Combined Central and Peripheral Demyelination: Two Case Reports.

Combined central and peripheral demyelination (CCPD) is a rare disease characterized by demyelinating lesions in both the central nervous system (CNS) and peripheral nervous system (PNS). CCPD can present with acute, subacute, or chronic onset. The initial symptom may be of CNS origin, PNS origin, or both. The clinical manifestations of CCPD are quite heterogeneous, and there are no well-defined diagnostic criteria. In MRI imaging of CCPD cases, demyelinating lesions can be seen in areas such as the brain, cerebellum, brainstem, optic nerve, and spinal cord. Common electromyography (EMG) findings in patients with CCPD include decreased motor nerve conduction velocities, decreased or absent sensory nerve action potentials, prolonged F-wave latency, and decreased amplitude of compound muscle action potentials. Neurofascin (NF) is a transmembrane protein and anti-neurofascin (anti-NF) antibodies directed against NF can be positive in cases of CCPD. Four main NF polypeptides are produced by alternative splicing: NF 186, NF 180, NF 166, and NF 155. The investigation of anti-NF in CCPD cases is therefore important for etiological considerations. Here, we discussed three cases diagnosed with CCPD based on clinical, neuroimaging, EMG, and anti-NF antibody results in light of the literature.

Recurrent simultaneous central nervous system demyelination with possible peripheral demyelination / nodopathy in a seronegative patient.

Combined central and peripheral demyelination (CCPD) is a rare disease entity. Onset with the simultaneous central nervous system (CNS) and peripheral nervous system (PNS) involvement and its recurrence are exceptional. Anti-neurofascin antibodies have been shown to be present in up to 70% of cases, yet seronegative patients also exist. We present a case of seronegative recurrent CCPD. The PNS involvement was compatible with two episodes of recurrent Guillain-Barre syndrome (GBS), whereas the CNS involvement pattern was not typical for either multiple sclerosis (MS) or acute disseminated encephalomyelitis. The prognosis was excellent with pulse methylprednisolone, intravenous immunoglobulin, and plasmapheresis. This case highlights the varied clinical presentations of CCPD, extending beyond the realms of MS and chronic inflammatory demyelinating polyneuropathy, and underscores the potential for relapse. Importantly, to the best of our knowledge, this represents the inaugural instance of CCPD featuring PNS involvement in the form of recurrent GBS.

Immune-mediated diseases involving central and peripheral nervous systems.

BACKGROUND AND PURPOSE: In addition to combined central and peripheral demyelination, other immune diseases could involve both the central nervous system (CNS) and peripheral nervous system (PNS). METHODS: To identify immune-mediated diseases responsible for symptomatic combined central/peripheral nervous system involvement (ICCPs), we conducted a multicentric retrospective study and assessed clinical, electrophysiological, and radiological features of patients fulfilling our ICCP criteria. RESULTS: Thirty patients (20 males) were included and followed during a median of 79.5 months (interquartile range [IQR] = 43-145). The median age at onset was 51.5 years (IQR = 39-58). Patients were assigned to one of four groups: (i) monophasic disease with concomitant CNS/PNS involvement including anti-GQ1b syndrome (acute polyradiculoneuropathy + rhombencephalitis, n = 2), checkpoint inhibitor-related toxicities (acute polyradiculoneuropathy + encephalitis, n = 3), and anti-glial fibrillary acidic protein astrocytopathy (subacute polyradiculoneuropathy and meningoencephalomyelitis with linear gadolinium enhancements, n = 2); (ii) chronic course with concomitant CNS/PNS involvement including paraneoplastic syndromes (ganglionopathy/peripheral hyperexcitability + limbic encephalitis, n = 4); (iii) chronic course with sequential CNS/PNS involvement including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome (polyradiculoneuropathy + strokes, n = 2), histiocytosis (polyradiculoneuropathy + lepto-/pachymeningitis, n = 1), and systemic vasculitis (multineuropathy + CNS vasculitis/pachymeningitis, n = 2); and (iv) chronic course with concomitant or sequential CNS/PNS involvement including combined central and peripheral demyelination (polyradiculoneuropathy + CNS demyelinating lesions, n = 10) and connective tissue diseases (ganglionopathy/radiculopathy/multineuropathy + limbic encephalitis/transverse myelitis/stroke, n = 4). CONCLUSIONS: We diagnosed nine ICCPs. The timing of central and peripheral manifestations and the disease course help determine the underlying immune disease. When antibody against neuroglial antigen is identified, CNS and PNS involvement is systematically concomitant, suggesting a common CNS/PNS antigen and a simultaneous disruption of blood-nerve and blood-brain barriers.

The clinical features of combined central and peripheral demyelination and antibodies against the node of Ranvier.

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.

Myelin oligodendrocyte glycoprotein-IgG-positive, steroid-responsive combined central and peripheral demyelination with recurrent peripheral neuropathy.

Myelin oligodendrocyte glycoprotein (MOG)-IgG detected by the cell-based assay is associated with demyelinating diseases of the central nervous system, such as optic neuritis, myelitis, and acute disseminated encephalomyelitis, but rarely with peripheral neuropathy. Here, we describe the case of a 32-year-old MOG-IgG+ woman who developed central and peripheral demyelinating lesions. In contrast to previous similar cases, she uniquely presented with repeated subsequent relapses in the peripheral nerve, mimicking chronic inflammatory demyelinating polyneuropathy. Possible pathogenic implications of MOG-IgG in combined central and peripheral nervous system diseases are considered.

Acute simultaneous development of brain tumour-like lesion and demyelinating polyneuropathy in a patient with chronic relapsing myelitis.

Combined central and peripheral demyelination (CCPD) is a rare chronic inflammatory disorder of the nervous system. We describe the case of a patient with a history of recurrent myelitis that acutely and simultaneously developed a brain tumour-like lesion and a sensitive-motor demyelinating polyneuropathy. The diagnosis of CCPD was supported by a detailed diagnostic workup. Up to date, no similar cases have been reported in the literature.

Combined Central and Peripheral Demyelination (CCPD) Associated with MOG Antibodies: Report of Four New Cases and Narrative Review of the Literature.

Background/Objectives: Myelin oligodendrocyte glycoprotein (MOG) is exclusively expressed in the central nervous system (CNS) and is found on the outer surface of oligodendrocytes. Antibodies to MOG are associated with CNS demyelination, whereas peripheral nervous system (PNS) demyelination is seldom reported to be related to MOG-IgG. Methods: The database of patients seen in our neurological academic center was searched for MOG-IgG seropositivity and concomitant demyelinating polyneuropathy. For the purpose of the review, in March 2024, we searched for case reports and case series in the following databases: PubMed, Scopus, Cochrane, and ScienceDirect. Inclusion criteria were MOG-IgG seropositivity and demyelinating polyneuropathy. Exclusion criteria were type of publication other than case reports and case series, unconfirmed diagnosis of demyelinating polyneuropathy, and other diseases causing demyelination in either the CNS or PNS. Critical appraisal of the selected case reports and case series was realized by JBI. Results: Four new cases were identified with MOG-IgG and confirmed demyelinating polyneuropathy. This review identified 22 cases that have been published since 2018. Clinical, imaging, neurophysiological, and immunological characteristics, as well as treatment options and outcomes are presented and compared to those of other cases with combined central and peripheral demyelination (CCPD). Conclusions: The pathogenetic mechanism is unclear; thus, different hypotheses are discussed. New case reporting and large cohort studies will help further the exploration of the underlying mechanism and guide more effective therapeutic interventions.

Asynchronous combined central and peripheral demyelination (CCPD) in a girl with anti-MOG positivity: A case report and review of the literature.

The occurrence of combined central and peripheral demyelination (CCPD) is rare, data are limited to small case and cohort studies, mainly concerning adults. In few patients positivity to anti MOG antibody is reported, thus widening the spectrum of anti-MOG associated disorders (MOGAD). We describe a 7-year-old girl with optic neuritis followed 8 years later by peripheral demyelination, with fluctuating anti-MOG antibody positivity at cell-based assay. From the review of the literature, MOGAD-CCPD appear very rare in childhood, especially with asynchronous course. Clinicians should keep this possibility in mind to better define diagnosis in atypical demyelination syndromes, with therapeutical implications.

Anti-Lactosylceramide antibody positive combined central peripheral demyelination emerging from long-standing juvenile-onset chronic inflammatory polyradiculoneuropathy; a report of two cases.

Anti-Lactosylceramide (LacCer) antibodies are associated with neurological inflammation involving both the peripheral and central nervous system (PNS, CNS respectively), however, the documented number of cases is small. Uncertainty remains whether its positivity can identify a unique clinical entity. Here, we describe two anti-LacCer antibody positive cases, both with long histories (> 30 years) of teenage-diagnosed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). CNS lesions including the medulla oblongata were observed for the first time in adulthood. We suggest that this secondary progression of CNS lesions in juvenile-onset CIDP can be one of the characteristic features of anti-LacCer antibody associated neurological disorder.

Paraneoplastic Syndrome Presenting Combined Central and Peripheral Demyelination Associated with Anti-CV2/CRMP5 and Anti-NF186 Antibodies: A Case Report.

The anti-CV2/CRMP5 antibody is a well-characterized biomarker of paraneoplastic neurological syndrome. The anti-NF186 antibody is a recently discovered antibody associated with central or peripheral demyelination. The co-occurrence of these two antibodies has not been reported. Herein, we report a case with anti-CV2/CRMP5 and anti-NF186 antibodies in a 57-year-old male presenting with progressive numbness and weakness in his four limbs. At first admission, the spinal cord MRI showed a cervical cord demyelinating lesion and electrophysiological examination showed a mixed demyelinating and axonal polyneuropathy. Anti-CV2/CRMP5 and anti-NF186 antibodies were both detected in his serum. Initially, the patient showed a positive response to IVIG and glucocorticoid treatment. However, the syndrome relapsed and mass lesions in lung and mediastinum were detected at second admission. This time the anti-NF186 antibody was not detected but the anti-CV2/CRMP5 antibody was still present. IVIG and glucocorticoid treatment was no longer effective. This case illustrated that paraneoplastic syndrome should be considered when diagnosing patients with central and peripheral demyelination, and that the anti-NF186 antibody may help distinguish a subset of patients who can benefit from immunomodulatory treatments.

Combined central and peripheral demyelination: a case report resembling encephalomyeloradiculoneuropathy.

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.

[A patient with anti-myelin oligodendrocyte glycoprotein antibody-associated combined central and peripheral demyelination with anti-galactocerebroside and anti-GM1 antibodies].

A 48-year-old male was admitted to our hospital because of chronic progressive demyelination of the peripheral nerves of the upper limbs, as well as acute myelitis presenting with sensory disturbance from the left chest to the left leg. We established a diagnosis of combined central and peripheral demyelination (CCPD). The patient was positive for serum anti-myelin oligodendrocyte glycoprotein (MOG), anti-galactocerebroside IgG, and anti-GM1 IgG antibodies. Intravenous methylprednisolone therapy and plasma exchange improved myelitis, and the subsequent administration of oral prednisolone yielded a gradual improvement of the peripheral nerve damage with a mostly negative result for the antibodies. However, the patient experienced a relapse of radiculitis eight months later. Relapses of anti-MOG antibody-associated disease can provoke new immune reactions, leading to CCPD.

The first pediatric anti-lactosylceramide antibody-positive encephalomyeloradiculoneuropathy.

Introduction: The anti-lactosylceramide (LacCer) antibody is an anti-neutral glycolipid antibody that is involved in the pathogenesis of encephalomyeloradiculoneuropathy (EMRN). It causes acute and subacute injuries to both the central and peripheral nerves. However, no pediatric cases of anti-LacCer antibody-positive EMRN have been reported so far. Case: A 12-year-old girl presented with signs of meningitis. She subsequently showed disturbance of consciousness and flaccid tetraplegia and was placed on mechanical ventilation due to respiratory failure. MRI showed lesions in the cerebral white matter, basal ganglia, medulla oblongata, as well as the anterior horn of the spinal cord at the C2 to Th1 and Th11 to L1 levels. Nerve-conduction studies showed axonal neuropathy of the motor nerves. After steroid pulse therapy, high-dose immunoglobulin therapy, and plasma exchange, the lesions gradually regressed, and the neurological symptoms improved steadily. The neurological sequelae were minimal at 6 months after disease onset. Although serum anti-aquaporin 4 and anti-myelin oligodendrocyte glycoprotein antibodies were negative, she showed positive anti-lactosylceramide antibody in both serum and cerebrospinal fluid, indicating that these antibodies may be involved in the pathogenesis of this disease. Conclusion: The first pediatric case of anti-LacCer antibody-positive EMRN showed similar features to the same disease in adults. Anti-neutral glycolipid antibodies should be measured in children presenting with a wide range of neurological symptoms involving both central and peripheral nerves.

Anti-Neurofascin Antibodies Associated with White Matter Diseases of the Central Nervous System: A Red Flag or a Red Herring?

Autoantibodies against nodal and paranodal proteins, specifically anti-neurofascin antibodies (ANFAs), have been recently described in central and peripheral nervous system demyelinating disorders. We retrospectively reviewed the charts of six individuals evaluated at our Multiple Sclerosis Program who tested positive for serum ANFAs on Western blot. We describe these patients' clinical and diagnostic findings and attempt to identify features that might guide clinicians in checking for ANFAs. In our series, the women-to-men ratio was 2:1. At presentation, the median age was 60 years (range 30-70). The clinical presentation was pleiotropic and included incomplete transverse myelitis (n = 3), progressive myelopathy (n = 1), recurrent symmetric polyneuropathy (n = 1), and nonspecific neurological symptoms (n = 1). Atypical features prompting further workup included coexisting upper and lower motor neuron features, older age at presentation with active disease, atypical spinal cord MRI features, and unusual cerebrospinal fluid findings. The serum ANFAs panel was positive for the NF-155 isoform in five patients (IgM n = 2; IgG n = 2; both n = 1) and the NF-140 isoform in two (IgG n = 2). Larger studies are needed to assess the relevance of ANFAs in demyelinating nervous system diseases, their impact on long-term clinical outcomes, and associated therapeutic implications.

Combined Central and Peripheral Demyelination in a Patient of Multifocal Motor Neuropathy and Positive Anti-myelin Oligodendrocyte Glycoprotein (MOG) Antibodies.

Myelin oligodendrocyte glycoprotein (MOG) antibodies have been identified in central nervous system inflammatory demyelinating disorders (MOG antibody disease), inclusive of optic neuritis, transverse myelitis, or acute disseminated encephalomyelitis. The association of MOG antibodies with combined central and peripheral demyelination (CCPD) is not clear. It has been reported in a few cases where MOG antibodies were detected in the serum of patients with chronic inflammatory demyelinating polyneuropathy. However, multifocal motor neuropathy with MOG antibodies is extremely rare. We present a patient who had clinical, neurophysiological, radiological, and biochemical findings that support the diagnosis of CCPD (multifocal motor neuropathy and cord lesion) with MOG antibodies. The patient was treated with a combination therapy of intravenous immunoglobulins plus high-dose methylprednisolone, which resulted in significant improvement.

Combined central and peripheral demyelination: a case report.

Overlapping central nervous system (CNS) and peripheral nervous system (PNS) demyelination is a rare clinical entity, more frequently seen in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multiple sclerosis (MS). This case report showcases a patient with atypical CIDP and CNS demyelination lesions. Demographic data, disease course, treatment responsiveness, neurological examination, laboratory tests, nerve conduction studies (NCS), and brain and spinal cord MRI were registered. The case highlights the difficulty of diagnosis establishment and treatment selection, given the atypical course of the disease and limited answers to the indicated therapies. The data from our report suggest that specific and widely available immunological targets are necessary for diagnosing combined central and peripheral demyelination cases appropriately. The association of different immunotherapeutic agents may be necessary to induce and maintain disease remission.

The Oldest Japanese Case of Combined Central and Peripheral Demyelination, which Developed Nine Years After the First Instance of Optic Neuritis.

Combined central and peripheral demyelination (CCPD) causes demyelination in both the central and peripheral nervous systems. Anti-neurofascin 155 antibody plays an important pathogenic role in CCPD, but evidence concerning an association between this antibody and CCPD remains inconclusive. Although there have been no reports of precedent optic neuritis developing into CCPD, we herein report a Japanese man in whom optic neuritis recurred four times over nine years and who developed CCPD without positive anti-neurofascin 155 antibody. This case suggests the possibility of developing CCPD after optic nerve neuritis and the existence of an unknown antibody that induces CCPD.

Optic Nerve Demyelination in IgG4 Anti-Neurofascin 155 Antibody-Positive Combined Central and Peripheral Demyelination Syndrome.

Optic nerve demyelination is one of the clinical features of combined central and peripheral demyelination (CCPD), an entity with heterogenous immunopathogenesis and clinical characteristics, overlapping between multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Of interest, earlier studies among patients with CIDP prior to discovery of antibodies against paranodal protein neurofascin 155 (anti-NF 155) also reported optic nerve dysfunction. We aimed to evaluate optic nerve demyelination among anti-NF 155 CIDP patients. We studied 2 patients with anti-NF 155 CIDP using visual-evoked potentials (VEP) and optical coherence tomography (OCT). Both patients had distal acquired demyelinating symmetric (DADS) subtype CIDP. Other common features were prominent sensory ataxia, hand tremors, significantly elevated cerebral spinal fluid protein, high titre anti-NF 155 antibodies and poor response to corticosteroid and intravenous immunoglobulin (IVIg). No central nervous system neuroradiological abnormality detected. Both had normal visual acuity and colour vision, but one had subclinical right relative afferent pupillary defect (RAPD). VEP of both showed bilateral prolonged P100 latencies. OCT for patient with RAPD demonstrated moderate to severe retinal nerve fibre layer (RNFL) thinning. Identification of optic nerve demyelination among subclinical CIDP with anti-NF 155 antibodies expanded the spectrum of demyelination within the subset of CCPD.

Anti-Neurofascin 155 Antibody-Positive Chronic Inflammatory Demyelinating Polyneuropathy/Combined Central and Peripheral Demyelination: Strategies for Diagnosis and Treatment Based on the Disease Mechanism.

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 IL1ß, 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 IL1ß 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 Demyelinating Disease With Good Response to B-Cell Depleting Therapy.

Combined central and peripheral demyelination (CCPD) is a rare disorder characterized by demyelinating lesions in both the central and peripheral nervous systems. The following case report is of a 29-year-old man who presented with a three-month history of progressive lower and upper limb weakness associated with facial and arm tremor, as well as urinary hesitancy. Brain and spine magnetic resonance imaging showed multiple demyelinating plaques. Nerve conduction studies revealed evidence of demyelination with severe prolongation of distal motor latencies and reduced conduction velocities. The patient received plasmapheresis and high-dose corticosteroids, which lead to clinical improvement. A rituximab infusion protocol was subsequently started, and the patient received two cycles. There was a significant functional improvement upon the use of rituximab. This study reports a rare neurological disease entity and highlights the necessity for conducting larger studies to optimally demonstrate the efficacy of rituximab in CCPD.