Longitudinal extensive anti-AMPA-GluR3-related transverse myelitis and favorable therapeutic response: A case report and review of literature

Abstract

BACKGROUND

Longitudinally extensive transverse myelitis (LETM) is defined as a spinal cord lesion that extends over three or more consecutive vertebral segments. It is a key manifestation of various inflammatory and demyelinating disorders of the central nervous system. We have described a rare case of a probable association between LETM and the presence of high serum and cerebrospinal fluid levels of metabotropic glutamate receptor 3 antibodies (mGluR3abs) in a 5-year-old girl. LETM is a neurological disorder characterized by a spinal cord lesion extending over three or more vertebral segments.

CASE SUMMARY

We report a case of a 5-year-old Caucasian girl affected by LETM, along with a review of the literature. The patient presented with lower back pain, varying degrees of bilateral sensory and motor deficits, and autonomic dysfunction. Magnetic resonance imaging showed hyperintense signals involving the spinal cord from C3 to the conus medullaris, suggesting a diagnosis of LETM. Laboratory analysis revealed high levels of mGluR3abs in both serum and cerebrospinal fluid. The patient responded favorably to treatment with high doses of intravenous methylprednisolone and immunoglobulin therapy, which has been shown to be particularly effective in children.

CONCLUSION

The frequency of LETM associated with mGluR3abs is unknown; this report may contribute to expanding the understanding of it.

Key Words: Longitudinal extensive transverse myelitis; Spinal cord inflammation; Immune-mediated disorder; Central nervous system; Glutamate receptor 3 antibodies; Case report

Core Tip: This case report describes a potential link between longitudinally extensive transverse myelitis (LETM) and high levels of GluR3abs receptor 3 in a 5-year-old girl. LETM is a neurological disorder marked by a spinal cord lesion spanning three or more vertebral segments. The girl presented with lower back pain, bilateral sensory, motor impairments, and autonomic dysfunction. She had a positive response to high doses of intravenous methylprednisolone and immunoglobulin therapy. The frequency of LETM associated with GluR3abs is unknown, but this case could help expand understanding of this rare condition.

INTRODUCTION

Acute transverse myelitis (ATM) is a rare, rapidly progressive, immune-mediated disease of the central nervous system (CNS). It is mainly caused by an inflammatory process that affects the grey and white matter, including neurons, axons, oligodendrocytes, and myelin, resulting in demyelination of the affected tract[1-3]. The word transverse is used to indicate that the inflammatory process involves the entire cross-section, or more than two-thirds, of the spinal cord, including the posterior column and spinothalamic and pyramidal tracts. Longitudinally extensive transverse myelitis (LETM) refers to a lesion affecting the spinal cord over a length of three or more adjacent vertebral segments, visible as T2 hyperintensity in spinal magnetic resonance imaging (MRI)[4-6]. LETM has been reported to occur in 66% to 85% of pediatric ATM[7,8]. It is a heterogeneous, non-comprehensive myelopathy characterized by acute- or subacute-onset symptoms, progressing to maximum severity between 4 hours and 21 days following the onset, with clinical signs of neurologic dysfunction below the spinal level of the lesion[6-8]. LETM is an uncommon disorder presenting as signs of various illnesses; in particular, it is a clinical feature of the neuromyelitis optica (NMO)[8-10]. Various disorders such as multiple sclerosis, sarcoidosis, Sjogren syndrome, systemic lupus erythematosus (SLE), other autoimmune and inflammatory diseases, and infectious diseases with CNS involvement may manifest with signs of LETM[11]. Clinical manifestations of LETM are usually severe and may present with paraparesis or tetraparesis, sensory dysfunction, gait imbalance, and bladder and bowel incontinence[12]. LETM shows a bimodal distribution, peaking between the ages of 10-19 and 30-39, with no sex-based differences[2]. In recent years, advanced studies on neurological autoimmune diseases have led to the identification of an increasing number of different antibodies linked to inflammatory CNS diseases. The aquaporin-4 antibodies immunoglobulin G (abAQP4 IgG) and the myelin oligodendrocyte glycoprotein (abMOG) antibodies have been shown to play a crucial role in the pathogenesis of NMO. abAQP4 IgG constitutes a highly sensitive serologic marker (around 70% to 80% and > 99% specificity) for this disorder[13,14]. MOG and abAQP4 IgG are produced peripherally and enter the CNS through an altered blood-brain barrier. The deposition of these antibodies on the perivascular astrocytes induces complement-mediated cytotoxicity, leading to inflammatory infiltration and neuronal death[14,15]. LETM positive for abAQP4 IgG can be part of NMO spectrum disorder (NMOSD)[11]. Herein, we report on a 5-year-old Caucasian girl affected by LETM. Laboratory analysis of serum and cerebrospinal fluid (CSF) showed the presence of high levels of GluR3abs. A thorough review of the literature was conducted to clarify the clinical and etiological aspects of LETM, which revealed a frequent immune-mediated pathogenesis. However, the correlation with GluR3abs remains unclear, particularly in children. Therefore, this work could serve as both a contribution and a starting point for future studies aimed at better understanding the role of mGluR3abs in immunomediated CNS disorders.

CASE PRESENTATION

Chief complaints

A 5-year-old girl was admitted to the Emergency Department of Cannizzaro Hospital in Catania, Italy, due to the acute onset of weakness in both lower extremities, difficulty walking, and acute urinary and fecal dysfunction.

History of present illness

The symptoms were preceded by spinal and abdominal pain approximately six days earlier. Additionally, the patient had experienced an upper respiratory tract infection with fever about two weeks prior to the onset of neurological symptoms, which was treated with antipyretics.

History of past illness

The child was previously healthy. Furthermore, the parents denied any history of trauma or recent vaccinations.

Personal and family history

The child was born at term via normal vaginal delivery. Early childhood was uneventful, and motor and language developmental milestones were achieved on time. Family history was irrelevant for neurologic, muscle, and autoimmune disorders.

Physical examination

At the time of admission, the general physical examination was unremarkable. Neurological examination revealed preserved consciousness, with no cranial nerve palsies or meningeal signs, except for mild dermographism. Muscle tone was decreased in both axial and appendicular regions. Deep tendon reflexes were brisk in all limbs, more pronounced in the lower extremities. Touch sensation was impaired in the lower limbs and abdominal region, while temperature and proprioceptive sensations were preserved. Furthermore, the patient presented with urinary and fecal retention.

Laboratory examinations

CSF analysis revealed an elevated nucleated cell count of 27/µL (reference range: 0/µL-7/µL), with a predominance of mononuclear cells (98.5%). Glycorrhachia and proteinorrachia were within normal limits. Polymerase chain reaction testing of the CSF for Mycobacterium tuberculosis, varicella zoster virus (VZV), John Cunningham polyomavirus, measles virus, parvovirus B19, human herpes simplex virus (HSV) types 1, 2, and 6, cytomegalovirus (CMV), Epstein-Barr virus (EBV), enterovirus, adenovirus, and bocavirus was negative. Fungal staining, culture, and antibody titers against Coxsackie viruses in the CSF were also negative. Notably, GluR3abs (both A and B peptides) were detected in both CSF and serum. All other neural autoantibodies in serum and CSF were within normal limits. A comprehensive infectious and autoimmune screening, including antibodies against EBV, Toxoplasma gondii, adenovirus, bocavirus, HSV-1 and -2, rubella virus, CMV, VZV, Borrelia, and Chlamydia, as well as cytoplasm-labeling antineutrophil cytoplasmic autoantibodies, perinuclear antineutrophil cytoplasmic antibody, anti-tissue transglutaminase, anti-endomysial, anti-nuclear antibody, anti-mitochondrial antibody, anti-smooth muscle antibody, and extractable nuclear antigen antibody panel, revealed no significant findings.

Imaging examinations

Brain and whole-spine contrast-enhanced MRI revealed a diffuse increase in spinal cord volume and an intramedullary hyperintense signal extending from C3 to the conus medullaris (Figure 1). Post-contrast imaging also demonstrated diffuse leptomeningeal enhancement.

Figure 1 Acute magnetic resonance imaging shows signal hyperintensities indicating transverse myelitis with longitudinal cervical and dorsal extension, extensively involving. A: The spinal cord from C3 (as indicated by the arrow); B: To the conus medullaris (as indicated by the arrow).

FINAL DIAGNOSIS

These imaging findings were consistent with a diagnosis of transverse myelitis with longitudinal cervical and thoracic involvement.

TREATMENT

The patient was treated with high-dose intravenous (IV) methylprednisolone (30 mg/kg/day) for five days, followed by IV immunoglobulin (IVIg) (1 g/kg/day for three days). This was succeeded by oral prednisone for three weeks, with subsequent progressive tapering. Ceftriaxone and ranitidine were also administered concurrently with steroid therapy.

OUTCOME AND FOLLOW-UP

A rapid and progressive improvement in motor function, along with resolution of urinary and fecal retention, was observed. By the time of discharge, the patient's muscle strength had significantly improved bilaterally, and she was able to walk independently. There were no deficits in touch, temperature, or proprioceptive sensation. Neurogenic bladder and bowel function gradually normalized following treatment. During neurological follow-up, the patient showed no recurrence of symptoms, and muscle strength returned to normal. A brain and whole-spine MRI performed nine months after discharge showed complete resolution of the previously observed lesions. At the three-year follow-up, the patient remained completely asymptomatic, with normal gait and negative diagnostic findings.

DISCUSSION

LETM is a neurological disorder characterized by a spinal cord lesion extending over three or more vertebral segments. In children, LETM is often preceded by an infectious event, followed by the onset of neurological symptoms involving sensory, motor, and autonomic deficits. This is likely the result of an abnormal immune response within the CNS to the infectious agent, possibly mediated by a mechanism of molecular mimicry[16]. Immune cells activated to fight the infection may also target neuronal cells, leading to inflammation, demyelination, and neuronal injury within the spinal cord[16,17]. In autoimmune etiologies - particularly in NMOSD - abMOG and abAQP4 IgG are frequently reported. In this patient, elevated levels of mGluR3abs were detected in both serum and CSF. Glutamate, one of the primary excitatory neurotransmitters in the CNS, acts on both ionotropic and metabotropic receptors. It plays a crucial role in numerous neuronal functions and is essential for normal brain activity. The two main families of anti-glutamate receptor antibodies implicated in autoimmune neurological disorders are (1) Antibodies directed against ionotropic glutamate receptors, including mGluR3abs, anti-N-Methyl-D-aspartate receptor subunit 1, and anti-N-Methyl-D-aspartate receptor subunit 2 antibodies; and (2) Antibodies directed against metabotropic glutamate receptors, such as anti-mGluR1 and anti-mGluR5 antibodies[18]. Glutamate receptors are a family of receptors that include both ionotropic and metabotropic subtypes. The mGluRs are G protein-coupled receptors that have been classified into three groups based on sequence homology, signal transduction pathways, and pharmacological properties[18,19]. From a pathogenic perspective, antibodies against GluR1, GluR3, and GluR5 have been associated with various clinical conditions, most notably autoimmune encephalitis[20]. mGluR3abs have been detected in individuals with intractable seizures[21], schizophrenia[22], and bipolar disorder[23,24]. Clinical descriptions of LETM are relatively uncommon. Nightingale et al[13] reported two adult cases, aged 78 years and 31 years. The first patient presented with progressive bilateral leg weakness and sensory changes in the feet, and areflexia. NMO-IgG antibodies were positive. The second patient presented with progressive leg weakness and numbness lasting 5 days. NMO-IgG antibodies were negative. In the first case, treatment with IV methylprednisolone and plasma exchange resulted in improvement in sensation, but not in motor function. In contrast, the second patient showed rapid improvement following methylprednisolone treatment, with complete remission within 3 months. A retrospective 20-year study by Koul et al[25] examined. 19 children diagnosed with ATM, 18 (94.6%), presented with LETM lesions. Additionally, Celik et al[26] analyzed a cohort of 15 children, including 8 girls and 7 boys. The clinical symptoms in the cohort included inability to walk in 12 children (80%), incontinence in 9 (60%), low back pain in 4 (26.6%), abdominal pain in 2 (13.3%), and inability to use the arms in 2 (13.3%). The authors observed a more favorable prognosis in children who received immunomodulatory therapy sooner after symptom onset, with greater improvement in motor function and incontinence[25]. A case of a 61-year-old woman with multiple comorbidities, including SLE and rheumatoid arthritis, was reported by Chawla et al[1]. She presented with an acute onset of constrictive, band-like sensations around the chest, along with paresthesia and numbness in the trunk and bilateral lower extremities, as well as urinary incontinence. On examination, mild bilateral lower extremity weakness, sensory loss below the T4 level, and an unsteady gait were noted. CSF analysis was unremarkable. Additionally, Chandrasekar et al[2] reported three pediatric cases. The cases showed variability in clinical presentation: The first had gradual bilateral painless vision loss accompanied by headache, vomiting, and seizures; the second presented with abdominal pain, urinary retention, constipation, and patchy sensory loss without a definite sensory level; and the third experienced fever, lower limb weakness, hypotonia, and muscle strength graded 1-2/5 in the lower limbs. Early and aggressive immunomodulatory therapy was effective in two of the cases. LETM has been associated with various pathological conditions. It has been reported in a patient with serum IgG4 levels at the upper limit of normal[26] as well as in patients with NMO and in association with several inflammatory etiologies, infections, malignancies, and metabolic disturbances[27]. The literature review, which is summarized in Table 1, included studies of both adult and pediatric patients, underscoring the marked clinical heterogeneity of ATM, particularly LETM. This condition may affect individuals across all age groups; however, no specific biomarker or consistent clinical course has been identified to date. Notably, in line with previous reports and as illustrated by our case, pediatric patients appear to have a more favorable long-term prognosis than adults, especially regarding the recovery of neuromotor functions. More recently, LETM has been reported in patients affected by coronavirus disease 2019 (COVID-19), caused by coronavirus 2, as well as by other coronaviruses[28]. Several studies have identified LETM as a potential neurological complication of COVID-19[29-33]. Additionally, a causal relationship between LETM and COVID-19 vaccination has been reported[34-38]. LETM has also been observed following vaccination in a patient who tested positive for abMOG[39,40]. We considered and excluded several differential diagnoses during the diagnostic workup. The absence of anti-AQP4 and anti-MOG antibodies in the CSF and serum allowed us to rule out NMOSD and MOGAD, respectively. Similarly, the lack of anti-Hu and anti-collapsin response mediator protein 5 antibodies excluded paraneoplastic immune-mediated forms, while negative tests for viral (HSV, VZV, EBV, CMV, human immunodeficiency virus, enteroviruses), bacterial (tuberculosis, syphilis, Lyme disease), and fungal antibodies ruled out infectious causes. The absence of autoantibodies also excluded systemic autoimmune diseases such as SLE, Sjogren’s syndrome, sarcoidosis, and vasculitis. Additionally, MRI findings ruled out spinal cord infarction, arteriovenous malformations, and fistulas. Although multiple sclerosis typically presents with shorter spinal cord lesions (< 3 vertebral segments), it can occasionally mimic LETM.

Table 1 Literature data reviewed and summarized.

Ref.	Patients (age/sex)	Clinical presentation	NMO-IgG/CSF	Treatment	Outcome
Nightingale et al[13], 2011 (case 1)	78 years, adult	Bilateral leg weakness, sensory changes in feet, areflexia	NMO-IgG positive	IV methylprednisolone + plasma exchange	Sensory improvement, persistent motor deficit
Nightingale et al[13], 2011 (case 2)	31 years, adult	Leg weakness + paresthesia (5 days)	NMO-IgG negative	IV methylprednisolone	Complete remission within 3 months
Koul et al[25], 2017	19 children (20-year retrospective study)	18 (94.6%) with LETM lesions	-	Various therapies	Not reported in detail
Celik et al[26], 2021	15 children (8 female, 7 male)	Inability to walk (80%), incontinence (60%), low back pain (26.6%), abdominal pain (13.3%), upper limb weakness (13.3%)	-	Immunomodulators (early = better prognosis)	Better motor and continence recovery when treated early
Chawla et al[1], 2019	61 years, woman with SLE and RA	Chest/gait paresthesia, lower limb weakness, urinary incontinence, unsteady gait	CSF normal	-	Not specified
Chandrasekar et al[2], 2022 (3 cases)	3 children	Case 1 bilateral vision loss, headache, vomiting, seizures; case 2 abdominal pain, urinary retention, constipation, patchy sensory loss; case 3 fever, lower limb weakness, hypotonia, muscle strength 1-2/5	-	Early aggressive immunomodulatory therapy	Improvement in 2 cases
Celik et al[26], 2021	Various patients (IgG4, NMO, other etiologies)	LETM is associated with various conditions (inflammatory, infectious, neoplastic, metabolic)	Variable	-	Variable

NMO-IgG: Neuromyelitis optica immunoglobulin G; CSF: Cerebrospinal fluid; IV: Intravenous; LETM: Longitudinally extensive transverse myelitis.

The therapeutic approach for patients with LETM is similar to that for ATM and depends on the underlying cause. First-line treatment typically involves high-dose IV methylprednisolone (30 mg/kg/day) for 5 days, followed by a gradual tapering of oral steroids over 4 weeks to 6 weeks. If there is no clinical improvement or if symptoms worsen within 24 hours to 48 hours, plasmapheresis or IVIg therapy may be considered due to the high risk of severe sequelae[41,42]. Some centers administer plasmapheresis or IVIg therapy concurrently with steroids in patients who present with severe motor or respiratory dysfunction at onset[43]. Most patients have been shown to benefit from a combination of high-dose IV methylprednisolone and plasmapheresis[43]. Additionally, plasmapheresis, IVIg, or other immunosuppressive therapies may be employed in patients with severe clinical presentations or in those unresponsive to high-dose IV methylprednisolone[43]. In a recent study, all patients received high-dose IV methylprednisolone as first-line therapy. Due to severe symptoms, 40% of patients were additionally treated with IVIg, and another 40% underwent plasmapheresis. Furthermore, because of the risk of sequelae, azathioprine therapy was initiated in two patients who experienced recurrent events[25].

In the present case, the patient was treated with IV methylprednisolone at a dose of 30 mg/kg/day for 5 days combined with IVIg (1 g/kg/day) for 3 days, and then with oral prednisone for 3 weeks, with successive progressive tapering yielded a favorable response with a gradual but consistent valuable effect resulting in progressive and complete recovery. It is well established that early treatment is associated with better functional outcomes in spinal cord disorders. Therefore, to preserve spinal cord function, treatment should be initiated immediately in suspected cases. Favorable prognostic factors in patients with LETM and ATM include a slow progression of neurological symptoms from onset, signs of recovery within 1 week, and independent ambulation in less than 1 month. Conversely, negative prognostic factors include rapid progression of neurological symptoms within 24 hours, complete paraplegia, supraspinal symptoms, severe motor weakness, sphincter involvement, and spinal atrophy visible on MRI[43-45]. In a study of 39 children with ATM, Chen et al[46] identified poor prognostic indicators, including a short time to reach maximal deficits, prolonged duration of peak neurological impairment, delayed initiation of treatment, CSF protein levels, and secondary infections. As in our case - and consistent with the literature - combination therapies should be considered when a severe clinical course is anticipated. Although no standardized treatment guidelines exist, literature evidence indicates that combined therapy with high-dose steroids and plasmapheresis or immunoglobulins should be initiated as early as possible, especially in patients with poor prognostic factors, such as rapid progression to maximal deficits or prolonged peak neurological impairment[10]. Early combination treatment with high-dose steroids may improve outcomes in pediatric ATM[10]. Compared with adults, children generally have better outcomes, with nearly half achieving full recovery within two years of onset[20,47]. In other patients, long-term neurological sequelae may occur, particularly cognitive impairments and motor deficits of varying severity, influenced by baseline prognostic factors and the promptness of therapy initiation. Remarkably, our patient, who received early combined therapy following symptom onset, showed substantial regression of neuromotor deficits within one year and remained free of clinical or neuroradiological relapses at the three-year follow-up.

CONCLUSION

LETM represents a severe cause of neurological manifestations at all ages. The patient in this case presented with LETM and tested positive for mGluR3abs in both serum and CSF, which helped to better define the diagnosis. The frequency of LETM-related mGluR3abs is unknown, and this report may contribute to increasing knowledge about this disorder. Treatment with high doses of methylprednisolone and immunoglobulin yielded favorable results, confirming that rapid and early recognition, along with prompt treatment, can lead to progressive and complete recovery. Nevertheless, much remains to be understood about LETM, especially in pediatric patients. Targeted studies are therefore warranted to better elucidate the clinical features of the condition and their correlation with autoantibodies, with the ultimate goal of enabling early diagnosis and establishing standardized treatment guidelines.

ACKNOWLEDGEMENTS

We thank our colleagues from the “Policlinico” and “Cannizzaro” hospitals for their contributions to the research, who endorse the data and conclusions.