Combined Central and Peripheral Demyelination with a Favorable Outcome: A Case with 10-Year Follow-up.

Combined central and peripheral demyelination (CCPD) refers to the demyelination concurrently or sequentially occuring in the central and peripheral nervous systems. CCPD is a new disease entity, which is different from the independent central or peripheral nervous system demyelination. The pathogenesis of CCPD is unclear. The immune abnormalities may be involved. CCPD has low incidence, various manifestations, no specific biomarkers, and no uniform diagnostic criteria. This review summarizes the etiology, pathogenesis, clinical features, specific biomarkers, imaging characteristics, treatments and prognoses of CCPD to improve our understanding of CCPD. Key words: Combined central and peripheral demyelination; Anti-neurofascin 155 antibody; Immune abnormality

129th ENMC International Workshop: Clinical Trials for Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Multifocal Motor Neuropathy, 27th October 2004, Schiphol airport, The Netherlands

Combined central and peripheral demyelination (CCPD) is a rare entity in which central and peripheral nervous system demyelination coexist. Herein, we present a patient with coexistence of Sjögren syndrome (SS) and CCPD. A 58-year-old female patient was admitted to our neurology clinic with paraparesis, difficulty walking, imbalance, and paresthesia. Neurological examination showed paraparesis, absence of lower extremity deep tendon reflex, sensory deficit at the T8 level, loss of deep sensory position, and vibration. Spinal magnetic resonance imaging revealed multiple focal T2-hyperintense and contrast-enhancing cord lesions. Fat-suppressed imaging disclosed T2 hyperintensity in lumbar nerve roots, diffuse linear enhancement of the cauda equina, and diffuse increased enhancement in lumbar nerve roots. Electrodiagnostic findings fulfilled the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy. Extensive laboratory workup excluded all possible pathologies. The Schirmer test detected positive in both eyes and minor salivary gland biopsy resulted in grade 3. These results were consistent with SS. The patient received intravenous methylprednisolone, azathioprine hydroxychloroquine. Approximately 2 years later, her complaints had completely disappeared, except for mild sensory complaints. It is unclear whether the association of central nervous system and peripheral nervous system demyelination and SS is a coincidence or a consequence. Our patient shows that patients with SS can have CCPD, and a significant clinical response can be obtained with early treatment. We hope that this unique case sheds light on the pathophysiology of CCPD.

Background: Combined central and peripheral demyelination (CCPD) is a disease of inflammatory demyelination that affects central and peripheral nerves simultaneously or temporally separated. Objectives: This study evaluated the clinical characteristics and the existence of antinodal/paranodal antibodies in patients with CCPD. Methods: We reviewed the clinical manifestations, laboratory tests, electrophysiological examinations, neuroimaging findings, treatment, and prognosis of 31 patients with CCPD. Using a live cell–based assay, we tested antinodal/paranodal antibodies. Results: The most common symptoms were motor weakness (83.3%), hyporeflexia (63.3%), and sphincter disturbance (58.1%). In total, 16.6% of patients had impaired vision symptoms, whereas 33.3% of patients had abnormal visual-evoked potentials (VEPs). A total of 21.1% (4/19) of patients were positive for anti-AQP4 (aquaporin 4) antibodies, 20.0% (2/10) of patients were positive for anti-NF155 (neurofascin-155) antibodies, and 10.0% (1/10) of patients were positive for anti-MAG (myelin-associated glycoprotein) antibodies. The effective rates of intravenous corticosteroids, intravenous immunoglobulins, and rituximab were 72.2%, 37.5%, and 100%, respectively. At the illness peak, 75% of patients with CCPD had an mRS (modified Rankin Scale) score of 4 or greater. In remission, 37.5% had an mRS score of 4 or greater. Conclusion: The clinical manifestations of patients with CCPD are highly heterogeneous. We recommend testing antinodal/paranodal antibodies for patients with CCPD.

ObjectivesTo clarify the clinical features of combined central and peripheral demyelination (CCPD) via a nationwide survey.MethodsThe following characteristics were used to define CCPD: T2 high-signal intensity lesions in the brain,...

Combined central and peripheral demyelination (CCPD) is an extremely rare disease characterized by inflammatory demyelination in both the central and peripheral nervous systems. Herein, we reported case of a 14-year-old teenager who initially presented with the symptoms of acute myelitis (AM). Subsequently, the patient developed symptoms consistent with Guillain-Barré syndrome (GBS), which was supported by nerve conduction studies (NCV) and cerebrospinal fluid (CSF) analysis. Throughout the course of the disease, the patient experienced abdominal pain and abnormal liver function. After a comprehensive evaluation, we determined that the abnormal liver function was a result of hepatitis E virus (HEV) infection, which may have acted as a trigger for GBS. The patient was treated with corticosteroids, intravenous immunoglobulin and Rituximab, resulting in symptom relief and clinical improvement after therapy and follow-up. This case highlights the potential responsiveness and reversibility of CCPD. Given the heterogeneous nature of CCPD, there is currently no standardized diagnostic criteria or clear consensus on its treatment. Therefore, we recommend a thorough assessment of all possibilities and the development of consolidated management guidelines based on available data for this disorder.

We aimed to identify the target antigens for combined central and peripheral demyelination (CCPD). We screened target antigens by immunohistochemistry and immunoblotting using peripheral nerve tissues to identify target antigens recognized by serum antibodies from selected CCPD and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cases. We then measured the level of antibody to the relevant antigen in 7 patients with CCPD, 16 patients with CIDP, 20 patients with multiple sclerosis, 20 patients with Guillain-Barré syndrome, 21 patients with other neuropathies, and 23 healthy controls (HC) by ELISA and cell-based assays using HEK293 cells. At the initial screening, sera from 2 patients with CCPD showed cross-like binding to sciatic nerve sections at fixed intervals, with nearly perfect colocalization with neurofascin immunostaining at the node and paranode. ELISA with recombinant neurofascin revealed significantly higher mean optical density values in the CCPD group than in other disease groups and HC. Anti-neurofascin antibody positivity rates were 86% in patients with CCPD, 10% in patients with multiple sclerosis, 25% in patients with CIDP, 15% in patients with Guillain-Barré syndrome, and 0% in patients with other neuropathies and HC. The cell-based assay detected serum anti-neurofascin antibody in 5 of 7 patients with CCPD; all others were negative. CSF samples examined from 2 patients with CCPD were both positive. In anti-neurofascin antibody-positive CCPD patients, including those with a limited response to corticosteroids, IV immunoglobulin or plasma exchange alleviated the symptoms. Anti-neurofascin antibody is frequently present in patients with CCPD. Recognition of this antibody may be important, because patients with CCPD who are antibody positive respond well to IV immunoglobulin or plasma exchange.

Combined central and peripheral demyelination (CCPD) is a term used to describe a rare condition involving demyelinating lesions of both the central and the peripheral nervous system. Its etiology remains unclear, and a pathogenic role of cell-mediated and/or humoral immunity has been proposed. A number of patients with CCPD are positive to antineurofascin (anti-NF), antigalactocerebroside, and antilactosylseramide antibodies. The relation between CCPD and multiple sclerosis (MS) is unclear. We report the case of a 30-year-old man who was referred for evaluation after having episodes of numbness and gait impairment worsened by intravenous Methylprednisolone and was found to have demyelination in both central and peripheral nervous system. The patient was eventually diagnosed with anti-NF 155 CCPD and received multiple courses of intravenous immunoglobulin without significant improvement, while he remained stable under Rituximab. Interestingly, the patient's father suffered from a mild form of relapsing remitting MS. Our case emphasizes that clinicians need to keep in mind the possibility of a coexisting demyelination in both central and peripheral nervous system, even in patients with a family history of MS. The need for a timely diagnosis is imperative since several drugs used in the management of MS can worsen the patient's symptoms in CCPD. This is, to our knowledge, the first reported case of a patient with anti-NF 155 positive CCPD and a family history of MS.

Atypical inflammatory demyelinating syndrome with central and peripheral nerve involvement

Combined central and peripheral demyelination: Clinical features, diagnostic findings, and treatment

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated demyelinating disease of the peripheral nervous system (PNS). A small number of CIDP patients harbors autoantibodies against nodal/paranodal proteins, such as neurofascin 155 (NF155), contactin 1, and contactin-associated protein 1. In most cases, the predominant immunoglobulin (IgG) subclass is IgG4. Node/paranode antibody-positive CIDP demonstrates distinct features compared with antibody-negative CIDP, including a poor response to intravenous immunoglobulin. The neuropathology of biopsied sural nerve shows Schwann cell terminal loop detachment from axons without macrophage infiltration or inflammation. This is partly attributable to IgG4, which blocks protein–protein interactions without inducing inflammation. Anti-NF155 antibody-positive (NF155+) CIDP is unique because of the high frequency of subclinical demyelinating lesions in the central nervous system (CNS). This is probably because NF155 coexists in the PNS and CNS. Such cases showing demyelinating lesions in both the CNS and PNS are now termed combined central and peripheral demyelination (CCPD). NF155+ CIDP/CCPD commonly presents hypertrophy of spinal nerve roots and cranial nerves, such as trigeminal and oculomotor nerves, and extremely high levels of cerebrospinal fluid (CSF) protein, which indicates nerve root inflammation. In the CSF, the CXCL8/IL8, IL13, TNFα, CCL11/eotaxin, CCL2/MCP1, and IFNγ levels are significantly higher and the IL1β, IL1ra, and GCSF levels are significantly lower in NF155+ CIDP than in non-inflammatory neurological diseases. Even compared with anti-NF155 antibody-negative (NF155−) CIDP, the CXCL8/IL8 and IL13 levels are significantly higher and the IL1β and IL1ra levels are significantly lower than those in NF155+ CIDP. Canonical discriminant analysis revealed NF155+ and NF155− CIDP to be separable with IL4, IL10, and IL13, the three most significant discriminators, all of which are required for IgG4 class switching. Therefore, upregulation of both Th2 and Th1 cytokines and downregulation of macrophage-related cytokines are characteristic of NF155+ CIDP, which explains spinal root inflammation and the lack of macrophage infiltration in the sural nerves. All Japanese patients with NF155+ CIDP/CCPD have one of two specific human leukocyte antigen (HLA) haplotypes, which results in a significantly higher prevalence of HLA-DRB1*15:01-DQB1*06:02 compared with healthy Japanese controls. This indicates an involvement of specific HLA class II molecules and relevant T cells in addition to IgG4 anti-NF155 antibodies in the mechanism underlying IgG4 NF155+ CIDP/CCPD.

Combined central and peripheral demyelination (CCPD) has been proposed to describe the occurrence of demyelination in both central and peripheral nervous systems. The aetiopathogenesis of combined demyelination is unknown, but the possibility of a shared pathogenic epitope has been suggested. Although it has been described in paediatric patients, reports of simultaneous onset CCPD with short segment myelitis among adults are scarce. We report a case of simultaneous onset monophasic CCPD in an adult who developed both Guillain-Barre syndrome and short segment spinal cord demyelination that responded to immunomodulation with intravenous immunoglobulins and plasmapheresis. The patient also had evidence of chronic thyroiditis which supports an autoimmune aetiopathogenesis of CCPD. Differentiating this diagnosis from multiple sclerosis has therapeutic implications.

A 21-year-old man was admitted to our hospital in June 2015. He felt paresthesia of toes in April 2015, which had been spreading upward, and he became difficult to walk in June. Nerve conduction study showed peripheral demyelinating neuropathy that met the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), and the cerebrospinal fluid (CSF) examination revealed the remarkably increased protein level. In addition, magnetic resonance imaging of his brain showed a few plaques in white matter, so he was finally diagnosed with combined central and peripheral demyelination (CCPD). Moreover, anti-neurofascin155 (NF155) antibodies assayed in his serum and CSF turned out to be positive. Although he was treated with intravenous immunoglobulin and intravenous methylprednisolone, his symptoms were not ameliorated. However, plasma exchange therapy was apparently effective, and the titer of anti-NF155 antibody was reduced. Recently, the number of case reports of CIDP with CNS lesions has gradually been increasing, while the information about the diagnosis and the treatment responses are not enough. Thus, we reported our case with CCPD who was successfully treated with plasma exchange.

Sirs: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated neuropathy [13] characterized by symmetrical sensory and/or motor symptoms persisting for more than 8 weeks. The disease course may be progressive or relapsing [13]. On the basis of randomized trials, high dose intravenous immunoglobulin (IVIg), corticosteroids and plasma exchange have been established as effective treatments for CIDP. The main limitations of these approaches are lack of long term efficacy, difficulties in their use and high costs; thus, alternative immunosuppressive treatments have been proposed (azathioprine, cyclosporine and cyclophosphamide) [2, 9, 11]. The immune-mechanisms responsible for CIDP resemble those implicated in multiple sclerosis (MS) [13], thus making CIDP the peripheral counterpart of MS. In addition, similar to MS, neuropathological studies support heterogeneity of CIDP pathogenesis, with concomitant demyelination and axonal damage [13]. Some studies have recently been performed to evaluate the usefulness of Interferon (IFN) β1a in CIDP patients unresponsive to conventional therapies [1, 7, 14]. We present the case of a 43year-old woman, who in July 1997 complained of progressive weakness in both lower limbs, as well as sensory symptoms. Clinical symptoms persisted until December 1997 and a diagnosis of CIDP was made according to INCAT criteria [3]. Neurological examination revealed generalized areflexia, while an electrophysiological study showed partial conduction block for stimulation at the fibular head of peroneal nerves (–50 % amplitude on the right and –49 % on the left) and absent F wave on the left median nerve and right peroneal nerve. Cerebrospinal fluid analysis produced evidence of albuminocytological dissociation (total protein 82 mg/dL without cells) and isoelectrofocusing was within normal limit. After a first treatment schedule of IVIg with a good response, she became refractory to this treatment. She presented nine relapses throughout 27 months (treated with plasma exchange with transient and partial response) despite the specific drugs used (Figure). In July 2001 she started IFNβ-1b (Betaferon) 8MUI with subcutaneous injections every other day. No other relapses occurred. At present, she has been relapsefree for 40 months and shows marked improvement in clinical conditions (Table 1). Nerve conduction studies also showed marked improvement in motor and sensory velocities (Figure). In April 2002, serological examination showed the presence of anti-thyreoglobulin and anti-thyroid peroxidase antibodies, with an increase in free triiodothyronine and free thyroxin. Autoimmune thyreopathy was diagnosed, and the patient started treatment with an antithyroid drug. IFN beta has been proven efficient in treating MS [4, 5, 12] reducing the number of relapses. Due to clinical similarities between MS and CIDP, there is emerging interest in the use of IFN in CIDP. As far as we know, this is the first report in which IFNβ-1b has been used to treat a CIDP patient. Our patient showed good clinical and neurophysiological response to long-term IFNβ1b treatment (40 months). The stabilization observed was judged by the absence of relapses. IFN beta acts as an immunomodulatory agent, exerting its action at different levels in the inflammatory process. Two recombinant forms of IFN beta are used in clinical practice: IFNβ-1a and INFβ-1b. The use of IFNβ-1a in the treatment of CIDP is controversial, and contradictory results have been reported in different studies [1, 6, 12]. It should be noted that LETTER TO THE EDITORS

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive or relapsing disease with a worldwide prevalence of up to nine individuals per 100 000 1. Randomized trials suggest that corticosteroids, plasma exchange and intravenous immunoglobulin (IVIg) can temporarily reduce impairment and disability. Although approximately 60–70% of the patients respond to the initial therapy, reports on long-term experience of IVIg use in CIDP are rare. Corticosteroids, plasma exchange and IVIg are first-line treatment options in CIDP; however, a risk of long-term adverse effects is the main disadvantage of corticosteroids. Long-term plasma exchange may be less tolerated, and expense can be a concern with IVIg. Two Phase III clinical trials proved the efficacy of IVIg for long-term treatment in CIDP. The IVIg CIDP Efficacy (ICE) trial was a large study that evaluated for the first time the long-term efficacy of IVIg in 117 patients with CIDP 2. Of the 57 patients who received IVIg and were first-period or cross-over-period responders, as assessed with the adjusted inflammatory neuropathy cause and treatment (INCAT) scale, 31 were reassigned randomly to IVIg and 26 were assigned randomly to placebo. IVIg-treated patients (13%) showed a significantly lower relapse rate compared to placebo-treated patients (45%), meaning that 55% of those who were re-randomized to placebo in the extension trial did not deteriorate in a time-frame of approximately 24 weeks 2. In the Privigen Impact on Mobility and Autonomy (PRIMA) study, IVIg-pretreated and IVIg-naive CIDP patients were enrolled and treated for 21 weeks 3. Approximately 61% of the patients showed a significant improvement according to the INCAT scale. Fifty per cent of patients responded to IVIg within the first 4 weeks and 88% of patients within 10 weeks. Of the 31 screened patients, only one CIDP patient (9%) failed the IVIg dependency test and did not deteriorate in the wash-out phase 3. Recently, a retrospective study aimed to evaluate the long-term outcomes in 86 CIDP patients treated with IVIg 4. Data were collected at four time-points: baseline (prior to the start of IVIg treatment); at short-term visit (approximately 6 weeks after IVIg initiation); at mid-term visit (approximately 24 weeks after IVIg); and at last follow-up visit (more than 48 weeks after initiating IVIg treatment). At the mid-term visit, 31 patients had only one IVIg course throughout the entire observation period. Twenty CIDP patients did not receive IVIg at all. Of these 20 patients, 12 were stable. At the long-term visit, 22 patients (25·6%) showed no signs of deterioration 4. There are limited data available on the long-term treatment of CIDP and multifocal motor neuropathy (MMN) with subcutaneous immunoglobulin (SCIg). In a recent report, two patients with atypical CIDP (multifocal acquired demyelinating sensory and motor neuropathy – MADSAM), were treated with SCIg over a time-period of 46 months 5. The Medical Research Council (MRC) sum score remained stable during the entire time-period. In a randomized Phase II study, 30 CIDP patients were enrolled and randomized to placebo and SCIg 6. The treatment period was 12 weeks, with twice- or thrice-weekly SCIg injections (30–300 ml/week; 4·8–48 g/week). After 12 weeks, significant increases (P > 0·05) in isokinetic muscle strength were observed in SCIg-treated patients (5·5 ± 9·5%) compared to the decline observed in the placebo group (14·4 ± 20·3%) 6. Two small case series investigated the effect of SCIg in MMN 7,8. SCIg proved its effectiveness in MMN in short- 7 and long-term use 8. It should be noted that the initial SCIg dose should be 100% equivalent to the monthly IVIg dose 7. A Phase III study proving the efficacy of SCIg in treating CIDP (PATH-Study) is still ongoing (ClinicalTrials.gov identifier: NCT01545076). More recently, a cost-effectiveness study comparing IVIg and SCIg was performed in Italy. Assuming that approximately 2100 CIDP patients exist in Italy, and 50% of those patients were prescribed SCIg, the estimated cost-saving in their model was approximately €1·4 million for the health-care sector 9. However, it should be noted that the cost of SCIg differs within Europe. In conclusion, both IVIg and SCIg are safe and well tolerated for long-term treatment in CIDP and MMN. The most common side effects are headaches (IVIg) and local skin reactions (SCIg). Although not very common, haemolysis is a severe side effect seen with IVIg that can potentially lead to hospitalization, especially when higher doses are administered (2 g/kg body weight).