient. Finally, 22 patients from 788 demyelination cases fulfilled the CCPD criteria.
In this study, there were 4 patients diagnosed with both MS and PNS demyelination from 125 MS patients (3.2%), 4 patients diagnosed with both NMOSD and PNS demyelination from 178 NMOSD patients (2.2%), 4 patients diagnosed with both Spinal demyelination and PNS demyelination from 145 Spinal demyelination patients (2.8%), 9 patients diagnosed with both GBS and CNS demyelination from 241 GBS patients (3.7%), 1 patient diagnosed with both CIDP and CNS demyelination from 99 CIDP patients (1.0%). 3.3. Clinical manifestations The majority of the 22 CCPD patients presented with sensory disturbance (86.4%), plegia (77.3%), cranial nerve involvement (77.3%), and deep tendon reflexes (72.7%), followed by pathological sign (27.3%), ataxia (18.2%), sphincter disturbance (18.2%) and muscle atrophy (18.2%), sequentially. Respiratory disturbance was observed in two cases. Unconsciousness (1/22), mental disturbance (1/22), epilepsy (1/22) were rare. The common symptoms and onset of p-CNSD and pPNSD were different. For p-CNSD, subjective paresthesia (5/9) was common, and half of the p-PNSD patients were found to have a sensory Table 1 Demographic data of CCPD patients.
2.2. Data collection
Demographics Gender (male/female) Onset age (years, mean ± SD) Disease model Acute Subacute Chronic Disease course Monophasic Relapsing-remitting Chronic-progressive Previous infection
The initial clinical data was collected by accessing the medical records, and the follow-up data was obtained from the outpatients' clinic or a telephone visit during January 2014 to January 2017 in the Second Affiliated Hospital of Zhejiang University School of Medicine. The laboratory data included: whole blood routine, blood biochemistry, glycosylated hemoglobin (HbA1C), vitamin12, folate, homocysteine, serum immunoglobulin, serology for human immunodeficiency virus, hepatitis C virus, syphilis, anti-dsDNA, antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), thyroid hormone level, Rheumatoid factor (RF), CSF IgG Index,
Note: CCPD (combined central and peripheral demyelination).
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11/11 47.72 ± 13.15 n/N (%) 12/22 (54.5%) 3/22 (13.6%) 7/22 (31.8%) 15/22 (68.1%) 3/22 (13.6%) 4/22 (18.2%) 5/22 (27.2%)
Journal of Neuroimmunology 317 (2018) 32–36
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Table 2 Comparison of the common clinical features between p-CNSD and p-PNSD.
Sensory disturbance Subjective paresthesia Sensory level Glove and stocking type Plegia Paraplegia The four limbs Double upper limbs Double lower limbs Hemiplegia Cranial nerve involvement Decreased vision Unilateral Bilateral Diplopia Facial paralysis Bulbar paralysis Tongue paralysis Deep tendon reflexes Hyporeflexia Hyper-reflexia Both hyporeflexia and hyper-reflexia
p-CNSD
p-PNSD
9/22 (40.8%) 5/22 (22.7%) 3/22 (13.6%) 1/22 (4.5%) 9/22 (40.8%) 6/22 (27.2%) 2/22 (9.1%) 1/22 (4.5%) 3/22 (13.6%) 3/22 (13.6%) 12/22 (54.5%) 4/22 (18.2%) 2/22 (9.1%) 2/22 (9.1%) 2/22 (9.1%) 2/22 (9.1%) 2/22 (9.1%) 2/22 (9.1%) 7/22 (31.8%) 4/22 (18.2%) 3/22 (13.6%) 0/22 (0.0%)
10/22 (45.5%) 3/22 (13.6%) 5/22 (22.7%) 2/22 (9.1%) 8/22 (36.4%) 8/22 (36.4%) 5/22 (22.7%) 2/22 (9.1%) 1/22 (4.5%) 0/22 (0.0%) 5/22 (22.7%) 0/22 (0.0%) 0/22 (0.0%) 0/22 (0.0%) 1/22 (4.5%) 2/22 (9.1%) 1/22 (4.5%) 1/22 (4.5%) 9/22 (40.8%) 8/22 (36.4%) 0/22 (0.0%) 1/22 (4.5%)
Table 4 MRI findings in CCPD.
Brain Cortical or juxtacortical lesion Periventricular lesions Three or more lesions Less than three lesions Infratentorial lesions Optic nerve lesion T1 lesions with Gd-enhanced Spinal cord Cervical Thoracic Lumbosacral Focal Multifocal LETM T1 lesions with Gd-enhanced
All patients
p-CNSD
p-PNSD
15 5/15 (33.3%) 5/15 (33.3%) 4/15 (26.7%) 1/15 (6.7%) 4/15 (26.7%) 0/15 (0.0%) 1/15 (6.7%) 21 11/21 (52.4%) 9/21 (42.8%) 1/21 (4.8%) 4/21 (19.0%) 4/21 (19.0%) 13/21 (61.9%) 2/21 (9.5%)
11 4/11 (36.4%) 4/11 (36.4%) 4/11 (36.4%) 0/11 (0.0%) 3/11 (27.3%) 0/11 (0.0%) 0/11 (0.0%) 6 4/6 (66.7%)
4 1/4 (25%) 1/4 (25%) 0/4 (0.0%) 1/4 (25%) 1/4 (25%) 0/4 (0.0%) 1/4 (25%) 15 7/15 (46.7%)
2/6 0/6 2/6 0/6 4/6
7/15 1/15 2/15 4/15 9/15
(33.3%) (0.0%) (33.3%) (0.0%) (66.7%)
0/6 (0.0%)
(46.7%) (6.7%) (13.3%) (26.7%) (60%)
2/15 (13.3%)
Note: All data was reported as number of cases (%). CCPD (Combined central and peripheral demyelination), p-CNSD (primary-diagnosed CNS demyelinating), p-PNSD (primary-diagnosed PNS demyelinating), MRI (magnetic resonance imaging), LETM (longitudinally extensive transverse myelitis).
Note: CCPD (combined central and peripheral demyelination), p-CNSD (primary-diagnosed CNS demyelinating), p-PNSD (primary-diagnosed PNS demyelinating).
showed increased IgG Index. In addition, OB was negative in six patients delete. Table 3 showed the peripheral blood tests. One patient had positive antiganglioside Ab, three had positive Anti-AQP4 Ab. All ANA, anticardiolipin Ab, anti-SSA ab, anti-SSB ab, anti-RO52 Ab, RF, syphilis, HIV, hepatitis B and C were negative.
level. Paraplegia, diplopia, facial paralysis, bulbar paralysis and tongue paralysis were present in both of the two subgroups, but the p-PNSD group did not show hemiplegia or decreased vision. More than half (4/ 7) of the p-CNSD presented with hyporeflexia, while all 8 p-PNSD patients showed hyporeflexia except one with mixed reflexes (Table 2).
3.5. MRI and VEPs
3.4. Laboratory findings
Table 4 showed brain and spinal cord lesions findings in CCPD patients. Among the brain MRI, cortical or juxtacortical, periventricular, infratentorial and optic nerve lesion were found in 33.3% (5/15), 33.3% (5/15), 26.7% (4/15) and 0% patients respectively. Among the spinal cord MRI, cervical, thoracic and lumbosacral spinal cord lesions were found in 52.4% (11/21), 42.8% (9/21) and 4.8% (1/21) patients respectively. And there were significant difference in the distribution of brain and spinal cord lesions between the two groups (11/4 vs. 6/15, p < 0.05). P-CNSD patients had more brain lesions, especially the periventricular lesions, which were three or more. P-PNSD patient's spinal lesions including focal lesion, multifocal lesions and longitudinally extensive transverse myelitis were found in 13.3%, 26.7% and 60% patients, respectively. Only one patient was found a T1 lesions with Gd-enhanced in brain MRI and two patients had Gd-enhanced spinal cord lesions. And the three patients were all diagnosed as PNS demyelination patients primarily (Table 5). VEPs disclosed optic nerves demyelinating in 50% of the patients.
CSF data (Table 3) showed increased CSF protein and albuminocytologic dissociation in 81% and 47.7% patients, respectively. There were eight patients who showed increased cell-counts and four cases Table 3 Laboratory examination of 22 patients with CCPD. CSF
n/N (%)
Increased CSF protein Cell-counts > 5/μl Albuminocytologic dissociation Increased IgG Index OB
17/21 (81%) 8/21 (38.1%) 10/21 (47.7%) 4/18 (22.2%) 0/6 (0.0%)
Blood
n/N (%)
Antiganglioside Abs Anti-AQP4 Ab ANA Anticardiolipin Ab ANCA Anti-SSA Ab Anti-SSB Ab Anti-RO52 Ab RF Thyroid function disorder High CRP level High HbA1C level Low VitaminB12 level
1/9 (11.1%) 3/8 (37.5%) 0/20 (0.0%) 0/20 (0.0%) 0/20 (0.0%) 0/20 (0.0%) 0/20 (0.0%) 0/20 (0.0%) 0/19 (0.0%) 0/19 (0.0%) 0/21 (0.0%) 0/20 (0.0%) 0/19 (0.0%)
3.6. Nerve conduction study In motor NCS, decreased conduction velocity of peroneal and median nerve was the most frequently affected, and were recognized in 72.2% and 50% of our study subjects respectively. F-wave was detected only in 9 cases and H-reflex only in 4 patients. Decreased or absent Fwave and H-reflex were the most common results, presenting in 88.9% (8/9) and 66.7% (4/6) of CCPD patients, respectively. In sensory NCS, median and peroneal nerve also was the most frequently affected. Decreased or absent amplitude was present in 61.1% and 68.8% of CCPD patients, respectively; while decreased conduction velocity was 46.8%. This study measured and compared the amplitude, latency, and conduction velocity of the p-CNSD and p-PNSD patients. The results suggested distal latency of median and ulnar motor nerve of p-CNSD
Note: CSF (cerebrospinal fluid), Ab (antibodies), OB (oligoclonal IgG bands), AQP-4 (aquaporin 4), ANA (antinuclear antibody), ANCA (antineutrophil cytoplasmic antibody), CRP (C reactive protein), HbA1C (glycosylated hemoglobin), RF (Rheumatoid factor). One patient did not do the lumbar puncture because of skin infection.
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Table 5 Comparison of NCS features between p-CNSD and p-PNSD. Prolonged distal latency (n/N)
Decreased or absent amplitude (n/N)
Decreased CV (n/N)
M of p-CNSD (SD)
M of p-PNSD (SD)
P value
M of p-CNSD (SD)
M of p-PNSD (SD)
P value
M of p-CNSD (SD)
M of p-PNSD (SD)
P value
Motor Median Ulnar Peroneal Tibial
3.23 1.93 3.04 4.01
± ± ± ±
0.497 0.32 1.35 1.71
5.12 3.13 3.84 4.52
0.037 0.007 0.33 0.65
8.43 7.41 4.32 7.98
7.62 7.38 5.01 7.45
0.759 0.99 0.68 0.86
48.38 54.96 36.95 38.38
± ± ± ±
7.75 15.08 14.98 15.22
49.32 53.06 34.48 34.76
± ± ± ±
6.77 9.44 15.31 14.57
0.81 0.76 0.73 0.61
Sensory Median Ulnar Sural Peroneal
2.78 1.98 1.69 2.08
± ± ± ±
0.68 0.25 0.77 0.93
2.8 ± 0.99 2.46 ± 1.04 2.01 ± 0.51 2.51 ± 0.78
0.96 0.23 0.31 0.31
7.29 ± 6.42 7.16 ± 4.73 11.67 ± 11.09 5.94 ± 4.15
0.806 0.83 0.25 0.14
47.68 53.02 45.78 37.94
± ± ± ±
11.65 7.22 19.1 16.07
50.96 45.73 48.36 39.02
± ± ± ±
12.84 12.74 6.43 8.93
0.60 0.18 0.71 0.86
± ± ± ±
2.05 0.91 1.98 2.82
± ± ± ±
4.31 4.95 2.81 6.67
± ± ± ±
5.90 4.95 4.05 6.06
8.05 ± 5.69 7.72 ± 5.73 18.01 ± 11.51 10.62 ± 8.06
Note: CCPD (combined central and peripheral demyelination), p-CNSD (primary-diagnosed CNS demyelinating), p-PNSD (primary-diagnosed PNS demyelinating), M (Mean), CV (conduction velocity).
onset was found to be more common than subacute or chronic, while a monophasic course was more often than a relapsing or chronic progressive course. A cohort study based on a literature review showed that CNS demyelinating might occur early in the GBS course (Mao and Hu, 2014). It was thought that antibodies were produced against the myelin proteins of PNS resulting from T-cell reaction (Hughes and Cornblath, 2005). At the same time, we found that 5/22 (22.7%) CCPD patients with previous infectious manifested as acute onset and monophasic course. This percentage was 10% and 65% in other studies, respectively (Cortese et al., 2016, Ogata et al., 2016). It indicated that exogenous infections induced antibodies may promote auto-neuroimmune response. There were determined auto-antigen expressed by both CNS and PNS, such as myelin P1 found in PNS was identical to central myelin basic protein (Whitaker, 1981). We found albuminocytologic dissociation, increased protein and Cell-counts (> 5/μl) in CSF, indicating the presence of inflammatory response in CCPD patients. H Ze'phir reported a high level of protenorachia (> 1 g/l) may be observed before the occurrence of PNS involvement (Zephir et al., 2008). But all the OB results were negative. This finding was in keeping with the previous reports, suggesting the pathogenesis of CCPD was different from MS (Cortese et al., 2016, Ogata et al., 2016, Zephir et al., 2008). For CNS involvement, intracranial lesion (more than three) and LETM were more common, and over half (9/13) patients with LETM were p-PNSD. This results further proves that CCPD was a unique disease different from MS or NMOSD. Hidenori Ogata et al. also found these distinguishing features and proposed that CCPD should be considered as a differential diagnosis with longitudinally extensive spinal cord lesions and extensive brain lesions (Ogata et al., 2016). In the current study, four people had decreased vision, yet the optic nerve lesion had no MRI positive results. However, the VEPs disclosed optic nerves demyelinating in 50% of these patients. A. Cortese et al. found the VEPs of 64% CCPD patients were abnormal (Cortese et al., 2016). A VEP study (Stojkovic et al., 2000) in CIDP confirmed a high frequency of abnormal VEPs in CIDP patients that may be explained by the susceptibility to immune-mediated damage of both the PNS and optic nerve. As regards the PNS damage, NCS of the 22 CCPD patients showed mixed motor-sensory nerves demyelinating and axonal damage. This was in keeping with A. Cortes's study results (Cortese et al., 2016). We found that motor nerves presented with more axonal damage, while sensory nerves with more demyelinating. The abnormal NCS findings had been reported in patients with MS, especially the amplitude of the motor nerves (Ayromlou et al., 2013). Yoko Wasabi et al. reported the peripheral neuropathy in NMO patient and compared the NSC of NMO and MS patients, revealing that frequency of abnormal NSC findings might exhibit no significant difference between them (Warabi et al., 2013).
was shorter than that of p-PNSD. However, the NCS of peroneal and tibial motor nerves and the sensory nerves had no significant difference. 3.7. Treatment and outcomes In our studies, 3 cases (13.6%) were treated with intravenous immunoglobulin, 11cases (50%) were treated with steroids, and 7 cases (31.8%) received both intravenous immunoglobulin and steroids. As shown in Table 6, the average of increased mRS was 1, 1.5 and 2 and the efficacy was 33.3%, 54.5%, 71.4%, respectively. The mRS of a patient showed no response to steroids and intravenous immunoglobulin treatment; however it increased by 2 after using cyclophosphamide. Overall, 13 CCPD cases were effective, 6 unchanged and 3 aggravated. Patients with a monophasic course had the best outcomes, while the chronic progressive course had the worst prognosis. 4. Discussion The present study discovered 22 CCPD patients from 788 demyelination cases, indicating CCPD–in Han Chinese population was rare, which was consistent with the previous two large reports. One was a nationwide survey of CCPD in Japan with 40 cases, showing different characteristics from classical demyelinating diseases (Ogata et al., 2016). The other one was a retrospective two-center study in a series of 31 Italy adult patients with CCPD, presenting the broad spectrum of combined inflammatory damage of the CNS and PNS (Cortese et al., 2016). And these two studies suggested that CCPD couldn't be regarded as a simple combination of MS and CIDP. In our study, the mean age at onset (AAO) was 47 (ranged from 23 to 68). The Japanese survey (Ogata et al., 2016) had a younger AAO of 31.7, which may be caused by the inclusion of pediatric patients and the Italy study (Cortese et al., 2016) showed an older AAO of 57. Acute Table 6 Treatment and response in 22 patients with CCPD. Aggravate n/N (%)
Invalid n/N (%)
Efficacy n/N (%)
Increased mRS (average)
IVIg (3)
1/3 (33.3%) 1/11 (9.1%)
Steroids + IVIg (7)
1/7 (14.3%)
CTX + Steroids + IVIg (1)
0/1 (0.0%)
1/3 (33.3%) 6/11 (54.5%) 5/7 (71.4%) 1/1 (100%)
1
Steroids (11)
1/3 (33.3%) 4/11 (36.4%) 1/7 (14.3%) 0/1 (0.0%)
1.5 2 2
Note: CCPD (combined central and peripheral demyelination), IVIg (intravenous immunoglobulin), CTX (cyclophosphamide).
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References
In our study, CCPD patients treated with a combination of steroids and intravenous immunoglobulin had higher increased mRS than those who used steroids or intravenous immunoglobulin alone. One patient who fulfilled the EFNS/PNS criteria for CIDP and the McDonald criteria (2011) for MS had no response to steroids plus intravenous immunoglobulin, but improved significantly after receiving cyclophosphamide. Cyclophosphamide was proved to have effect on MS and CIDP (Cocito et al., 2011; Khan et al., 2001), it was also administered to 2 CCPD patients in France and the response was good (Zephir et al., 2008). Although there were only a small number of cases, it may represent an option for the treatment of cases that have poor response to steroids or intravenous immunoglobulin. On the other hand, patients with a monophasic course had the best outcomes, while the chronic progressive course had the worst prognosis. This suggested that there may be a sustained immune inflammatory response in CCPD, but the exact pathogenesis was still unclear. The Japanese nationwide survey (Ogata et al., 2016) reported that CCPD patients treated with plasmapheresis resulted in 87.5% improvement, and the Italy cohort study (Cortese et al., 2016) observed rituximab efficacy in CCPD patient. In contrast, interferon-β and natalizumab may invalid or even exacerbated PNS demyelination (Wolf et al., 2010, Zephir et al., 2008). These results suggest that we need to understand the specific immune mechanisms of CCPD in order to select a better immunosuppressive therapy. Recently, anti-neurofascin antibodies that were found in the Ranvier nodes were regarded as a biomarker to improve the diagnosis and guide treatments for Asiatic patients with CIDP showing CNS demyelination (Devaux et al., 2016). Nobutoshi Kawamura et al. (2013) showed CCPD patients with positive anti-neurofascin antibodies were responded well to intravenous immunoglobulin or plasma exchange. While a study in Turkey suggested that patients with central plus peripheral nervous demyelination had no anti-neurofascin155 antibodies (Vural et al., 2016). And Lius Querol et al. reported none of the 4 CIPD patients with positive anti–neurofascin155 antibodies responded to intravenous immunoglobulin (Querol et al., 2014). Different ethnic group or a comparatively small sample size may explain this discrepancy. Our study also has some limitations. Firstly, this was a retrospective study. We only enrolled patients that were in our hospital, which may cause some study bias. Besides, we had no objective examinations to exclude the PNS demyelination before onset of MS or NMOSD, but only based on the clinical symptoms or signs. Lastly, the follow up period was only a few years and is still going on, so the long term prognosis and the efficacy of treatment is still unknown. In conclusion, CCPD is a spectrum disease. Definite international criteria for CCPD need to be established from well-characterized cohorts and prospective studies in more centers. A suspected CCPD should receive brain and spinal MRI as well as electrophysiological examination to obtain a precise diagnosis. Monophasic course had a better response to steroids or a combination of steroids and intravenous immunoglobulin and had the best outcomes, while chronic progressive course had the worst prognosis and was responded poorly to steroids or a combination of steroids and intravenous immunoglobulin, and cyclophosphamide may represent a second option for the treatment.
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Falcone, M., Scalise, A., Minisci, C., Romito, D., Cancelli, I., Gigli, G.L., 2006. Spreading of autoimmunity from central to peripheral myelin: two cases of clinical association between multiple sclerosis and chronic inflammatory demyelinating polyneuropathy. Neurol. Sci. 27, 58–62. Forrester, C., Lascelles, R.G., 1979. Association between polyneuritis and multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 42, 864–866. Hughes, R.A., Cornblath, D.R., 2005. Guillain-Barre syndrome. Lancet 366, 1653–1666. Kawamura, N., Yamasaki, R., Yonekawa, T., Matsushita, T., Kusunoki, S., Nagayama, S., et al., 2013. Anti-neurofascin antibody in patients with combined central and peripheral demyelination. Neurology 81, 714–722. Khan, O.A., Zvartau-Hind, M., Caon, C., Din, M.U., Cochran, M., Lisak, D., et al., 2001. Effect of monthly intravenous cyclophosphamide in rapidly deteriorating multiple sclerosis patients resistant to conventional therapy. Mult. Scler. 7, 185–188. 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Querol, L., Nogales-Gadea, G., Rojas-Garcia, R., Diaz-Manera, J., Pardo, J., OrtegaMoreno, A., et al., 2014. Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg. Neurology 82, 879–886. Stojkovic, T., de Seze, J., Hurtevent, J.F., Arndt, C., Beaume, A., Hache, J.C., et al., 2000. Visual evoked potentials study in chronic idiopathic inflammatory demyelinating polyneuropathy. Clin. Neurophysiol. 111, 2285–2291. Thomas, P.K., Walker, R.W., Rudge, P., Morgan-Hughes, J.A., King, R.H., Jacobs, J.M., et al., 1987. Chronic demyelinating peripheral neuropathy associated with multifocal central nervous system demyelination. Brain J. Neurol. 110 (Pt 1), 53–76. Van den Bergh, P.Y., Hadden, R.D., Bouche, P., Cornblath, D.R., Hahn, A., Illa, I., et al., 2010. 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The protein antigens of peripheral nerve myelin. Ann. Neurol. 9 (Suppl), 56–64. Wingerchuk, D.M., Banwell, B., Bennett, J.L., Cabre, P., Carroll, W., Chitnis, T., et al., 2015. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85, 177–189. Wolf, C., Menge, T., Stenner, M.P., Meyer zu Horste, G., Saleh, A., Hartung, H.P., et al., 2010. Natalizumab treatment in a patient with chronic inflammatory demyelinating polyneuropathy. Arch. Neurol. 67, 881–883. Zephir, H., Stojkovic, T., Latour, P., Lacour, A., de Seze, J., Outteryck, O., et al., 2008. Relapsing demyelinating disease affecting both the central and peripheral nervous systems. J. Neurol. Neurosurg. Psychiatry 79 (9), 1032.
Declaration of conflicting interests The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. Source(s) of support None. Conflicting interest There are no conflicts of interest in the submitted article.
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Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
The clinical features of combined central and peripheral demyelination in Chinese patients Yan-Qin Wanga, Han Chena, Wu-Ping Zhuanga, Hong-Lei Lib,
T
⁎
a
Fuqing Hospital of Fujian Province, The Affiliated Fuqing Hospital to Fujian Health College, China Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Medical Neurobiology, Zhejiang Province, Hangzhou, China b
A R T I C L E I N F O
A B S T R A C T
Keywords: Combined central and peripheral demyelination (CCPD) Multiple sclerosis (MS) Neuromyelitis optical spectrum disorders (NMOSD) Chronic inflammatory demyelinating polyneuropathy (CIDP) Guillain-Barre syndrome (GBS)
Background: Combined central and peripheral demyelination (CCPD) is rare and has never been reported as a spectrum disease in Han Chinese population. Objectives: To study the clinical features of CCPD in Han Chinese patients. Methods: Twenty-two CCPD patients were selected from 788 demyelination cases. We reviewed and compared the clinical manifestation, laboratory data, electrophysiological examination, MRI and the prognosis. Results: CCPD patients presented with sensory disturbance (86.4%), plegia (77.3%), cranial nerve involvement (77.3%), abnormal deep tendon reflexes (72.7%). CSF data showed increased CSF protein in 81% patients. Oligoclonal IgG bands (OB) were negative. Cortical or juxtacortical, periventricular, infratentorial lesions, thoracic and cervical spinal cord were mostly affected. Visual evoked potentials indicated optic nerves demyelinating in 50% cases. 21 CCPD patients were treated with intravenous immunoglobulin or steroids or both of them, and the efficacy was 33.3%, 54.5%, 71.4%, respectively. One case that showed no response to steroids plus intravenous immunoglobulin treatment was improved significantly after using cyclophosphamide. Conclusions: CCPD is a spectrum disease that can't be regarded as a simple combination of MS and CIDP. A suspected CCPD should receive brain and spinal MRI as well as electrophysiological examination to obtain a precise diagnosis.
1. Introduction In the common concept, inflammatory demyelinating disorders selectively affect either the central or peripheral nervous system, such as multiple sclerosis (MS) or chronic inflammatory demyelinating polyneuropathy (CIDP). But concurrent central and peripheral demyelination is a real-world phenomenon. Forrester and Lascelles firstly reported 2 cases of MS and polyneuritis in 1979 (Forrester and Lascelles, 1979). In 1987 a series of 6 cases were reported firstly proposing the name of combined central and peripheral demyelination (CCPD), which was not widely appreciated at that time (Thomas et al., 1987). Since then some case reports or case series have been reported about CCPD but using different diagnostic names such as MS with peripheral neuropathy, CIDP with central demyelination or Guillain-Barre syndrome (GBS) and acquired central nervous system (CNS) demyelinating, etc. (Falcone et al., 2006; Krivickas et al., 2006; Mao and Hu, 2014; Mehndiratta and Gulati, 2014). But combined central and peripheral demyelination (CCPD) has never been reported as a spectrum disease in Han Chinese population. ⁎
In this study, in order to investigate CCPD as a spectrum disease to gain a better understanding and avoid misdiagnosis, we reviewed and compared the clinical manifestation, laboratory data, results of the nerve conduction study (NCS), magnetic resonance imaging (MRI) and the prognosis of 22 CCPD patients enrolled in our department. To our understanding, this is the first study on CCPD in Chinese population. 2. Methods 2.1. Study subjects This is a retrospective, observational analysis in the Second Affiliated Hospital of Zhejiang University School of Medicine between January 2014 and January 2017. All the study subjects were in hospital and were evaluated by at least two experienced neurologists. In our study, the criteria of CCPD are determined as follows, referring to a nationwide survey of CCPD in Japan (Ogata et al., 2016): 1) peripheral nervous system (PNS) involvement criteria:
Corresponding author at: No 88, Jiefang Road, Hangzhou, Zhejiang, China. E-mail address: [email protected] (H.-L. Li).
https://doi.org/10.1016/j.jneuroim.2018.02.006 Received 9 November 2017; Received in revised form 30 December 2017; Accepted 5 February 2018 0165-5728/ © 2018 Elsevier B.V. All rights reserved.
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amounts of protein, anti-gangliosides, anti AQP-4 antibodies, oligoclonal IgG bands (OB). Brain and spinal MRI were performed on a 1.5 T/3.0 T MR scanner. NCS were performed at the median, ulnar, tibial, common peroneal, superficial peroneal and sural nerves. The modified Rankin Scale (mRS) was employed to measure disability and prognosis. Improvers were defined as patients who were recorded an increase of at least one point on the mRS 30 days after treatment. Variables were analyzed by descriptive statistics and expressed by the mean (standard deviation-SD) or frequency. The mean (SD) NCS parameters of the p-CNSD patients were recorded and compared with the p-PNSD patients by a two-sample of t-test: p value < 0.05 were considered to be statistically significant. We used Statistical Package of Social Science (SPSS 15.0) for all statistical analyses.
a. Supportive symptoms: lower paralysis, glove and stocking sensory disturbance, muscle atrophy, hyporeflexia (> 1 month). b. Necessary (Ogata et al., 2016): NCS indicated immediate prolonged distal latency, decreased motor conduction velocity (MCV)/sensory conduction velocity (SCV), decreased or absent compound muscle action potential (CMAP)/sensory nerve action potential (SNAP), F-Waves/H-reflex abnormalities; CSF albuminocytologic dissociation. 2) central nervous system (CNS) involvement criteria: a. Supportive symptoms: upper paralysis, sphincter disturbance, sensory level, hyperreflexia, pathological sign, decreased vision, epilepsy, mental disturbance, and unconsciousness. b. Necessary (Ogata et al., 2016): T2 high-signal intensity lesions in the brain, optic nerves or spinal cord on MRI, or abnormalities on visual-evoked potentials (VEPs). 3) exclusion criteria (Ogata et al., 2016): secondary demyelinating diseases or changes, such as infectious diseases (e.g., human T lymphocyte trophic virus type 1-associated myelopathy, syphilis, neuroborreliosis, HIV infection or progressive multifocal leucoencephalopathy), pre-existing inflammatory diseases (e.g., sarcoidosis, Behçet's disease, Sjögren's syndrome, vasculitis or other collagen diseases), mitochondrial disease, metabolic/toxic diseases (e.g. Vitamin deficiency, amyloidosis, chronic alcoholism, diabetes mellitus or subacute myelo-opticoneuropathy due to clioquinol intoxication, cervical spondylotic myelopathy, syringomyelia, spinocerebellar degeneration, multiple myeloma, other tumors, inherited diseases (e.g., leucodystrophies), cerebrovascular disease and nonspecific lesions on T2-weighted MRI (e.g., leucoaraiosis).
3. Results 3.1. Demographic data The proportion of men and women was just 1:1; and the mean onset age was 47.72 ± 13.15 years (range, 23-68 years). The number of patients with antecedent infection was 5 (22.7%). The model of onset was acute in 12 cases (54.5%), subacute in 3 (13.6%) and chronic in 7 (31.8%). Disease courses were monophasic in 15 cases (68.1%), relapsing-remitting in 3 (13.6%) and chronic-progressive in 4 (18.2%), respectively (Table 1). 3.2. Prevalence
Patients with CCPD may involve CNS and PNS simultaneously or subsequently. The duration of sequential attack was defined as two months (Ogata et al., 2016). Onset of CCPD was defined as acute (within 1 month), subacute (1–2 months) or chronic (> 2 months), and the disease course was classified as monophonic, relapsing-remitting or chronic-progressive. The target patients were divided into two groups. One was CCPD patients primarily diagnosed as CNS demyelinating patients (p-CNSD). There were 125 multiple sclerosis, 178 neuromyelitis optical spectrum disorders and 145 spinal demyelination patients. The revised 2010 McDonald Criteria (Polman et al., 2011) and the 2015 International consensus diagnostic criteria (Wingerchuk et al., 2015) were applied for the diagnosis of MS and NMOSD respectively. According to the CCPD criteria, 12 p-CNSD patients were diagnosed with CCPD, including 4 MS, 4 NMOSD and 4 Spinal demyelination patients. The other group was CCPD patients primarily diagnosed as PNS demyelinating patients (p-PNSD). There were 241 Guillain-Barre syndrome (GBS) patients and 99 CIDP patients. GBS fulfilled the new diagnostic classification in 2014 and CIDP fulfilled the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria (Van den Bergh et al., 2010; Wakerley et al., 2014). According to the CCPD criteria, 10 p-PNSD patients were diagnosed with CCPD finally, including 9 GBS patients and 1 CIDP patient. Finally, 22 patients from 788 demyelination cases fulfilled the CCPD criteria.
In this study, there were 4 patients diagnosed with both MS and PNS demyelination from 125 MS patients (3.2%), 4 patients diagnosed with both NMOSD and PNS demyelination from 178 NMOSD patients (2.2%), 4 patients diagnosed with both Spinal demyelination and PNS demyelination from 145 Spinal demyelination patients (2.8%), 9 patients diagnosed with both GBS and CNS demyelination from 241 GBS patients (3.7%), 1 patient diagnosed with both CIDP and CNS demyelination from 99 CIDP patients (1.0%). 3.3. Clinical manifestations The majority of the 22 CCPD patients presented with sensory disturbance (86.4%), plegia (77.3%), cranial nerve involvement (77.3%), and deep tendon reflexes (72.7%), followed by pathological sign (27.3%), ataxia (18.2%), sphincter disturbance (18.2%) and muscle atrophy (18.2%), sequentially. Respiratory disturbance was observed in two cases. Unconsciousness (1/22), mental disturbance (1/22), epilepsy (1/22) were rare. The common symptoms and onset of p-CNSD and pPNSD were different. For p-CNSD, subjective paresthesia (5/9) was common, and half of the p-PNSD patients were found to have a sensory Table 1 Demographic data of CCPD patients.
2.2. Data collection
Demographics Gender (male/female) Onset age (years, mean ± SD) Disease model Acute Subacute Chronic Disease course Monophasic Relapsing-remitting Chronic-progressive Previous infection
The initial clinical data was collected by accessing the medical records, and the follow-up data was obtained from the outpatients' clinic or a telephone visit during January 2014 to January 2017 in the Second Affiliated Hospital of Zhejiang University School of Medicine. The laboratory data included: whole blood routine, blood biochemistry, glycosylated hemoglobin (HbA1C), vitamin12, folate, homocysteine, serum immunoglobulin, serology for human immunodeficiency virus, hepatitis C virus, syphilis, anti-dsDNA, antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), thyroid hormone level, Rheumatoid factor (RF), CSF IgG Index,
Note: CCPD (combined central and peripheral demyelination).
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11/11 47.72 ± 13.15 n/N (%) 12/22 (54.5%) 3/22 (13.6%) 7/22 (31.8%) 15/22 (68.1%) 3/22 (13.6%) 4/22 (18.2%) 5/22 (27.2%)
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Table 2 Comparison of the common clinical features between p-CNSD and p-PNSD.
Sensory disturbance Subjective paresthesia Sensory level Glove and stocking type Plegia Paraplegia The four limbs Double upper limbs Double lower limbs Hemiplegia Cranial nerve involvement Decreased vision Unilateral Bilateral Diplopia Facial paralysis Bulbar paralysis Tongue paralysis Deep tendon reflexes Hyporeflexia Hyper-reflexia Both hyporeflexia and hyper-reflexia
p-CNSD
p-PNSD
9/22 (40.8%) 5/22 (22.7%) 3/22 (13.6%) 1/22 (4.5%) 9/22 (40.8%) 6/22 (27.2%) 2/22 (9.1%) 1/22 (4.5%) 3/22 (13.6%) 3/22 (13.6%) 12/22 (54.5%) 4/22 (18.2%) 2/22 (9.1%) 2/22 (9.1%) 2/22 (9.1%) 2/22 (9.1%) 2/22 (9.1%) 2/22 (9.1%) 7/22 (31.8%) 4/22 (18.2%) 3/22 (13.6%) 0/22 (0.0%)
10/22 (45.5%) 3/22 (13.6%) 5/22 (22.7%) 2/22 (9.1%) 8/22 (36.4%) 8/22 (36.4%) 5/22 (22.7%) 2/22 (9.1%) 1/22 (4.5%) 0/22 (0.0%) 5/22 (22.7%) 0/22 (0.0%) 0/22 (0.0%) 0/22 (0.0%) 1/22 (4.5%) 2/22 (9.1%) 1/22 (4.5%) 1/22 (4.5%) 9/22 (40.8%) 8/22 (36.4%) 0/22 (0.0%) 1/22 (4.5%)
Table 4 MRI findings in CCPD.
Brain Cortical or juxtacortical lesion Periventricular lesions Three or more lesions Less than three lesions Infratentorial lesions Optic nerve lesion T1 lesions with Gd-enhanced Spinal cord Cervical Thoracic Lumbosacral Focal Multifocal LETM T1 lesions with Gd-enhanced
All patients
p-CNSD
p-PNSD
15 5/15 (33.3%) 5/15 (33.3%) 4/15 (26.7%) 1/15 (6.7%) 4/15 (26.7%) 0/15 (0.0%) 1/15 (6.7%) 21 11/21 (52.4%) 9/21 (42.8%) 1/21 (4.8%) 4/21 (19.0%) 4/21 (19.0%) 13/21 (61.9%) 2/21 (9.5%)
11 4/11 (36.4%) 4/11 (36.4%) 4/11 (36.4%) 0/11 (0.0%) 3/11 (27.3%) 0/11 (0.0%) 0/11 (0.0%) 6 4/6 (66.7%)
4 1/4 (25%) 1/4 (25%) 0/4 (0.0%) 1/4 (25%) 1/4 (25%) 0/4 (0.0%) 1/4 (25%) 15 7/15 (46.7%)
2/6 0/6 2/6 0/6 4/6
7/15 1/15 2/15 4/15 9/15
(33.3%) (0.0%) (33.3%) (0.0%) (66.7%)
0/6 (0.0%)
(46.7%) (6.7%) (13.3%) (26.7%) (60%)
2/15 (13.3%)
Note: All data was reported as number of cases (%). CCPD (Combined central and peripheral demyelination), p-CNSD (primary-diagnosed CNS demyelinating), p-PNSD (primary-diagnosed PNS demyelinating), MRI (magnetic resonance imaging), LETM (longitudinally extensive transverse myelitis).
Note: CCPD (combined central and peripheral demyelination), p-CNSD (primary-diagnosed CNS demyelinating), p-PNSD (primary-diagnosed PNS demyelinating).
showed increased IgG Index. In addition, OB was negative in six patients delete. Table 3 showed the peripheral blood tests. One patient had positive antiganglioside Ab, three had positive Anti-AQP4 Ab. All ANA, anticardiolipin Ab, anti-SSA ab, anti-SSB ab, anti-RO52 Ab, RF, syphilis, HIV, hepatitis B and C were negative.
level. Paraplegia, diplopia, facial paralysis, bulbar paralysis and tongue paralysis were present in both of the two subgroups, but the p-PNSD group did not show hemiplegia or decreased vision. More than half (4/ 7) of the p-CNSD presented with hyporeflexia, while all 8 p-PNSD patients showed hyporeflexia except one with mixed reflexes (Table 2).
3.5. MRI and VEPs
3.4. Laboratory findings
Table 4 showed brain and spinal cord lesions findings in CCPD patients. Among the brain MRI, cortical or juxtacortical, periventricular, infratentorial and optic nerve lesion were found in 33.3% (5/15), 33.3% (5/15), 26.7% (4/15) and 0% patients respectively. Among the spinal cord MRI, cervical, thoracic and lumbosacral spinal cord lesions were found in 52.4% (11/21), 42.8% (9/21) and 4.8% (1/21) patients respectively. And there were significant difference in the distribution of brain and spinal cord lesions between the two groups (11/4 vs. 6/15, p < 0.05). P-CNSD patients had more brain lesions, especially the periventricular lesions, which were three or more. P-PNSD patient's spinal lesions including focal lesion, multifocal lesions and longitudinally extensive transverse myelitis were found in 13.3%, 26.7% and 60% patients, respectively. Only one patient was found a T1 lesions with Gd-enhanced in brain MRI and two patients had Gd-enhanced spinal cord lesions. And the three patients were all diagnosed as PNS demyelination patients primarily (Table 5). VEPs disclosed optic nerves demyelinating in 50% of the patients.
CSF data (Table 3) showed increased CSF protein and albuminocytologic dissociation in 81% and 47.7% patients, respectively. There were eight patients who showed increased cell-counts and four cases Table 3 Laboratory examination of 22 patients with CCPD. CSF
n/N (%)
Increased CSF protein Cell-counts > 5/μl Albuminocytologic dissociation Increased IgG Index OB
17/21 (81%) 8/21 (38.1%) 10/21 (47.7%) 4/18 (22.2%) 0/6 (0.0%)
Blood
n/N (%)
Antiganglioside Abs Anti-AQP4 Ab ANA Anticardiolipin Ab ANCA Anti-SSA Ab Anti-SSB Ab Anti-RO52 Ab RF Thyroid function disorder High CRP level High HbA1C level Low VitaminB12 level
1/9 (11.1%) 3/8 (37.5%) 0/20 (0.0%) 0/20 (0.0%) 0/20 (0.0%) 0/20 (0.0%) 0/20 (0.0%) 0/20 (0.0%) 0/19 (0.0%) 0/19 (0.0%) 0/21 (0.0%) 0/20 (0.0%) 0/19 (0.0%)
3.6. Nerve conduction study In motor NCS, decreased conduction velocity of peroneal and median nerve was the most frequently affected, and were recognized in 72.2% and 50% of our study subjects respectively. F-wave was detected only in 9 cases and H-reflex only in 4 patients. Decreased or absent Fwave and H-reflex were the most common results, presenting in 88.9% (8/9) and 66.7% (4/6) of CCPD patients, respectively. In sensory NCS, median and peroneal nerve also was the most frequently affected. Decreased or absent amplitude was present in 61.1% and 68.8% of CCPD patients, respectively; while decreased conduction velocity was 46.8%. This study measured and compared the amplitude, latency, and conduction velocity of the p-CNSD and p-PNSD patients. The results suggested distal latency of median and ulnar motor nerve of p-CNSD
Note: CSF (cerebrospinal fluid), Ab (antibodies), OB (oligoclonal IgG bands), AQP-4 (aquaporin 4), ANA (antinuclear antibody), ANCA (antineutrophil cytoplasmic antibody), CRP (C reactive protein), HbA1C (glycosylated hemoglobin), RF (Rheumatoid factor). One patient did not do the lumbar puncture because of skin infection.
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Table 5 Comparison of NCS features between p-CNSD and p-PNSD. Prolonged distal latency (n/N)
Decreased or absent amplitude (n/N)
Decreased CV (n/N)
M of p-CNSD (SD)
M of p-PNSD (SD)
P value
M of p-CNSD (SD)
M of p-PNSD (SD)
P value
M of p-CNSD (SD)
M of p-PNSD (SD)
P value
Motor Median Ulnar Peroneal Tibial
3.23 1.93 3.04 4.01
± ± ± ±
0.497 0.32 1.35 1.71
5.12 3.13 3.84 4.52
0.037 0.007 0.33 0.65
8.43 7.41 4.32 7.98
7.62 7.38 5.01 7.45
0.759 0.99 0.68 0.86
48.38 54.96 36.95 38.38
± ± ± ±
7.75 15.08 14.98 15.22
49.32 53.06 34.48 34.76
± ± ± ±
6.77 9.44 15.31 14.57
0.81 0.76 0.73 0.61
Sensory Median Ulnar Sural Peroneal
2.78 1.98 1.69 2.08
± ± ± ±
0.68 0.25 0.77 0.93
2.8 ± 0.99 2.46 ± 1.04 2.01 ± 0.51 2.51 ± 0.78
0.96 0.23 0.31 0.31
7.29 ± 6.42 7.16 ± 4.73 11.67 ± 11.09 5.94 ± 4.15
0.806 0.83 0.25 0.14
47.68 53.02 45.78 37.94
± ± ± ±
11.65 7.22 19.1 16.07
50.96 45.73 48.36 39.02
± ± ± ±
12.84 12.74 6.43 8.93
0.60 0.18 0.71 0.86
± ± ± ±
2.05 0.91 1.98 2.82
± ± ± ±
4.31 4.95 2.81 6.67
± ± ± ±
5.90 4.95 4.05 6.06
8.05 ± 5.69 7.72 ± 5.73 18.01 ± 11.51 10.62 ± 8.06
Note: CCPD (combined central and peripheral demyelination), p-CNSD (primary-diagnosed CNS demyelinating), p-PNSD (primary-diagnosed PNS demyelinating), M (Mean), CV (conduction velocity).
onset was found to be more common than subacute or chronic, while a monophasic course was more often than a relapsing or chronic progressive course. A cohort study based on a literature review showed that CNS demyelinating might occur early in the GBS course (Mao and Hu, 2014). It was thought that antibodies were produced against the myelin proteins of PNS resulting from T-cell reaction (Hughes and Cornblath, 2005). At the same time, we found that 5/22 (22.7%) CCPD patients with previous infectious manifested as acute onset and monophasic course. This percentage was 10% and 65% in other studies, respectively (Cortese et al., 2016, Ogata et al., 2016). It indicated that exogenous infections induced antibodies may promote auto-neuroimmune response. There were determined auto-antigen expressed by both CNS and PNS, such as myelin P1 found in PNS was identical to central myelin basic protein (Whitaker, 1981). We found albuminocytologic dissociation, increased protein and Cell-counts (> 5/μl) in CSF, indicating the presence of inflammatory response in CCPD patients. H Ze'phir reported a high level of protenorachia (> 1 g/l) may be observed before the occurrence of PNS involvement (Zephir et al., 2008). But all the OB results were negative. This finding was in keeping with the previous reports, suggesting the pathogenesis of CCPD was different from MS (Cortese et al., 2016, Ogata et al., 2016, Zephir et al., 2008). For CNS involvement, intracranial lesion (more than three) and LETM were more common, and over half (9/13) patients with LETM were p-PNSD. This results further proves that CCPD was a unique disease different from MS or NMOSD. Hidenori Ogata et al. also found these distinguishing features and proposed that CCPD should be considered as a differential diagnosis with longitudinally extensive spinal cord lesions and extensive brain lesions (Ogata et al., 2016). In the current study, four people had decreased vision, yet the optic nerve lesion had no MRI positive results. However, the VEPs disclosed optic nerves demyelinating in 50% of these patients. A. Cortese et al. found the VEPs of 64% CCPD patients were abnormal (Cortese et al., 2016). A VEP study (Stojkovic et al., 2000) in CIDP confirmed a high frequency of abnormal VEPs in CIDP patients that may be explained by the susceptibility to immune-mediated damage of both the PNS and optic nerve. As regards the PNS damage, NCS of the 22 CCPD patients showed mixed motor-sensory nerves demyelinating and axonal damage. This was in keeping with A. Cortes's study results (Cortese et al., 2016). We found that motor nerves presented with more axonal damage, while sensory nerves with more demyelinating. The abnormal NCS findings had been reported in patients with MS, especially the amplitude of the motor nerves (Ayromlou et al., 2013). Yoko Wasabi et al. reported the peripheral neuropathy in NMO patient and compared the NSC of NMO and MS patients, revealing that frequency of abnormal NSC findings might exhibit no significant difference between them (Warabi et al., 2013).
was shorter than that of p-PNSD. However, the NCS of peroneal and tibial motor nerves and the sensory nerves had no significant difference. 3.7. Treatment and outcomes In our studies, 3 cases (13.6%) were treated with intravenous immunoglobulin, 11cases (50%) were treated with steroids, and 7 cases (31.8%) received both intravenous immunoglobulin and steroids. As shown in Table 6, the average of increased mRS was 1, 1.5 and 2 and the efficacy was 33.3%, 54.5%, 71.4%, respectively. The mRS of a patient showed no response to steroids and intravenous immunoglobulin treatment; however it increased by 2 after using cyclophosphamide. Overall, 13 CCPD cases were effective, 6 unchanged and 3 aggravated. Patients with a monophasic course had the best outcomes, while the chronic progressive course had the worst prognosis. 4. Discussion The present study discovered 22 CCPD patients from 788 demyelination cases, indicating CCPD–in Han Chinese population was rare, which was consistent with the previous two large reports. One was a nationwide survey of CCPD in Japan with 40 cases, showing different characteristics from classical demyelinating diseases (Ogata et al., 2016). The other one was a retrospective two-center study in a series of 31 Italy adult patients with CCPD, presenting the broad spectrum of combined inflammatory damage of the CNS and PNS (Cortese et al., 2016). And these two studies suggested that CCPD couldn't be regarded as a simple combination of MS and CIDP. In our study, the mean age at onset (AAO) was 47 (ranged from 23 to 68). The Japanese survey (Ogata et al., 2016) had a younger AAO of 31.7, which may be caused by the inclusion of pediatric patients and the Italy study (Cortese et al., 2016) showed an older AAO of 57. Acute Table 6 Treatment and response in 22 patients with CCPD. Aggravate n/N (%)
Invalid n/N (%)
Efficacy n/N (%)
Increased mRS (average)
IVIg (3)
1/3 (33.3%) 1/11 (9.1%)
Steroids + IVIg (7)
1/7 (14.3%)
CTX + Steroids + IVIg (1)
0/1 (0.0%)
1/3 (33.3%) 6/11 (54.5%) 5/7 (71.4%) 1/1 (100%)
1
Steroids (11)
1/3 (33.3%) 4/11 (36.4%) 1/7 (14.3%) 0/1 (0.0%)
1.5 2 2
Note: CCPD (combined central and peripheral demyelination), IVIg (intravenous immunoglobulin), CTX (cyclophosphamide).
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Journal of Neuroimmunology 317 (2018) 32–36
Y.-Q. Wang et al.
References
In our study, CCPD patients treated with a combination of steroids and intravenous immunoglobulin had higher increased mRS than those who used steroids or intravenous immunoglobulin alone. One patient who fulfilled the EFNS/PNS criteria for CIDP and the McDonald criteria (2011) for MS had no response to steroids plus intravenous immunoglobulin, but improved significantly after receiving cyclophosphamide. Cyclophosphamide was proved to have effect on MS and CIDP (Cocito et al., 2011; Khan et al., 2001), it was also administered to 2 CCPD patients in France and the response was good (Zephir et al., 2008). Although there were only a small number of cases, it may represent an option for the treatment of cases that have poor response to steroids or intravenous immunoglobulin. On the other hand, patients with a monophasic course had the best outcomes, while the chronic progressive course had the worst prognosis. This suggested that there may be a sustained immune inflammatory response in CCPD, but the exact pathogenesis was still unclear. The Japanese nationwide survey (Ogata et al., 2016) reported that CCPD patients treated with plasmapheresis resulted in 87.5% improvement, and the Italy cohort study (Cortese et al., 2016) observed rituximab efficacy in CCPD patient. In contrast, interferon-β and natalizumab may invalid or even exacerbated PNS demyelination (Wolf et al., 2010, Zephir et al., 2008). These results suggest that we need to understand the specific immune mechanisms of CCPD in order to select a better immunosuppressive therapy. Recently, anti-neurofascin antibodies that were found in the Ranvier nodes were regarded as a biomarker to improve the diagnosis and guide treatments for Asiatic patients with CIDP showing CNS demyelination (Devaux et al., 2016). Nobutoshi Kawamura et al. (2013) showed CCPD patients with positive anti-neurofascin antibodies were responded well to intravenous immunoglobulin or plasma exchange. While a study in Turkey suggested that patients with central plus peripheral nervous demyelination had no anti-neurofascin155 antibodies (Vural et al., 2016). And Lius Querol et al. reported none of the 4 CIPD patients with positive anti–neurofascin155 antibodies responded to intravenous immunoglobulin (Querol et al., 2014). Different ethnic group or a comparatively small sample size may explain this discrepancy. Our study also has some limitations. Firstly, this was a retrospective study. We only enrolled patients that were in our hospital, which may cause some study bias. Besides, we had no objective examinations to exclude the PNS demyelination before onset of MS or NMOSD, but only based on the clinical symptoms or signs. Lastly, the follow up period was only a few years and is still going on, so the long term prognosis and the efficacy of treatment is still unknown. In conclusion, CCPD is a spectrum disease. Definite international criteria for CCPD need to be established from well-characterized cohorts and prospective studies in more centers. A suspected CCPD should receive brain and spinal MRI as well as electrophysiological examination to obtain a precise diagnosis. Monophasic course had a better response to steroids or a combination of steroids and intravenous immunoglobulin and had the best outcomes, while chronic progressive course had the worst prognosis and was responded poorly to steroids or a combination of steroids and intravenous immunoglobulin, and cyclophosphamide may represent a second option for the treatment.
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Declaration of conflicting interests The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. Source(s) of support None. Conflicting interest There are no conflicts of interest in the submitted article.
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