Simultaneous combined central and peripheral demyelination with acute inflammatory demyelinating polyradiculoneuropathy and short segment myelitis

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.


INTRODUCTION
Combined central and peripheral demyelination (CCPD) describes demyelination in both central and peripheral nervous systems (PNS).It is a distinct disease rather than co-existence of central and peripheral demyelination.Most CCPD patients respond to immunotherapies, particularly systemic steroids and plasma exchange (PLEX), suggesting an underlying immune-inflammatory mechanism. 1However, interferon-beta (IFN-β) therapy, used in multiple sclerosis, can at times exacerbate CCPD. 1 Since IFN stimulates antibody production of all subclasses, an autoantibody-mediated mechanism is postulated in the pathogenesis of CCPD.Furthermore, improvement with PLEX and intravenous immunoglobulin (IVIg) favours an antibody-mediated immunepathology.
Literature on adult simultaneous onset CCPD with short segment myelitis is scarce and to the best of our knowledge, this is the first case reported from Sri Lanka.

CASE REPORT
A 52-year-old woman presented with four days of back pain and difficulty walking.She had difficulty climbing stairs.There was no recent infection.Examination revealed pallor and a diffuse goitre.Muscle power in the upper limbs were 3/5 proximally and 4/5 distally; and in the lower limbs, were 0/5 proximally and 1/5 distally.Reflexes were absent globally.Plantar responses were flexor.She had a T4 sensory level with sacral sparing.Intravenous methylprednisolone was initiated for presumptive myelitis.https://orcid.org/0000-0003-3373-0432 SLJoN ⏐ ALAHAKOON et al On day 5 of the illness, she developed urine retention requiring catheterization.On day 6, a left lower motor facial nerve palsy was noted, progressing to facial diplegia.The patient progressed to respiratory failure requiring mechanical ventilation.On repeat examination, extensor plantar reflexes were noted with absent joint position sense.
Cerebrospinal fluid (CSF) analysis showed a protein of 60 g/l (20-40g/l), with 10/mm 3 (0-5/mm 3 ) lymphocytes.CSF and serum did not reveal monoclonal bands.Magnetic resonance imaging (MRI) of the brain was normal, MRI spine showed an intramedullary lesion at C5-C6 level without contrast enhancement (Figure 1).Nerve conduction studies showed features of focal segmental demyelinating motor and sensory polyneuropathy.Presence of uneven conduction slowing, temporal dispersion in compound muscle action potentials and conduction blocks favoured an acquired cause.evidence.The patient was treated with intravenous methylprednisolone 1g/day for 3 days, but did not improve.Subsequently, she was treated with IVIg followed by five cycles of PLEX.By the second week of treatment, she was weaned off artificial ventilation.She regained 5/5 upper limb power, four weeks after immunomodulatory treatment.After five weeks, lower limb power returned to 5/5 with bilateral flexor plantar responses, normal deep tendon reflexes and normal sensory examination.Repeat MRI after five weeks of treatment was normal.The patient went home with a tapering dose of prednisolone.She was asymptomatic at 3-months follow-up.

DISCUSSION
Combined central and peripheral demyelination (CCPD) is predominantly reported in children. 2 In the largest case series involving 40 patients with CCPD, two subtypes, depending on whether symptoms in the central nervous system (CNS) and peripheral nervous system (PNS) appeared simultaneously (within 2 months of one another -simultaneous-onset group) or at different times of disease progression (>2 monthstemporally separated-onset group), has been proposed. 3imultaneous-onset disease is associated with severe deficits, respiratory failure, and more extensive cerebral and spinal cord lesions.Isolated short segment spinal cord lesions are not observed in the simultaneous-onset group. 3The temporally separated-onset disease exhibits a more indolent course and is usually associated with optic nerve involvement. 3This subtype can have a monophasic, relapsing and remitting or a chronic progressive course.The monophasic course is observed more often in the simultaneous onset subtype.Our patient had early bladder involvement, a sensory level with extensor plantar responses and disproportionate lower limb involvement coupled with imaging abnormalities in the cervical cord suggestive of central demyelination.Although the sensory level was keeping with a thoracic cord lesion, this was thought to be a false localizing sign of a cervical cord lesion which has been described previously. 4The pathophysiology of this phenomenon is poorly understood.Simultaneously, she developed lower motor facial diplegia, upper and lower limb weakness with prominent proximal weakness and global areflexia with demonstrable electrophysiological evidence of peripheral demyelination.Reduced motor nerve conduction velocities, motor conduction blocks and abnormal temporal dispersion with prolonged distal motor latencies, combined with its acute progression was consistent with an acute inflammatory demyelinating polyradiculoneuropathy (AIDP).Thus, she fulfilled criteria described by Ogata et al. for simultaneous onset monophasic CCPD with severe motor impairment and respiratory failure. 3Although rare, several case reports have described features of AIDP as evidence of PNS demyelination in CCPD (Table 1).In contrast to classical simultaneous CCPD in which longitudinally Hematological analysis revealed normochromic normocytic anaemia (haemoglobin -8.2 g/dL) and normal white cells and platelet counts.Liver and renal profiles were normal.Thyroid stimulating hormone (TSH) was high: 12.2 ug/dl (4.6-12) with a free T4 of 0.9 ng/dl (0.7-1.9).Thyroid ultrasonography showed features of chronic thyroiditis.Thyroid receptor antibodies and anti-thyroid peroxidase antibodies were negative.Fine needle aspiration cytology was reported as a benign smear with follicular nodules (class-Thy2 -features consistent with nodular goitre or thyroiditis).Anti-nuclear antibodies, antineutrophil cytoplasmic antibodies (cANCA, pANCA), Hepatitis B and C serology, human immunodeficiency virus (HIV) screening, and venereal disease research laboratory (VDRL) tests were negative.Cytomegalovirus IgM antibodies was negative.Mycoplasma antibodies (IgM and IgG) were positive with a titre of 1:60 (IgG) without subsequent rise.

Case Report
Simultaneous onset combined Not responded to steroids.T2 weighted MRI of the brain Kinoshita A et al. 6 acute disseminated encephalo-Responded to IVIg and PLEX.showed extensive multifocal high myelopathy and demyelinating intensity lesions in the cerebral polyradiculoneuritis, 12 days.white matter, with Gd enhancement in the corpus callosum and left internal capsule.

Case Series
Multiple sclerosis and peripheral Satisfactory clinical and 75% fulfilled 2010 McDonald Yuceyar et al. 7 segmental demyelinating radiological responses to criteria for multiple sclerosis for N=4 neuropathy.high dose IVMP.dissemination in space.Specific location of lesions -not reported.

Case Report
Simultaneous onset acute, Marked improvement T2 weighted patchy hyper Joshi et al. 8 demyelinating type of with steroids.intensities in the cervical cord.sensory-motor peripheral neuropathy and transverse myelitis, 2 years, one relapse.

Case Report
Temporarily separated acute Immediate improvement Multiple subcortical and Bezerra et al. 9 demyelinating polyneuropathy with IVIg, 0.4 g/kg/day and periventricular white matter and MRI evidence of multiple oral prednisolone 1 mg/kg/day.lesions, hyperintense in T2 subcortical and periventricular weighted images and hypointense white matter lesions, 2 years, in T1, with Gd enhancement.two relapses.
Cervical spinal cord nonenhancing intramedullary signal changes similar to the cerebral lesions.
PNS involvement and isolated spinal cord involvement, without concurrent cerebral involvement, unlike that seen in our patient.

Case Series
Temporarily separated multiple An improvement in clinical Barkhof's criteria on MRI and Zéphir et al. 10 sclerosis and demyelinating status and neurophysiological the McDonald criteria N=5 peripheral neuropathy, parameters in three patients for MS met -100% 1 year, two relapses.
after treatment with either Brain lesions -100% IVIg or cyclophosphamide.

Case Report
Simultaneous onset combination Not responded to steroids.Multiple dot-like cortical and Katchanov et al. 11 of acute disseminated Responded to IVIg and PLEX.subcortical lesions were encephalomyelopathy and delineated, predominantly demyelinating polyradiculoneuritis, located in the frontoparietal 1 year, no relapses.
gray and white matter.

Case Report
Simultaneous onset bilateral optic Complete recovery Enlargement of both optic nerves Baheerathan et al. 12 13 neuritis and GBS secondary to IVMP and PLEX.

Mycoplasma pneumoniae
Recovery of mobility infection, 1 month, no relapses.
with minor residual sensory disturbances.
Complete recovery of visual acuity of the left eye, grossly impaired vision on the right.

Case Report
Simultaneous onset bilateral Partial recovery following Cerebral white matter lesions -Nadkarni and optic neuritis, acute disseminated IVMP and PLEX.multiple T2 and proton density-Lisak. 14ncephalomyelitis and GBS Poorly sighted -able only intense lesions that secondary to Mycoplasma to discern shapes and enhanced with Gd. pneumoniae infection, several identify faces.months, no relapses.
Near normal mobility and activities of daily living.

Case Report
Simultaneous onset bilateral Partial recovery following Normal MRI brain and spine.Henderson et al. 15 optic

SLJoN
The aetiopathogenesis of CCPD remains unknown, but the possibility of a shared pathogenic CNS and PNS epitope has been suggested. 5It has been proposed that antigenic crossreactivity with myelin proteins and other antigens may elicit similar immune responses, thereby producing demyelination in immunologically susceptible individuals.Several studies identified anti-ganglioside antibodies (anti-GM1 IgG) and neurofascin antibodies in patients with CCPD and hypothesized that central and peripheral demyelination may have a common pathophysiology. 5Moreover, identifying such antibodies is important, especially in patients with neurofascin antibodies as they respond well to IVIg or PLEX. 5 CCPD has been reported to be associated with autoimmune thyroid disease with high titres of thyroid antibodies. 17It is reported that patients with Hashimoto thyroiditis can have anti-GM1 antibodies.Our patient demonstrated chronic thyroiditis on sonography though autoimmune antibodies were negative.We postulate that our patient was predisposed to CCPD due to sero-negative Hashimoto thyroiditis.However, GM1 antibodies were unavailable to test.
CCPD with long-segment myelitis has been reported to show a greater response to high dose steroids than CCPD with short segment myelitis. 3Additional IVIg and PLEX are required in CCPD patients with inadequate response to high dose steroids.
Since CCPD can worsen with IFN-β, it is important to differentiate it from multiple sclerosis.

FIGURE 1
FIGURE 1 T2 weighted MRI axial image of the spine showing an intramedullary lesion within the cervical cord (arrow).
Guillain-Barre syndrome (GBS) were diagnosed on clinical, radiological and neurophysiological ALAHAKOON et al SLJoN extensive myelitis is observed, our patient had short segment spinal cord demyelination.Furthermore, none of the patients in the previously described simultaneous-onset group had 3

TABLE 1 Summary of presentation and clinical response to management of CCPD in adults
neuritis and GBS secondary IVMP and IVIg.