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.


Introduction
Combined central and peripheral demyelination (CCPD), although rare, is being increasingly described in case reports. The presentation was previously considered a combination of two diseases that occurred simultaneously [1]. As more cases are reported, it is now a recognized disease spectrum. Patients with CCPD demonstrate neurophysiological findings that are consistent with demyelinating peripheral neuropathy in association with spatial dissemination of demyelination lesions on MRI brain or spinal cord that resemble those of multiple sclerosis (MS) or neuromyelitis optica (NMO) [2]. In almost two-thirds of cases, the nerve conduction study (NCS) was consistent with chronic inflammatory demyelinating peripheral neuropathy (CIDP) [2]. However, any other form of demyelinating peripheral neuropathy may exist. Myelin oligodendrocyte glycoprotein (MOG) antibodies have been reported in multiple cases of CCPD [3][4][5]. However, it is not clear whether MOG is a serological marker of the disease or CCPD in these cases is part of the MOG antibody disease spectrum with peripheral nervous system involvement.

Case Presentation
A 24-year-old man presented with a four-month history of asymmetrical numbness and weakness in both upper and lower extremities. The numbness started in his left-hand fingers and soon spread to the entire hand and forearm. It then involved the right thigh, followed by the right foot. Eventually, he had numbness and reduced sensation all over his body. He reported difficulty in walking with a weak hand grip. He had two falls in the bathroom when closing his eyes. He had no visual or facial symptoms. There was no bowel or bladder dysfunction. He had presented to another hospital during his illness, two months prior to his current presentation, where he was admitted with the impression of CIDP and treated with intravenous immune globulin (IVIG). He reported some subjective improvement initially, but he subsequently deteriorated. There was no preceding infection or fever. He had received the coronavirus disease 2019 (COVID-19) vaccine two months after the onset of his symptoms. On examination, he had features of both central and peripheral nervous system involvement; he had bilateral lower motor neuron weakness, more apparent in lower extremities with absent reflexes, and a sensory level at C4 and equivocal plantar responses. Romberg's sign was strongly positive along with sensory ataxia and pseudo-athetosis. NCS showed normal distal latency, and distal compound muscle action potential (CAMP) with reduced conduction velocity proximally in the median, ulnar, tibial, and peroneal nerves (Figures 1-5). It also revealed features of conduction block with temporal dispersion. F-wave was prolonged or absent ( Figures 6,  7). The sensory study was normal. These findings were consistent with multifocal motor neuropathy with conduction block.  The patient came for follow-up 10 days later in the outpatient clinic with a complete improvement of motor power in upper and lower limbs, no more gait difficulty, improvement of sensory symptoms, minimal pseudo athetosis of upper limbs, and deep tendon reflexes were depressed.

Discussion
CCPD presents as a combination of CNS demyelination lesions, such as optic neuritis and transverse myelitis, and demyelinating peripheral neuropathy. CCPD can present as myeloradiculoneuropathy, encephalopathy, cranial neuropathy, length-dependent peripheral neuropathy, or pseudo-Guillain-Barré syndrome [2,3]. There are no clear diagnostic criteria though. Some proposed the combination of T2 high signal intensity lesions in the brain, optic nerves, or spinal cord on MRI, abnormalities in visual evoked potential, conduction delay, conduction block, temporal dispersion, or F-wave abnormalities suggesting demyelinating neuropathy based on NCS with the exclusion of secondary demyelination, as a reasonable approach [6]. NCS findings may resemble CIDP in two-thirds of patients. MRI findings may be typical of those of MS in almost half of the patients [2].
Serological markers may add great value if present. We propose MOG IgG1 as a potential marker that may be associated with CCPD. MOG IgG1 may also aid in predicting prognosis for these patients, as in MOG encephalomyelitis where persistent seropositivity is associated with an increased chance of relapse when compared with transient seropositivity (patients who are MOG IgG1 negative on follow-up) [7]. MOG antibodies-positive patients are also thought to be at lower risk of further relapses than aquaporin-4-positive patients [8].
MOG antibodies are known to be associated with CNS demyelinating disorders. MOG is found on CNS surface myelin sheath and oligodendrocytes processes [9]. Peripheral nervous system involvement in MOGantibody-related demyelinating diseases is, therefore, poorly understood. Three hypotheses were proposed to explain it. First, MOG in CSF may trigger autoimmunity by mimicry with peripheral myelin proteins. In addition, peripheral expression of MOG was identified in rats and primates [10,4]. Similar findings in humans may explain the associated peripheral nervous system involvement. Individuals with increased susceptibility to autoimmunity are prone to autoimmune attacks that could potentially target nonshared antigens in both central and peripheral nervous system compartments [4].
In our case, the patient's NCS was consistent with multifocal motor neuropathy with conduction block. The presence of concomitant transverse myelitis on MRI suggested the diagnosis of CCPD. He showed seroconversion as MOG antibodies were initially negative, but became positive on repeat testing.
Multiple treatment options are available with variable outcomes. Corticosteroids, IVIG, and plasmapheresis had different results in different studies. However, the combination of IVIG and pulsed steroid therapy has persistently been superior to either modality alone [11]. The course of MOG antibody-associated CCPD may mimic other MOG antibody-associated disorders, where residual disability develops in 50-80% of patients, with transverse myelitis at onset being the most significant predictor of long-term outcome [12].

Conclusions
CCPD is uncommon. Furthermore, the combination of MOG antibodies and multifocal motor neuropathy is extremely rare. MOG antibodies may be transiently positive. This seroconversion may be a prognostic indicator of the risk of further relapses and disease outcomes. Combination treatment with IVIG and pulsed steroid therapy is superior to either by itself and results in significant recovery. CCPD has to be acknowledged as a distinct entity and a disease spectrum rather than a combination of two diseases.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.