Non‐Syndromic Tumefactive Demyelinating Lesions in the Pediatric Population: Four Case Reports and Review of the Literature

ABSTRACT

Introduction

Tumefactive demyelinating lesions (TDLs) are large lesions (> 2 cm) seen in demyelinating syndromes such as multiple sclerosis, myelin oligodendrocyte glycoprotein antibody‐associated disorder, and neuromyelitis optica spectrum disorder. They rarely occur in children and most often have a monophasic course. TDLs can cause severe presentations given their size, edema, and associated mass effect, making prompt diagnosis and effective treatment crucial.

Patient Description

We present four adolescents with TDLs who tested negative for aquaporin‐4‐IgG and myelin oligodendrocyte glycoprotein (MOG)‐IgG and did not meet diagnostic criteria for any known demyelinating disorder. All four patients underwent extensive and inconclusive workup for the etiology of their radiographic and clinical findings and received multiple immunomodulators with some clinical improvement, although three of the four had multiple relapses.

Conclusions

TDLs that do not meet criteria for the known demyelinating syndromes can cause significant neurological sequelae. We describe four adolescents with neurological symptoms associated with TDLs. Given the rare but serious occurrence of these non‐syndromic TDLs, more well‐powered studies are critical to guide diagnosis, management, and response to therapies and eventually develop evidence‐based protocols to manage other patients with similar presentations.

1. Introduction

Tumefactive demyelinating lesions (TDLs) are large (> 2 cm) lesions characterized by severe clinical manifestations related to their location. On magnetic resonance imaging (MRI), they appear as T2‐hyperintense brain lesions with contrast enhancement and some degree of mass effect. Although they can be found throughout the central nervous system, TDLs tend to occur in cerebral hemispheric white matter and can also involve the brainstem [1]. TDLs can be associated with demyelinating syndromes such as multiple sclerosis (MS) and its variants [2], neuromyelitis optica spectrum disorder (NMOSD) [3], and myelin oligodendrocyte glycoprotein antibody‐associated disorder (MOGAD) [4] but may also present as idiopathic demyelinating disease [5]. One recent study found that more than half of patients with TDLs lacked a clear etiology [6]. Their true frequency and rate of relapse remain unknown due to the lack of a systematic evaluation of TDL in neuroinflammatory conditions or the general population.

TDLs pose unique challenges to diagnosis and treatment. They may be radiographically similar to other CNS processes, such as neoplasms, rheumatologic conditions, infections, genetic/metabolic disorders, and neurotoxic leukoencephalopathy secondary to drugs like methotrexate or tacrolimus [7]. Patient presentation may parallel that of other conditions, depending on the location and size of the TDL. Biopsy and histopathological examination may be necessary, particularly if the patient continues to deteriorate without a known etiology and after empiric immunomodulatory treatment.

The clinical variability, radiographic heterogeneity, and epidemiological uncertainty of TDLs make these lesions challenging to characterize or prognosticate [8]. Their complexity may require an invasive diagnostic evaluation [4]. Therefore, it is critical to detail the spectrum of TDLs so that neurologists are able to optimally diagnose and treat them. Here, we present four adolescents with TDLs who did not meet diagnostic criteria for any known demyelinating syndrome and received immunomodulatory therapy with clinical and radiographic improvement.

2. Methods

All children under 18 years of age seen at Texas Children's Hospital between 2022 and 2024 with a first‐time demyelinating event of the brain were identified and reviewed (isolated optic neuritis and/or isolated spinal cord involvement were excluded). Of the eighty‐five patients reviewed, those who had a TDL (defined as a > 2 cm confluent lesion) and no identified underlying syndrome (i.e., MS/MOGAD/NMOSD) were included. All serum MOG‐IgG and AqP4‐IgG assays were live‐cell assays performed at Mayo Clinic Laboratories (Rochester, MN), and CSF MOG‐IgG was performed at Quest Diagnostics (Secaucus, NJ). During their course, all patients were screened for infectious etiologies with a cerebrospinal fluid (CSF) culture and CSF viral studies. All but patient 1 were additionally screened with a comprehensive infectious meningitis/encephalitis panel, and all were screened for autoimmune etiologies with an autoimmune encephalitis panel and a basic rheumatologic evaluation (erythrocyte sedimentation rate, C‐reactive protein, anti‐nuclear antibody, anti‐double‐stranded DNA antibody, anti‐SS‐A/La antibody, anti‐SS‐B/Ro antibody). All patients were screened for vascular etiologies with MRI angiography. These screenings did not reveal alternative diagnoses in any of the patients.

This study was approved by the Baylor College of Medicine Institutional Review Board, IRB# H‐35069. It was funded through support from the Research Vision at Texas Children's Hospital. Informed consent was obtained in writing from all patients or from their legal guardians.

3. Results

3.1. Patient 1

This 16‐year‐old boy presented with an acute onset of mixed aphasia and ataxia 1 month after a SARS‐CoV‐2 infection. MRI showed a left frontal and right occipital TDL (Figure 1A). Diagnostic evaluation included normal/negative oligoclonal bands, CSF white blood cell (WBC) (4 cells/mm³), and CSF protein (35 mg/dL). He improved with intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIG) followed by an oral steroid taper. Given the severity of his initial presentation and incomplete recovery at discharge, he was prescribed monthly IVIG; however, he completed only one infusion. He later developed seizures, which responded well to antiseizure medication (ASM). Interval MRI obtained 3 months after initial presentation showed near‐complete resolution of the FLAIR (fluid‐attenuated inversion recovery) hyperintensity, although with a small area of residual T2 hyperintensity. He had returned to his neurological baseline at follow‐up 5 months after presentation.

Figure 1.

Magnetic resonance imaging findings and clinical course of patient 1. (A) Brain imaging at presentation demonstrated a large 7.3 × 3.4 cm white matter lesion of the left frontoparietal region (i), as well as a smaller lesion of the right mesial occipital lobe (ii). (B) Brain imaging at first clinical relapse, 7 months after original presentation, showed a large 8.6 × 5.5 cm white matter lesion of the frontoparietal region now on the right side. (C) Brain imaging at radiographic relapse 14 months after original presentation, demonstrating interval improvement of prior TDLs (i) but a new left temporo‐occipital lesion (ii). (D) Brain imaging from clinical relapse 27 months after original presentation showing large right posterior temporoparietal TDL. (E) Timeline of clinical events, neuroimaging, and immunotherapies. IVIG, intravenous immunoglobulin; TDL, tumefactive demyelinating lesion.

He presented again 7 months after the original presentation with an acute onset of left hemiplegia and hemisensory deficits. MRI confirmed a new right frontoparietal TDL (Figure 1B). His evaluation was significant for elevated serum IL‐6 (23.9 pg/mL). CSF IL‐6 was not obtained. Serum screening tests for hemophagocytic lymphohistiocytosis (HLH) were not consistent with this diagnosis. Symptoms resolved with IVMP followed by an oral steroid taper, and rituximab was initiated due to concerns of a potentially relapsing condition.

One month later, he presented again with recurrence of left hemiplegia and hemisensory deficits, now with mild aphasia and headache. MRI showed the presence of the right frontoparietal TDL, though slightly smaller in volume. He improved with IVMP, although he continued to have residual left foot drop at discharge. He was discharged with an oral steroid taper and again prescribed monthly IVIG but completed only one infusion. Interval imaging 2 months later showed dramatic improvement of the right TDL, with a small area of residual T2 hyperintensity. The previously seen residual area of T2 hyperintensity on the left remained stable.

Surveillance testing on follow‐up ~4 months later (6 months after relapse) showed that serum IL‐6 had decreased to near normal, but imaging revealed a new, clinically silent demyelinating plaque (14 mm × 14 mm) in the left temporo‐occipital lesion (Figure 1C). He started monthly tocilizumab infusions, after which he remained clinically and radiographically stable for 12 months.

Twenty‐seven months after the original presentation, he re‐presented with confusion and abnormal movements after self‐discontinuing his ASM. MRI revealed a new right temporoparietal TDL (Figure 1D). He underwent repeat serum screening labs for HLH, which were again inconsistent with this diagnosis. He was treated with IVIG and IVMP followed by an oral steroid taper. At the time of discharge, he had returned to neurological baseline. He continued monthly tocilizumab, restarted ASMs, and started monthly IVIG. At last follow‐up ~30 months after the original presentation, he had made a full recovery. His clinical course is summarized in Figure 1E. Spinal imaging, serum MOG‐IgG, and serum AqP4‐IgG testing were negative on original presentation and on multiple repeats. CSF MOG‐IgG testing was negative. Genetic testing for mitochondrial variants was unrevealing. Further genetic testing was not performed due to logistical challenges with follow‐up. Repeat CSF testing was not performed on his admission for relapse due to concerns for increased intracranial pressure.

3.2. Patient 2

This 14‐year‐old girl with a history of migraine presented with worsening atypical headache. MRI showed multifocal areas of abnormal T2 signal, mostly involving the frontal and parietal lobes bilaterally, predominantly on the right (Figure 2A). Her evaluation was significant for negative oligoclonal bands, normal CSF protein (35 mg/dL), and mildly elevated CSF WBC (13 cells/mm³). She received IVMP followed by an oral steroid taper and subsequently improved.

Figure 2.

Magnetic resonance imaging findings and clinical course of patient 2. (A(i–ii)): Brain imaging at presentation demonstrating acute disseminated encephalomyelitis–like findings. (B) Brain imaging at first clinical relapse, 1 month after original presentation, showed a large right frontal white matter lesion. (C(i–ii)) Brain imaging at radiographic relapse 7 months after original presentation, demonstrating new subcortical white matter lesions bilaterally. (D) Brain imaging from clinical relapse 8 months after original presentation showing large right frontal TDL. (E(i–ii)) Brain imaging from clinical relapse 9 months after original presentation showing right frontal TDL as well as new left posterior orbital white matter lesion and pontine T2 signal abnormality. (F) Timeline of clinical events, neuroimaging, and immunotherapies. IVIG, intravenous immunoglobulin; PLEX, plasmapheresis/plasma exchange; TDL, tumefactive demyelinating lesion.

One month later, she re‐presented with worsening headache and developed focal status epilepticus. MRI showed a right frontal TDL with associated edema and midline shift (Figure 2B). She received IVMP, plasmapheresis/plasma exchange (PLEX), IVIG, and levetiracetam for seizure control. At discharge, her mild left hemibody weakness persisted. She completed an oral steroid taper and 6 months of monthly IVIG. Surveillance imaging improved, and the electroencephalography normalized, so levetiracetam was weaned off.

Three months later, surveillance imaging revealed new, silent FLAIR hyperintensities (Figure 2C). Repeat evaluation was significant for CSF with normal protein (36 mg/dL) and WBC (3 cells/mm³) but positive oligoclonal bands and mildly elevated serum IL‐6 (3.0 pg/mL). Cytokine testing from the CSF showed elevated IL‐2 (89.6 pg/mL) but was otherwise normal. Serum screening labs for HLH were inconsistent with this diagnosis. She was subsequently started on rituximab.

One month later, she presented with a recurrence of focal seizures. MRI revealed recurrence of right frontal TDL (Figure 2D). Her evaluation was significant for elevated serum IL‐6 (20.3 pg/mL). She received IVIG and IVMP, followed by an oral steroid taper. She returned to her neurological baseline within 3 days and was discharged.

The next month, she presented with worsening headache, emesis, diplopia, and facial asymmetry. Imaging revealed new brainstem and left cerebral hemisphere TDLs (Figure 2D). Her evaluation was significant for mildly elevated CSF WBC (7 cells/mm³), normal CSF protein (45 mg/dL), and normalized serum IL‐6. CSF cytokines revealed elevated IL‐6 (38.4 pg/mL) but were otherwise normal. Testing for oligoclonal bands was not repeated at this time. She received IVMP and PLEX and rapidly improved. Upon discharge, she started biweekly tocilizumab and a prolonged steroid taper. She underwent surveillance imaging 2 months later and significantly improved, although with residual encephalomalacia in the right frontal lobe. She remained clinically and radiographically stable for 10 months, so tocilizumab infusions were weaned from biweekly to once monthly. The most recent imaging, obtained 27 months after the original presentation, was stable. Her clinical course is summarized in Figure 2F. MRI spine, serum MOG‐IgG, and serum AqP4‐IgG testing were negative on presentation and on follow‐up. CSF MOG‐IgG testing was negative. Trio whole‐genome sequencing of nuclear and mitochondrial DNA was unrevealing for any known genetic/metabolic disorder. Notably, although this patient had relapsing disease, positive oligoclonal bands, and accrued silent lesions, her lesions were not typical in appearance for MS (classically ovoid, well circumscribed) and were not in a distribution consistent with perivenular inflammation as occurs in MS; therefore, she did not fulfill the McDonald criteria for MS.

3.3. Patient 3

This 17‐year‐old boy presented with fever, emesis, right‐sided hemiparesis, altered mentation, and seizures after 6 months of mood lability, memory issues, and worsening cognition. Initial imaging showed prominent left parieto‐occipital TDL with mass effect causing midline shift and elevated intracranial pressure requiring an external ventricular drain (Figure 3A). Seizures responded to ASM, and symptoms improved with IVMP and IVIG/PLEX via the zipper method [9]. His evaluation was significant for normal/negative CSF WBC (3 cells/mm³), CSF protein (27 mg/dL), oligoclonal bands, and serum IL‐6. CSF cytokines showed elevated IL‐6 (78.8 pg/mL) and elevated TNF‐α (10.2 pg/mL) but were otherwise normal. At discharge 5 weeks after the original presentation, he had ongoing spasticity, dystonia, and impaired arousal and cognition. He completed an oral steroid taper and was initiated on monthly IVIG for 6 months, after which his focal neurological symptoms resolved. Surveillance imaging obtained 3 months after the original presentation was significant for left hippocampal sclerosis, otherwise improved (Figure 3B). He continued to experience impulsivity, violence, emotional lability, and poor insight at the last follow‐up, 16 months after the original presentation, although he remained radiographically stable. His clinical course is summarized in Figure 3C. Spinal imaging during initial presentation did reveal a single, non‐enhancing lesion at the cervicomedullary junction that subsequently resolved. MOG‐IgG and AqP4‐IgG testing performed at presentation and upon multiple repeats were negative. Trio whole‐genome sequencing of nuclear and mitochondrial DNA was unrevealing for any known genetic/metabolic disorder. There was one region with an absence of heterozygosity larger than 5 Mb on chromosome 3.

Figure 3.

Magnetic resonance imaging findings and clinical course of patient 3. (A(i–ii)) Brain imaging at presentation demonstrating large left‐sided TDL involving the brainstem as well as the temporal, posterior frontal, parietal, and occipital lobes. (B) Follow‐up brain imaging obtained 3 months after original presentation showing left hippocampal sclerosis (i) and persistently abnormal T2 signal of the brainstem (i), inferior left occipital lobe (i) deep gray structures (ii), and corpus callosum (ii). (C) Timeline of clinical events, neuroimaging, and immunotherapies. IVIG, intravenous immunoglobulin; PLEX, plasmapheresis/plasma exchange; TDL, tumefactive demyelinating lesion.

3.4. Patient 4

This 5‐year‐old girl presented with vision loss and worsening headache after 3 weeks of progressively blurry vision, intermittent headaches, and several days of subjective fever. Initial MRI of the brain demonstrated T2 hyperintense lesions with patchy enhancement of the right parieto‐occipital region, the right cerebellum, and the left centrum semiovale, as well as enhancement of the bilateral optic nerves (Figure 4A). An evaluation revealed elevated WBC in the CSF (26 cells/mm3) but negative oligoclonal bands. She was treated with 5 days of IVMP followed by a 4‐week oral steroid taper. At follow‐up, her vision had recovered to baseline.

Figure 4.

Magnetic resonance imaging findings and clinical course of patient 4. (A(i–iii)) Brain imaging at presentation demonstrating T2 hyperintense lesions of the left centrum semiovale (i), the right parieto‐occipital region (i–ii), and the right cerebellum (iii). (B(i–ii)) Brain imaging at first clinical relapse 2 months after original presentation showed new patchy T2 hyperintense lesions of the left frontal, parietal, and occipital lobes (i), as well as of the right frontal lobe and bilateral cerebellar peduncles (ii). (C(i–ii)) Brain imaging from radiographic relapse 8 months after original presentation showing multifocal, punctate areas of abnormal signal in the subcortical white matter in the bilateral cerebral hemispheres (i), as well as in the left more than right cerebellum (ii). (D) Brain imaging from clinical relapse 11 months after original presentation showing diffuse leukodystrophy‐like lesions primarily of the bilateral frontal lobes and centrum semiovale. (E) Brain imaging at radiographic relapse 31 months after original presentation, showing a small new lesion (red circle). (F) Timeline of clinical events, neuroimaging, and immunotherapies. IVIG, intravenous immunoglobulin.

Seven weeks after the original presentation, she re‐presented with difficulty walking after a recent viral illness. MRI revealed new patchy T2 hyperintense lesions of the left frontal, parietal, and occipital lobes, as well as of the right frontal lobe and bilateral cerebellar peduncles (Figure 4B). CSF was bland with normal cytology. She was treated with 5 days of IVMP as well as IVIG and had a dramatic improvement in her symptoms. She was discharged on a 4‐week oral steroid taper. Her examination 2 weeks after discharge was nonfocal without evidence of ataxia.

Three months later (4½ months after original presentation), she re‐presented to an outside hospital with aphasia, ataxia, and left‐sided weakness after 2 days of worsening headaches and rhino/enterovirus infection. MRI revealed new multifocal areas of signal abnormality and enhancement in the bilateral cerebral hemispheres as well as the left thalamus, pons, and cerebellum (not available for review). CSF was again bland. She was treated with 5 days of IVMP as well as IVIG and maintained on oral steroids at discharge.

Three months later (8 months after original presentation), she underwent surveillance imaging, which revealed new, multifocal, punctate areas of subcortical white matter enhancement in bilateral cerebral hemispheres, as well as in the left more than right cerebellum (Figure 4C). These lesions were too numerous to count. IL‐6 testing in the serum revealed an elevation to 17.9 pg/mL. CSF was not obtained. She was treated with 5 days of pulse‐dose steroids, started on rituximab, and subsequently weaned off oral steroids. One month later, she was admitted for vomiting complicated by aspiration, atelectasis, and respiratory failure. She was presumptively treated for a relapse at this time, although imaging was ultimately stable.

Two months later (11 months after initial presentation), she re‐presented with ataxia, generalized weakness, decreased activity, and abnormal behavior after developing a urinary tract infection. MRI showed diffuse leukodystrophy‐like lesions primarily of the bilateral frontal lobes and centrum semiovale (Figure 4D). IL‐6 testing in the serum was normal. CSF was not obtained. Treatment with 5 days of IVMP was recommended but aborted after 3 days due to steroid‐induced psychosis. She received IVIG and was transitioned from rituximab to tocilizumab every 2 weeks for maintenance therapy. She remained clinically and radiographically stable, so tocilizumab was weaned to every 3 weeks and then to every 4 weeks. Surveillance imaging obtained 34 months after initial presentation revealed a small new lesion (Figure 4E), so the tocilizumab dose was escalated from 8 to 12 mg/kg, since which time she has remained clinically and radiographically stable. Her clinical course is summarized in Figure 4F. MOG‐IgG and AqP4‐IgG testing performed at presentation and upon multiple repeats were negative. Metabolomic and mitochondrial screening studies were normal. No further genetic testing was completed. Spinal imaging obtained with her first relapse showed an ill‐defined T2/STIR hyperintense lesion from C4‐T2 with patchy enhancement of both the cervical and distal cord, which resolved on subsequent imaging.

3.5. Aggregate Results

We present 13 total clinical presentations involving four patients (Figure 5). Patients 1, 2, and 4 each had four total clinical presentations, while patient 3 had only one. Encephalopathy and headache were the most common presenting symptoms and occurred in three of four patients and in 6/13 total events. Motor deficits were the next most common, also occurring in three of four patients and in 5/13 total events. Seizures and cerebellar deficits occurred in 4/13 clinical events and in three and two of four patients, respectively.

Figure 5.

Symptoms present during clinical attack.

4. Discussion

Here we describe four pediatric patients who presented with TDLs. Although these TDLs were of inflammatory origin, as evidenced by their elevated inflammatory markers and favorable response to immunotherapies, none of these children had neuroinflammatory diseases that are commonly associated with TDLs; thus, they are termed non‐syndromic TDLs (nsTDL). TDLs are rare in children, representing only 7% of all patients presenting with TDL in a recent review of more than 250 patients [10]. The average age of TDL onset was 9 years in that cohort, but onset in the teenage years has also frequently been reported [1, 10]. The patients described in our cohort ranged in age from 5 to 17 years at the time of presentation. Prior reports indicate motor deficits, sensory disturbances, and encephalopathy as the most common presenting symptoms of TDLs in both the pediatric and adult populations [10, 11]. In our cohort, encephalopathy and headache were the most common presenting symptoms, but motor and sensory deficits were also common (Figure 5). In all of our patients, TDL was the index demyelinating event. This is consistent with prior literature demonstrating that among children with TDL, TDL is the index demyelinating event in 89% [10, 11]. This is in contrast with the adult population, where up to 30% of patients with a TDL have had a prior demyelinating event [10, 11]. Many of the lesions described here resolved in between relapses, and two of the patients presented here had silent lesions, suggesting that silent lesions and lesion resolution—features that are characteristic of MS and MOGAD, respectively—are also possible in patients with nsTDL. Two of the patients also had spinal lesions during their course, suggesting that spinal lesions are similarly possible in patients with nsTDL.

One of the most striking features of our patients is the relentlessly relapsing course of patients 1, 2, and 4, who each experienced three clinical relapses to date. Reported rates of relapse among individuals with nsTDL are varied and range from < 4% to around 22% [6, 11, 12]. The delay to first relapse in our relapsing patients ranged from 1 to 7 months. This is similar to prior reports in the literature, which have described an average delay to relapse of 7 months among adults with relapsing nsTDLs [6]. The factors that may precipitate relapse remain unknown. One study in 116 adults with TDLs found that lesion location (infratentorial), quantity (multiple), and degree of infiltration (diffuse) may represent independent risk factors for relapse [6]. Notably, this study incorporated both syndromic and nsTDL and saw the highest recurrence rate in patients with MS, underscoring the need for further insight on relapse in non‐syndromic patients like those reported here [6]. Upon initial imaging, only patient 4 had infratentorial lesions, but both patients 2 and 4 had multiple lesions. Notably, half of the incidences of relapse reported here occurred while weaning steroids (Figures 1, 2, 4). In our sample, steroids were only successfully weaned without eliciting a relapse when bridging immunotherapies such as serial IVIG, tocilizumab, or rituximab were given simultaneously with the steroid wean. De Simone and colleagues reported TDL in a pediatric patient that progressed once the patient was transitioned to an oral steroid wean [13]. These lesions may therefore be exquisitely steroid sensitive, and attempts at a steroid wean may precipitate a rebound effect predisposing to relapse.

Optimal treatment for TDLs remains unknown, and patients with established diagnoses may benefit from different therapies than patients with nsTDLs. Moreover, the approach to treating asymptomatic lesions is also variable and requires further investigation. All clinical presentations for all patients reported here rapidly improved with pulse‐dose steroids. All of our patients also received second‐line immunotherapies such as IVIG, PLEX, rituximab, and tocilizumab. This is in keeping with previous trends in the literature where all children with TDLs received treatment with pulse‐dose steroids, and 80% received second‐line immunotherapies [1]. Notably, the longest interval between relapses for patient 1 (19 months, as compared with 7 months and 1 month between his other relapses) was observed after initiation of monthly tocilizumab. Patients 2 and 4 have not had any further clinical relapses after starting regular tocilizumab therapy, perhaps suggesting that this agent is particularly efficacious in preventing relapse and has the most durable effect of agents tried. Tocilizumab is a humanized antibody against IL‐6 that may prevent activation of innate and adaptive immune responses by blocking the pro‐inflammatory cytokine. Despite being touted for its efficacy in NMOSD by decreasing relapse and potentially decreasing neurological disability [14], there is no literature regarding its role in treating nsTDLs. Initial IL‐6 levels for patients 1 and 2 were not obtained, but both had elevated serum IL‐6 at relapse roughly 6 months after the original presentation. For patient 1, serum IL‐6 was markedly elevated to more than 10 times the upper limit of normal at his second relapse (23.9 pg/mL), but at his third relapse, it was only mildly elevated to 3.4 pg/mL. Meanwhile, patient 2 had elevated serum IL‐6 (3 pg/mL) at her first radiographic relapse, and it had increased more than six‐fold (20.3 pg/mL) when she became symptomatic a month later. By her next clinical relapse, several weeks after IL‐6 in the serum had normalized, IL‐6 in the CSF was elevated. Initial IL‐6 levels for patient 4 are similarly not available, but serum IL‐6 was elevated (17.6 pg/mL) at the time of her first radiographic relapse, although it had normalized at the time of her next clinical relapse. Patient 3 has followed a monophasic course, and it is unclear if monophasic nsTDL and relapsing nsTDL represent variants of the same disease with the same pathology or if they are distinct clinical entities. Interestingly, patient 3's serum IL−6 levels at presentation and 2 weeks into his admission were normal, although IL‐6 in the CSF was elevated. We report the serum and CSF IL‐6 levels in these patients because ultimately, tocilizumab, an IL‐6 antagonist, seemed efficacious. The rationale for choosing the agent was not because of the elevated IL‐6 levels but rather because other interventions had failed. Future studies investigating the role of serum IL‐6 as a biomarker for a relapsing course and the efficacy of tocilizumab in preventing relapse are needed. It is also worth noting that in our data set, no relapse occurred after treatment with PLEX. Although the number of patients discussed here is insufficient to draw conclusions regarding the potential for acute treatment with PLEX to prevent relapse, this may prove a fruitful avenue for future investigation with larger sample sizes.

5. Conclusion

NsTDLs are an uncommon presentation in the pediatric population but may occur in the absence of a known CNS demyelinating syndrome or disease. NsTDLs may be either relapsing or monophasic, and it is unclear if these represent variants of the same underlying immunopathology or are distinct disease entities. In our cohort, the highest risk for relapse occurred in the first 7 months after presentation and while weaning steroids. All attempts at weaning steroids without concomitant immunotherapy led to clinical relapse. Thus, in our experience, the use of bridging immunotherapies became a requirement during all clinical events while weaning steroids to prevent rebound and relapse. TDLs responded rapidly to pulse‐dose steroids during the acute phase and responded to tocilizumab in the chronic phase. The above findings are limited by the small number of patients reported here and by the variance in evaluation completed for each patient. More work is needed to confirm these findings in larger groups of patients with methodically protocolized evaluation. Future avenues of research also include defining the most appropriate surveillance and treatment regimens for these patients and ascertaining the relationship between syndromic and nsTDLs.

Author Contributions

Elizabeth C. Ballinger: data curation, writing – original draft, writing – review and editing, data visualization. Hannah F. Todd: data curation, writing – original draft, writing – review and editing. Jonathan M. Yarimi: writing – review and editing. Timothy E. Lotze: writing – review and editing. Nikita M. Shukla: writing–review and editing. Kristen S. Fisher: writing – review and editing. Alexander J. Sandweiss: conceptualization, investigation, writing – original draft, writing – review and editing, data visualization, supervision.

Ethics Statement

This study was approved by the Baylor College of Medicine Institutional Review Board, IRB# H‐35069. Informed consent was obtained in writing from all patients or from their legal guardians.

Conflicts of Interest

The authors declare no conflicts of interest.