Published online Sep 16, 2026. doi: 10.12998/wjcc.126833
Revised: August 25, 2026
Accepted: September 16, 2026
Published online: September 16, 2026
Processing time: 35 Days and 13.7 Hours
Acute disseminated encephalomyelitis (ADEM) is an acute inflammatory demye
We report two children with contrasting headache presentations in ADEM. Case 1 involved a 6-year-old boy who presented with isolated severe headache that evolved into encephalopathy and ataxia; brain magnetic resonance imaging (MRI) demonstrated multifocal bilateral cerebral lesions consistent with ADEM. After corticosteroid and intravenous immunoglobulin (IVIG) therapy, he fully recov
Headache significance in pediatric ADEM depends on its temporal relationship to neurological disease. Evolving encephalopathy or multifocal signs accompanying headache warrant evaluation for secondary CNS pathology. Conversely, persistent headache following ADEM-absent new encephalopathy, polyfocal events, or new MRI lesions-should not be interpreted as recurrent or multiphasic ADEM. Persistent headache resolved after corticosteroid retreatment, independent of new demyelinating lesions, and this temporal sequence does not establish a causal therapeutic or inflammatory mechanism.
Core Tip: Headache may occur at different stages of pediatric acute disseminated encephalomyelitis (ADEM) and can create distinct diagnostic challenges. In the first case, severe headaches preceded the development of encephalopathy and multifocal neurological abnormalities. In the second, persistent headache continued after neurological recovery and prompted reassessment for ongoing inflammatory disease. Importantly, persistent headache alone does not establish recurrent or multiphasic ADEM. These cases emphasize the importance of interpreting headache based on its temporal relationship to neurological findings and using repeat neuroimaging and cerebrospinal fluid evaluation selectively when clinically indicated.
- Citation: Al-Beltagi M, Nazeer JA, Elbeltagi RM. Contrasting diagnostic challenges of headache before and after acute disseminated encephalomyelitis in children: Two case reports and review of literature. World J Clin Cases 2026; 14(26): 126833
- URL: https://www.wjgnet.com/2307-8960/full/v14/i26/126833.htm
- DOI: https://dx.doi.org/10.12998/wjcc.126833
Acute disseminated encephalomyelitis (ADEM) is an acute inflammatory demyelinating disorder of the central nervous system (CNS) that occurs predominantly during childhood. The International Pediatric Multiple Sclerosis Study Group (IPMSSG) defines ADEM as a first acute or subacute polyfocal CNS event accompanied by encephalopathy and characteristic brain magnetic resonance imaging (MRI) abnormalities[1]. ADEM is typically monophasic, as outlined by established IPMSSG consensus definitions[2]; therefore, a subsequent clinical or radiological event requires formal reassessment for recurrent demyelination or an alternative acquired demyelinating disorder rather than being considered part of the initial episode. Persistent symptoms without a new encephalopathic or polyfocal neurological event should not, by itself, be interpreted as recurrent ADEM. Typical MRI findings in ADEM include large, poorly demarcated lesions predominantly involving the cerebral white matter, with possible involvement of deep gray matter structures such as the thalamus and basal ganglia[3].
The clinical presentation of ADEM can be heterogeneous, encompassing ataxia, weakness, altered consciousness, and other multifocal neurological manifestations. Headache is also recognized as a possible presenting feature, although it is not generally regarded as the defining or dominant manifestation of ADEM[4]. In a retrospective series of 18 children, headache was reported in 8 children and was the second most common presenting feature after ataxia, with authors emphasizing the importance of MRI in establishing the diagnosis[5]. The relationship between headache and ADEM can nevertheless be diagnostically challenging because headache may precede objective neurological abnormalities, as occurred in the first child described here[6]. Conversely, headache may persist after the acute demyelinating episode has apparently improved, raising questions about whether the symptom represents ongoing inflammatory activity, a treatment-related adverse effect, a post-infectious headache syndrome, a primary headache disorder, or an evolving demyelinating disease[7].
While headaches are a well-recognized component of acute presentations in pediatric ADEM, long-term or persistent post-demyelinating headache remains poorly characterized in pediatric neuro-immunology literature, lacking evidence-based algorithms to distinguish true multiphasic dissemination from secondary headache phenomena. We report two pediatric cases illustrating a severe headache preceding the recognition of ADEM and a persistent headache following an ADEM episode (Figures 1 and 2). This dual-temporal framework provides clinicians with a practical bedside model to avoid both premature diagnostic dismissal and unwarranted escalation of immunotherapy, addressing the diagnostic uncertainty that headache creates across the ADEM disease course.
Case 1: A 6-year-old boy initially presented with continuous severe frontal headache of approximately 1 week duration. His condition subsequently deteriorated, with development of fever, irritability, vomiting, abdominal pain, visual blurr
Case 2: A 10-year-old girl presented with headache, confusion, and ataxia. Following treatment for ADEM and partial neurological recovery, she developed persistent, daily, unremitting frontal headache that continued for approximately 3 months.
Case 1: A 6-year-old boy with a background of allergic rhinitis (previously managed intermittently with oral anti
At the initial medical assessment, his general physical examination was unremarkable, and his neurological examination was completely normal: Cranial nerves were intact with normal visual acuity and no papilledema; motor power was grade 5/5 bilaterally with normal tone and symmetric deep tendon reflexes (2++); sensory modalities were intact; gait and cerebellar coordination (finger-to-nose and tandem walking) were normal; and meningeal signs (nuchal rigidity, Kernig, and Brudzinski signs) were absent. Brain MRI was recommended because of the persistent, unremitting nature of the headache, but the parents initially declined imaging.
Over the following days, his clinical condition deteriorated with the development of low-grade fever, irritability, vomiting, abdominal pain, visual blurring, and progressive confusion. A repeat neurological examination performed upon admission demonstrated altered mental status, symmetric hyperreflexia, upgoing plantar responses bilaterally, and new-onset ataxia.
Brain MRI demonstrated multifocal bilateral cerebral white-matter abnormalities consistent with an acute disseminated demyelinating process. Cerebrospinal fluid (CSF) examination showed a lymphocytic pleocytosis with elevated protein and normal glucose. Infectious investigations were negative, and serum myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) were negative. Electroencephalography (EEG) demonstrated diffuse and focal slowing. Based on the acute encephalopathic presentation, multifocal neurological abnormalities, and characteristic MRI findings, a diagnosis of ADEM was made.
Case 2: A previously well 10-year-old girl presented with headache, confusion, and ataxia. Brain MRI demonstrated multiple multifocal bilateral cerebral white-matter lesions involving both cerebral hemispheres, consistent with an acute disseminated demyelinating process. Spinal MRI was normal. CSF examination was within normal limits, and serum MOG-IgG was negative by cell-based assay.
Based on the acute encephalopathic presentation, ataxia, and multifocal brain MRI abnormalities, a diagnosis of ADEM was made. Following initial treatment, her neurological manifestations improved partially.
After discharge, however, she developed a persistent, daily, moderate-to-severe, unremitting frontal headache. The headache persisted continuously for approximately 3 months despite lifestyle and dietary modifications and preventive pharmacological treatment.
During this period, there was no new encephalopathic or multifocal neurological episode. A repeat brain MRI perfor
Case 1: The child had a background of allergic rhinitis, previously managed intermittently with oral antihistamines, and no prior history of recurrent headaches or neurological disorders.
Case 2: The patient had an unremarkable past medical, developmental, psychosocial and school history, with normal academic performance. Two weeks prior to symptom onset, she experienced a mild, self-limiting upper respiratory tract infection without documented fever or systemic medication exposure. There was no recent immunization history.
Case 1: There was a positive family history of migraine (maternal history).
Case 2: There was no family history of migraine. No previous personal history of recurrent headache was reported.
Case 1: At the initial presentation with isolated headache, the general physical examination was unremarkable. Cranial nerves were intact, with normal visual acuity, full extraocular movements, and no papilledema. Motor strength was 5/5 in all limbs bilaterally, tone was normal, and deep tendon reflexes were symmetric at 2+. Light-touch and pinprick sensation were intact throughout. Gait and cerebellar coordination, including finger-to-nose testing and tandem walking, were normal, and there were no meningeal signs, including nuchal rigidity, Kernig sign or Brudzinski sign. After clinical deterioration during the following week, repeat neurological examination showed altered mental status with confusion and irritability, symmetric hyperreflexia, bilateral upgoing plantar responses, new-onset ataxia and visual blurring.
Case 2: At initial acute presentation, she exhibited confusion, prominent truncal and appendicular ataxia, and intact cranial nerves apart from mild visual blurring. During the subsequent 3-month period of persistent headache, her blood pressure was consistently normal for age and height. Fundoscopic examination confirmed normal optic discs without papilledema. The persistent headache was phenotyped as daily, continuous, unremitting, moderate-to-severe (6-7/10) frontal and holocranial pain lasting over 3 months, with a clear daily presence but no abrupt, sharply demarcated onset. It featured mild photophobia and phonophobia, showed no positional variation, and was entirely unresponsive to dietary modifications or preventive pharmacotherapy (amitriptyline, propranolol, and topiramate), as well as frequent analgesic use (non-steroidal anti-inflammatory drugs and paracetamol).
Case 1: CSF examination via lumbar puncture demonstrated a normal opening pressure of 140 mm CSF, with approximately 50 cells/mm3 showing lymphocytic predominance, elevated protein (75 mg/dL), and normal glucose (55 mg/dL; concurrent serum glucose 89 mg/dL). Oligoclonal bands (OCB) were negative in both CSF and serum. Extensive infectious investigations-including a multiplex real-time polymerase chain reaction panel performed on CSF for common neurotropic pathogens (herpes simplex virus types 1 and 2, varicella zoster virus, enteroviruses, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, and parechovirus)-were entirely negative, as were blood cultures and atypical respiratory serologies. Serum MOG-IgG and anti-aquaporin-4 IgG antibodies, evaluated via live cell-based assays on pre-treatment serum samples drawn prior to corticosteroid or immunoglobulin administration, were both definitively negative (titers below the standard clinical cut-off threshold of 1:16). Furthermore, an evaluation for autoimmune encephalitis (including anti-NMDA receptor antibodies), comprehensive metabolic screening (serum ammonia, lactate, blood gas, amino/organic acid profiles), and cerebral vascular evaluation via magnetic resonance angiography were all unremarkable, effectively ruling out metabolic leukodystrophies and CNS vasculitis. EEG demonstrated diffuse and focal background slowing (Tables 1 and 2).
| Diagnostic possibility | Findings supporting | Findings non-supportive |
| Primary migraine | Maternal migraine history | New continuous headache, fever, confusion, pyramidal signs, MRI abnormalities |
| Sinusitis | Allergic rhinitis, frontal pain | Neurological deterioration and MRI findings |
| Viral encephalitis | Fever, vomiting, CSF lymphocytic pleocytosis and elevated protein | Negative multiplex CSF PCR panel for neurotropic viruses, characteristic ADEM MRI pattern |
| ADEM | Encephalopathy, multifocal signs, characteristic MRI | - |
| MS | Demyelinating lesions | Large poorly marginated lesions, relative periventricular sparing, monophasic pediatric clinical phenotype |
| Serum MOGAD | ADEM phenotype | Serum MOG-IgG negative by cell-based assay |
| Raised intracranial pressure/intracranial structural disease | Severe persistent headache, vomiting, and transient visual blurring could raise concern for increased intracranial pressure or an intracranial structural lesion | Normal fundoscopic examination without papilledema; normal CSF opening pressure (140 mm H2O); brain MRI demonstrated multifocal bilateral white-matter lesions consistent with ADEM rather than a focal mass lesion or structural abnormality |
| Investigation (collection time point) | Reference range | Case 1 (day +3) | Case 2 (initial acute presentation)/case 2 (3-month readmission) |
| CSF opening pressure | 60-200 mm H2O | Normal (140 mm H2O) | Initial: Normal (130 mm H2O)/3-month: Normal (125 mm H2O) |
| CSF cells | 0-5 lymphocytes/μL | 50/μL (lymphocytic predominance) | Initial: 2 lymphocytes/μL/3-month: 1 lymphocyte/μL |
| CSF protein | 15-45 mg/dL | Elevated (75 mg/dL) | Initial: Normal (41 mg/dL)/3-month: Normal (38 mg/dL) |
| CSF glucose | 50-80 mg/dL (or ≥ 60% of serum) | Normal (55 mg/dL) | Initial: Normal (63 mg/dL)/3-month: Normal (60 mg/dL) |
| Serum glucose | 70-110 mg/dL | 89 mg/dL | 92 mg/dL |
| OCB | Negative | Negative (CSF and serum) | Not detected |
| Serum MOG-IgG (pre-treatment) | Negative (< 1:16 titer) | Negative (by live cell-based assay) | Negative (by live cell-based assay) |
| Serum AQP4-IgG (pre-treatment) | Negative (< 1:16 titer) | Negative (by live cell-based assay) | Negative (by live cell-based assay) |
| MRI brain | Normal | ADEM pattern (multifocal white matter lesions, no restricted diffusion, no contrast enhancement) | ADEM pattern (bilateral confluent white matter lesions, no restricted diffusion, no contrast enhancement) |
| MRI spine | Normal | Normal | Normal |
| EEG | Normal organization | Diffuse and focal background slowing | Not tested |
Case 2: Initial CSF examination via lumbar puncture demonstrated normal opening pressure, normal cytology (2 lymphocytes/μL), normal protein (41 mg/dL), and normal glucose (63 mg/dL; concurrent serum glucose 92 mg/dL). OCBs were not detected. Serum MOG-IgG and anti-aquaporin-4 IgG antibodies, evaluated via live cell-based assays on pre-treatment serum samples drawn prior to high-dose corticosteroid or immunoglobulin administration, were both definitively negative (titers below the standard clinical cut-off threshold of 1:16). Approximately 3 months after the initial ADEM episode, a repeat lumbar puncture performed during readmission for persistent headache demonstrated normal opening pressure (125 mm CSF), normal CSF chemistry (protein 38 mg/dL, glucose 60 mg/dL), and normal cytology (1 lymphocyte/μL with no malignant or inflammatory cells). Table 2 summarizes the laboratory and diagnostic findings for both patients.
Case 1: Initial brain MRI (Figure 3A and B) was acquired on a 3.0 Tesla MR system. Sequences included axial T1-weighted, T2-weighted, fluid-attenuated inversion recovery, diffusion-weighted imaging with apparent diffusion coefficient maps, and post-contrast T1-weighted imaging. Images demonstrated multifocal, large, asymmetric hyperintense lesions predominantly involving the subcortical and deep cerebral white matter, bilateral basal ganglia (notably the lentiform nuclei), and insular regions, with relative periventricular sparing. Lesions showed mild diffusion facilitation (no restricted diffusion) and no pathological contrast enhancement. Formal neuroradiology interpretation confirmed an acute inflammatory demyelinating process consistent with ADEM. Spinal MRI was completely normal. A follow-up brain MRI (Figure 3C), performed approximately 1 month after the initial presentation, showed marked radiological improvement of the previously identified lesions.
Case 2: The initial brain MRI (Figure 4A and B) showed diffuse bilateral, confluent, large, poorly marginated white-matter hyperintensities on fluid-attenuated inversion recovery and T2-weighted sequences involving both cerebral hemispheres, with no restricted diffusion and no contrast enhancement, consistent with an acute disseminated de
The patient underwent pediatric neurological and radiological assessment. The clinical presentation, neurological findings, laboratory investigations, EEG findings, and brain MRI abnormalities were reviewed and considered consistent with ADEM.
The patient underwent pediatric neurological and radiological reassessment because of the persistent headache following partial neurological recovery. Repeat brain MRI and lumbar puncture were performed to evaluate for a new demye
The absence of a new encephalopathic or multifocal neurological episode, the absence of new MRI lesions, normal CSF opening pressure, and normal CSF examination were considered when interpreting the persistent headache.
ADEM presenting initially with isolated severe headache followed by encephalopathy, ataxia, and multifocal neurological abnormalities, with characteristic multifocal bilateral cerebral MRI lesions.
ADEM presenting with headache, encephalopathy, ataxia, and multifocal bilateral cerebral MRI lesions, followed by persistent daily headache during neurological recovery. The persistent headache was not interpreted as evidence of recurrent or multiphasic ADEM, because no new encephalopathic or multifocal neurological event occurred and no new demyelinating lesions were identified on the approximately 3-month follow-up MRI.
The patient (body weight of 20 kg) initially received empirical antimicrobial therapy with intravenous ceftriaxone, vancomycin, and acyclovir for 5 days while infectious causes were evaluated. Following the confirmation of ADEM, he received high-dose intravenous methylprednisolone at 15 mg/kg/day for 3 days (days +4 to +6), followed by in
Adverse events: The patient experienced transient facial flushing and mild sleep disturbance during the intravenous methylprednisolone course, which resolved spontaneously without specific intervention. The patient had no infusion-related reactions or adverse events with IVIG.
Initial acute ADEM therapy: The patient (28 kg body weight) initially received acute immunomodulatory therapy consisting of high-dose intravenous methylprednisolone at 30 mg/kg/day (maximum 1 g/day) for 5 consecutive days, followed by an oral prednisolone taper starting at 1 mg/kg/day and tapered over 4 weeks. Due to incomplete neurological recovery of her baseline ataxia and persistent encephalopathic symptoms, this was followed by a 5-day course of IVIG at 2 g/kg total dose (administered as 400 mg/kg/day for 5 days), resulting in partial neurological recovery and hospital discharge.
Headache-directed pharmacological and supportive interventions: Following discharge, the persistent daily un
Supportive and acute measures: Acute rescue analgesics (paracetamol at 15 mg/kg/dose every 6 hours as needed and ibuprofen at 10 mg/kg/dose every 8 hours as needed) were utilized up to 3-4 days per week without adequate relief. Antiemetics (ondansetron) were used intermittently. Supportive care included structured sleep hygiene education, hydration protocols, and psychological support (relaxation therapy and cognitive coping strategies for chronic daily pain), without formal specialized multidisciplinary headache clinic referral.
Rationale for corticosteroid retreatment: Approximately 3 months post-initial ADEM, the patient was readmitted because the unremitting headache severely impaired her quality of life and failed all preventive trials. Although repeat MRI showed stable white-matter lesions without new demyelination and lumbar puncture revealed normal CSF opening pressure and chemistry, the multidisciplinary team evaluated the clinical risk-benefit rationale for a second course of high-dose corticosteroids. Given the temporal proximity to severe neuro-inflammation, the inability to completely rule out low-grade subclinical immune-mediated irritation or atypical persistent inflammatory edema not captured by standard MRI spatial resolution, and the profound disability caused by the unremitting headache refractory to conventional analgesics and neuromodulators, a short, bounded therapeutic trial of corticosteroids was deemed justified after fully informing the parents of the empirical nature and uncertainty of the intervention. She received intravenous methylprednisolone at 20 mg/kg/day for 3 days, followed by oral prednisolone at 1 mg/kg/day tapered over 4 weeks.
Adverse events: During the initial acute corticosteroid course, the patient experienced transient mood lability, increased appetite and mild cushingoid facial rounding. During the second course of intravenous methylprednisolone, she experienced transient insomnia and mild epigastric discomfort, which resolved with short-term antacid therapy. No adverse events were noted during the IVIG course.
Short-term outcomes: After completing corticosteroid and IVIG therapy, the patient achieved complete clinical resolution of encephalopathy, ataxia, visual blurring, and headache within 2 weeks. Follow-up brain MRI performed exactly 4 weeks (1 month) post-treatment demonstrated marked radiological improvement with near-complete resolution of the previously identified multifocal cerebral white-matter lesions.
Neurological & functional status: At the 1-month and subsequent 3-month follow-up assessments, formal neurological examinations were entirely normal, with grade 5/5 motor power, normal coordination, intact reflexes, and normal cognitive performance. He achieved full school attendance and age-appropriate academic function without cognitive or behavioral sequelae. No structured headache diaries were utilized, but clinical interviews confirmed complete absence of headache.
Long-term surveillance & limitations: The patient was monitored clinically for an extended follow-up of 6 months post-discharge. During this extended surveillance window, he experienced no clinical relapses, no new neurological deficits, and no delayed adverse events from corticosteroid or IVIG therapy. No repeat neuroimaging beyond the 1-month follow-up was performed.
Note: Extended structured follow-up beyond 6 months was limited by transition to primary pediatric care outside our tertiary neuro-immunology center.
Short-term outcomes: After the second course of intravenous methylprednisolone and the oral taper administered at 3 months post-initial presentation, the patient’s persistent daily headache completely resolved about 2 weeks after treatment initiation. A follow-up brain MRI performed exactly 4 weeks after completion of repeat corticosteroid therapy (and approximately 4 months after initial presentation) demonstrated near-complete resolution of the prior cerebral white-matter lesions.
Neurological & functional status: At the final formal outpatient evaluation-conducted exactly 8 weeks following complete headache resolution and 6 weeks following the final follow-up MRI - her neurological examination was completely normal, with full resolution of residual truncal ataxia and normal cognitive function. Headache outcome data, tracked via a daily semi-quantitative symptom log during the post-treatment taper, confirmed sustained headache freedom (0/10 pain score). She successfully returned to full, uninterrupted school attendance and normal extracurricular activities.
Long-term surveillance & limitations: The patient completed a total extended clinical follow-up of 6 months after resolution of her persistent headache (approximately 9 months total from initial ADEM presentation). Over this extended surveillance period, she exhibited no clinical relapses, no new focal neurological signs, and no delayed medication adverse effects. Longer-term prospective neuro-immunological surveillance beyond 9 months was unavailable as the patient continued subsequent routine health maintenance with her primary pediatrician.
These two cases illustrate two different temporal relationships between headache and ADEM. In the first child, headache was the dominant initial complaint and preceded the development of fever, vomiting, visual symptoms, confusion, and objective neurological abnormalities. In the second child, headache persisted for several months after the initial ADEM episode and ultimately resolved following repeat corticosteroid treatment. Headache is not an unusual symptom in pediatric ADEM. In the series reported by Gupte et al[5], headache occurred in 8 of 18 children and was second only to ataxia among the presenting manifestations. Their findings also emphasize that MRI was necessary to establish the diagnosis in all patients in that series. A broader review of pediatric ADEM likewise recognizes that children may initially present with relatively nonspecific manifestations, including headache, irritability, or somnolence, before the full neurological syndrome becomes apparent[6].
The first case demonstrates an important diagnostic problem. The child initially had isolated severe frontal headache, a normal neurological examination, allergic rhinitis, and a maternal history of migraine. These findings could reasonably lead to consideration of primary headache or sinus-related disease. However, the subsequent rapid development of fever, vomiting, visual blurring, confusion, and pyramidal signs substantially altered the diagnostic probability.
Temporal evolution was particularly important. ADEM typically evolves over several days and is characterized by multifocal neurological involvement and encephalopathy. The current pediatric criteria specifically require encephalopathy that cannot be explained by fever or systemic illness, in addition to a first polyfocal CNS event and characteristic MRI abnormalities[1].
In this child, the MRI findings provided a major diagnostic discriminator. The lesions were large, poorly marginated, predominantly within the white matter, and relatively spared the periventricular regions. There was no diffusion restriction or cortical involvement. This pattern is compatible with the typical MRI spectrum of pediatric ADEM[8]. Negative infectious investigations and the absence of OCBs further supported an inflammatory demyelinating process rather than documented viral encephalitis or an established multiple sclerosis phenotype[9]. However, these findings should be regarded as supportive rather than individually diagnostic. ADEM remains a clinical-radiological diagnosis reached after appropriate exclusion of competing diagnoses[7].
Persistent headache after ADEM raises multiple diagnostic possibilities that headache alone cannot distinguish. First, headaches may occur as an adverse effect of IVIG, particularly when symptoms begin during or shortly after administration[10,11]. However, in case 2, the headache persisted for approximately 3 months, making a transient infusion-related effect less convincing. Second, persistent headaches could represent a post-infectious headache syndrome, though the disappearance of headache following repeat corticosteroid therapy and concurrent radiological resolution raises the possibility of an inflammatory contribution. Although persistent white-matter hyperintensities on the 3-month follow-up MRI initially added complexity, persistent radiological abnormalities are well-documented following monophasic ADEM due to glial scar formation and do not inherently signify ongoing active inflammation[12]. Because this observation comes from a single case, a definitive causal relationship between repeat corticosteroid administration and clinical recovery cannot be established; spontaneous resolution or unmeasured confounding factors remain possible, and prospective controlled trials are required to validate repeat therapy. Third, the headache could represent a primary headache disorder emerging coincidentally after ADEM, which was treated with standard preventive medications like amitriptyline, propranolol, and topiramate without improvement[8]. Fourth, persistent headache might raise concern about ongoing or recurrent inflammatory CNS disease, as the patient had previously experienced ADEM. Repeat MRI and lumbar puncture were thus appropriate, with normal CSF findings and subsequent lesion resolution offering reassurance[13]. Fifth, the prolonged unremitting daily headache phenotype mirrors new daily persistent headache (NDPH), characterized by a continuous onset lasting over 3 months without remission. While secondary NDPH following neuro-inflammatory insults may involve low-grade meningeal irritation or central pain-modulatory alterations, limited efficacy from standard neuromodulators underscores the refractory nature of post-encephalitic headache syndromes[14]. Ultimately, NDPH remains a consideration in the differential diagnosis, while the subsequent resolution of headache following corticosteroid treatment and radiological clearing suggests a potential temporal relation to the preceding inflammatory demyelinating process[15,16].
A primary clinical challenge in our cases is differentiating a secondary persistent headache after ADEM from true disease recurrence or multiphasic disseminated encephalomyelitis. According to international consensus criteria established by the IPMSSG, multiphasic disseminated encephalomyelitis requires a new acute or subacute neurologic event developing 3 or more months after the initial episode, accompanied by new or evolving MRI lesions[17]. Furthermore, the current criteria emphasize that a monophasic ADEM diagnosis is retrospective and requires observation because symptoms and MRI abnormalities can fluctuate during the first 3 months[4]. A subsequent non-encephalopathic neurological event should prompt reassessment for alternative acquired demyelinating disorders, particularly myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), multiple sclerosis, and neuromyelitis optica spectrum disorder, rather than being automatically classified as recurrent ADEM[18].
In case 2, the persistence of daily unremitting headache beyond 3 months - in the complete absence of new focal neurological deficits, encephalopathy, or novel demyelinating lesions on serial neuroimaging clearly fulfills criteria for a secondary chronic headache disorder rather than clinical relapse. Therefore, in case 2, persistent headache alone should not be labeled as multiphasic ADEM. The available information documents persistent headache but does not document a second encephalopathic/polyfocal CNS episode or new MRI lesions. The appropriate interpretation is persistent headache following ADEM with clinical and radiological response to repeat corticosteroid treatment[19,20]. Conflating isolated post-therapeutic headache with disease reactivation risks exposing patients to unwarranted long-term immunotherapy.
The clinical lesson from these cases is not that every severe headache represents ADEM. Primary headache disorders remain common in children, whereas ADEM is uncommon[16,21]. Rather, the cases illustrate that headache should be interpreted according to its temporal profile and associated neurological features. A new, severe, progressively worsening headache accompanied by vomiting, visual disturbance, altered behavior or consciousness, ataxia, pyramidal signs, seizures, or other focal neurological abnormalities should prompt evaluation for secondary causes[22]. In a child with a previous demyelinating disorder, the threshold for neurological reassessment should be particularly low[23].
The first case demonstrates the danger of prematurely attributing severe headache to a common primary or ENT-related disorder when the clinical trajectory is evolving. The initial normal neurological examination did not exclude serious CNS disease. The subsequent appearance of encephalopathy and multifocal neurological signs substantially changed the clinical picture and justified MRI. The second case demonstrates the opposite diagnostic problem: Attributing persistent headache automatically to recurrent ADEM may also be inappropriate. Repeat imaging and, when clinically justified, CSF examination can help distinguish persistent headache from active CNS inflammation[24].
ADEM shares clinical and radiological features with several inflammatory, infectious, vascular, metabolic, and neoplastic disorders. The differential diagnosis includes viral encephalitis, multiple sclerosis, neuromyelitis optica spectrum disorder, MOG antibody-associated disease, CNS vasculitis, autoimmune encephalitis, mitochondrial disease, leukodystrophies, toxic leukoencephalopathy, and other structural CNS disorders[1,2].
The 2013 IPMSSG criteria emphasize that diagnosing ADEM requires careful exclusion of alternative diagnoses. MRI patterns can assist this process. Large, poorly demarcated lesions predominantly affecting cerebral white matter, sometimes accompanied by deep gray matter lesions, are typical of ADEM, whereas well-demarcated periventricular lesions and lesions of different ages raise greater concern for multiple sclerosis[17,25].
MOGAD represents an important differential diagnosis in children presenting with an ADEM phenotype, as ADEM is one of the common manifestations of MOG-IgG-associated demyelination in pediatric populations[26]. Both patients in the present report had negative serum MOG-IgG testing by cell-based assay, reducing the likelihood of MOGAD. However, negative MOG-IgG results should be interpreted cautiously and alongside clinical, radiological and follow-up findings, because seronegativity does not establish idiopathic ADEM[27]. Conversely, a positive MOG-IgG result would have substantially influenced disease classification and long-term follow-up considerations[28].
To help clinicians navigate the diagnostic dilemma of persistent headache after ADEM, we propose a structured, safety-oriented reassessment framework. Rather than relying on empiric therapeutic interventions or repeating high-dose corticosteroids for isolated pain, clinical evaluation should follow a tiered protocol: (1) Red-flag screening: Immediate evaluation for secondary CNS deterioration is mandatory if red flags emerge, including new focal neurological deficits, altered mental status, papilledema, acute visual changes, or intractable vomiting; (2) Serial neurological examinations: Standardized, longitudinal assessment of focal signs and cognitive function during outpatient follow-up to detect subtle, subacute disease evolution; and (3) Targeted neuroimaging: When persistent headache fails to respond to standard analgesics or exhibits atypical features (such as an NDPH phenotype), a repeat brain MRI (with and without contrast) is indicated to evaluate for new or expanding demyelinating lesions, structural complications, or parenchymal changes. Routine serial lumbar puncture or repeated CSF analysis is not recommended unless active infectious, inflammatory, or malignant etiologies are clinically suspected.
This conservative, diagnostic-first approach prevents premature disease reclassification and avoids exposing patients to unnecessary, high-risk immunomodulatory treatments.
High-dose intravenous corticosteroids remain the principal acute treatment for pediatric ADEM[9]. In the first case, intravenous methylprednisolone was followed by an oral prednisolone taper, with IVIG added because of persistent severe headache, irritability, and evolving encephalopathic features despite initial corticosteroid administration. In the second case, persistent daily unremitting headache after initial recovery prompted a second course of high-dose corticosteroids at 3 months post-initial presentation (days +93 to +95), after which the headache resolved (approximately day +110), and follow-up MRI at day +120 showed marked radiological improvement.
However, this therapeutic response must be interpreted with extreme caution and does not establish that corticosteroid retreatment is indicated for persistent post-ADEM headache in the absence of objective evidence of recurrent inflammatory disease[10]. A clinical response to corticosteroids is not pathognomonic for active ADEM, as glucocorticoids exert broad anti-inflammatory and modulatory effects across various immune-mediated and CNS disorders[8]. The temporal association between corticosteroid administration, headache resolution, and radiological clearing observed in case 2 is clinically suggestive but does not prove causality or support management of refractory post-ADEM headache.
These clinical trajectories emphasize the importance of systematic reassessment-including red-flag screening, serial neurological examinations, and targeted neuroimaging-for children whose symptoms deviate from the expected recovery course after initial ADEM treatment, ensuring patients are not prematurely subjected to unwarranted immunomodulatory therapies.
This report has several limitations. First, conclusions are based on two retrospective patients with limited follow-up, preventing generalization regarding the frequency, clinical spectrum, or causality between headache and ADEM. Second, negative MOG-IgG assays alone do not establish idiopathic ADEM or exclude MOGAD; interpret antibody results with clinical phenotype, MRI, and disease course[29]. Third, in case 2, the temporal association between repeat corticosteroids, headache resolution, and radiological improvement does not establish causality, while normal CSF and stable MRI argue against, but do not exclude, a new demyelinating attack[30,31]. Fourth, detailed headache characterization was limited, precluding a definitive diagnosis of alternative phenotypes such as NDPH. Finally, longer-term follow-up is needed to rule out subsequent acquired demyelinating disorders or recurrence, and prospective studies with standardized me
These two cases highlight contrasting headache trajectories in pediatric ADEM: An early warning sign preceding encephalopathy (case 1) vs a post-therapeutic persistent headache during neurological recovery (case 2). While headache progression demands prompt neuroimaging to evaluate for evolving CNS disease, isolated persistent headache must be assessed systematically and should not be misattributed to recurrent or multiphasic ADEM. Furthermore, although headaches are resolved after corticosteroid retreatment alongside radiological clearing, this temporal association does not establish an active inflammatory mechanism, underscoring the need for individualized, cautious management.
We thank all nursing and medical staff who cared for these two cases. We also thank the families of the two children for allowing us to publish these two case reports.
| 1. | Ferenc K, Semik P, Paprocka J. Acute Disseminated Encephalomyelitis (ADEM): Current View into Etiopathogenesis and Clinical Features. Brain Sci. 2026;16:201. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 2] [Reference Citation Analysis (0)] |
| 2. | Paolilo RB, Deiva K, Neuteboom R, Rostásy K, Lim M. Acute Disseminated Encephalomyelitis: Current Perspectives. Children (Basel). 2020;7:210. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 57] [Cited by in RCA: 44] [Article Influence: 7.3] [Reference Citation Analysis (0)] |
| 3. | Murray BJ, Apetauerova D, Scammell TE. Severe acute disseminated encephalomyelitis with normal MRI at presentation. Neurology. 2000;55:1237-1238. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 13] [Cited by in RCA: 12] [Article Influence: 0.5] [Reference Citation Analysis (0)] |
| 4. | Noorbakhsh F, Johnson RT, Emery D, Power C. Acute disseminated encephalomyelitis: clinical and pathogenesis features. Neurol Clin. 2008;26:759-780, ix. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 59] [Cited by in RCA: 63] [Article Influence: 3.5] [Reference Citation Analysis (0)] |
| 5. | Gupte G, Stonehouse M, Wassmer E, Coad NA, Whitehouse WP. Acute disseminated encephalomyelitis: a review of 18 cases in childhood. J Paediatr Child Health. 2003;39:336-342. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 70] [Cited by in RCA: 55] [Article Influence: 2.4] [Reference Citation Analysis (0)] |
| 6. | Tenembaum SN. Disseminated encephalomyelitis in children. Clin Neurol Neurosurg. 2008;110:928-938. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 32] [Cited by in RCA: 26] [Article Influence: 1.4] [Reference Citation Analysis (1)] |
| 7. | Massa S, Fracchiolla A, Neglia C, Argentiero A, Esposito S. Update on Acute Disseminated Encephalomyelitis in Children and Adolescents. Children (Basel). 2021;8:280. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 29] [Cited by in RCA: 29] [Article Influence: 5.8] [Reference Citation Analysis (0)] |
| 8. | Dale RC, de Sousa C, Chong WK, Cox TC, Harding B, Neville BG. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain. 2000;123 Pt 12:2407-2422. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 540] [Cited by in RCA: 414] [Article Influence: 15.9] [Reference Citation Analysis (0)] |
| 9. | Wang CX. Assessment and Management of Acute Disseminated Encephalomyelitis (ADEM) in the Pediatric Patient. Paediatr Drugs. 2021;23:213-221. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 34] [Cited by in RCA: 33] [Article Influence: 6.6] [Reference Citation Analysis (0)] |
| 10. | Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol. 2005;29:173-184. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 279] [Cited by in RCA: 234] [Article Influence: 11.1] [Reference Citation Analysis (0)] |
| 11. | Russo CC, Dalton LK, Grant L, Enos N, Evans DLA. Patient With Severe Headache After IV Immunoglobulin. Fed Pract. 2022;39:487-489. [RCA] [PubMed] [DOI] [Full Text] [Reference Citation Analysis (0)] |
| 12. | Prakash S, Patel N, Golwala P, Patell R. Post-infectious headache: a reactive headache? J Headache Pain. 2011;12:467-473. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 10] [Cited by in RCA: 9] [Article Influence: 0.6] [Reference Citation Analysis (0)] |
| 13. | Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24 Suppl 1:9-160. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 798] [Cited by in RCA: 2344] [Article Influence: 106.5] [Reference Citation Analysis (0)] |
| 14. | Kalika P, Monteith TS. New Daily Persistent Headache in the Pediatric and Adolescent Population: An Updated Review. Life (Basel). 2024;14:724. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 4] [Reference Citation Analysis (0)] |
| 15. | Gastaldi M, Scaranzin S, Jarius S, Wildeman B, Zardini E, Mallucci G, Rigoni E, Vegezzi E, Foiadelli T, Savasta S, Banfi P, Versino M, Benedetti L, Novi G, Mancardi MM, Giacomini T, Annovazzi P, Baroncini D, Ferraro D, Lampasona V, Reindl M, Waters P, Franciotta D. Cell-based assays for the detection of MOG antibodies: a comparative study. J Neurol. 2020;267:3555-3564. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 67] [Cited by in RCA: 62] [Article Influence: 10.3] [Reference Citation Analysis (6)] |
| 16. | Sechi E, Gastaldi M, Cortese R, Bisecco A, Vogrig A, Giannoccaro MP, Zuliani L, Zoccarato M, Casagrande S, Sartori S, Nosadini M, Iorio R, Spatola M, Damato V, Mariotto S. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Practical recommendations for diagnosis and management. J Neuroimmunol. 2026;410:578781. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 10] [Reference Citation Analysis (0)] |
| 17. | Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC, Ghezzi A, Hintzen R, Kornberg A, Pohl D, Rostasy K, Tenembaum S, Wassmer E; International Pediatric Multiple Sclerosis Study Group. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013;19:1261-1267. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 632] [Cited by in RCA: 807] [Article Influence: 62.1] [Reference Citation Analysis (0)] |
| 18. | Wingerchuk DM, Lucchinetti CF. Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2022;387:631-639. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 7] [Cited by in RCA: 160] [Article Influence: 40.0] [Reference Citation Analysis (1)] |
| 19. | Banwell B, Bennett JL, Marignier R, Kim HJ, Brilot F, Flanagan EP, Ramanathan S, Waters P, Tenembaum S, Graves JS, Chitnis T, Brandt AU, Hemingway C, Neuteboom R, Pandit L, Reindl M, Saiz A, Sato DK, Rostasy K, Paul F, Pittock SJ, Fujihara K, Palace J. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol. 2023;22:268-282. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 158] [Cited by in RCA: 929] [Article Influence: 309.7] [Reference Citation Analysis (0)] |
| 20. | Cohen O, Steiner-Birmanns B, Biran I, Abramsky O, Honigman S, Steiner I. Recurrence of acute disseminated encephalomyelitis at the previously affected brain site. Arch Neurol. 2001;58:797-801. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 50] [Cited by in RCA: 43] [Article Influence: 1.7] [Reference Citation Analysis (0)] |
| 21. | Diener HC, Charles A, Goadsby PJ, Holle D. New therapeutic approaches for the prevention and treatment of migraine. Lancet Neurol. 2015;14:1010-1022. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 111] [Cited by in RCA: 116] [Article Influence: 10.5] [Reference Citation Analysis (0)] |
| 22. | Szperka C. Headache in Children and Adolescents. Continuum (Minneap Minn). 2021;27:703-731. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 4] [Cited by in RCA: 37] [Article Influence: 7.4] [Reference Citation Analysis (0)] |
| 23. | Brenton JN. Pediatric Acquired Demyelinating Disorders. Continuum (Minneap Minn). 2022;28:1104-1130. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 5] [Reference Citation Analysis (0)] |
| 24. | Pohl D, Alper G, Van Haren K, Kornberg AJ, Lucchinetti CF, Tenembaum S, Belman AL. Acute disseminated encephalomyelitis: Updates on an inflammatory CNS syndrome. Neurology. 2016;87:S38-S45. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 356] [Cited by in RCA: 304] [Article Influence: 30.4] [Reference Citation Analysis (0)] |
| 25. | Boesen MS, Langkilde AR, Ilginiene J, Magyari M, Blinkenberg M. Oligoclonal bands, age 11-17 years, occipital lesion, and female sex differentiate pediatric multiple sclerosis from acute disseminated encephalomyelitis: A nationwide cohort study. Mult Scler Relat Disord. 2022;66:104008. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 4] [Reference Citation Analysis (0)] |
| 26. | Al-Ani A, Chen JJ, Costello F. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): current understanding and challenges. J Neurol. 2023;270:4132-4150. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 55] [Reference Citation Analysis (0)] |
| 27. | Jurynczyk M, Messina S, Woodhall MR, Raza N, Everett R, Roca-Fernandez A, Tackley G, Hamid S, Sheard A, Reynolds G, Chandratre S, Hemingway C, Jacob A, Vincent A, Leite MI, Waters P, Palace J. Clinical presentation and prognosis in MOG-antibody disease: a UK study. Brain. 2017;140:3128-3138. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 361] [Cited by in RCA: 589] [Article Influence: 84.1] [Reference Citation Analysis (0)] |
| 28. | Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, Pitarokoili K, Pache F, Stich O, Beume LA, Hümmert MW, Ringelstein M, Trebst C, Winkelmann A, Schwarz A, Buttmann M, Zimmermann H, Kuchling J, Franciotta D, Capobianco M, Siebert E, Lukas C, Korporal-Kuhnke M, Haas J, Fechner K, Brandt AU, Schanda K, Aktas O, Paul F, Reindl M, Wildemann B; in cooperation with the Neuromyelitis Optica Study Group (NEMOS). MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation. 2016;13:280. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 767] [Cited by in RCA: 706] [Article Influence: 70.6] [Reference Citation Analysis (0)] |
| 29. | Cobo-Calvo A, Ruiz A, Maillart E, Audoin B, Zephir H, Bourre B, Ciron J, Collongues N, Brassat D, Cotton F, Papeix C, Durand-Dubief F, Laplaud D, Deschamps R, Cohen M, Biotti D, Ayrignac X, Tilikete C, Thouvenot E, Brochet B, Dulau C, Moreau T, Tourbah A, Lebranchu P, Michel L, Lebrun-Frenay C, Montcuquet A, Mathey G, Debouverie M, Pelletier J, Labauge P, Derache N, Coustans M, Rollot F, De Seze J, Vukusic S, Marignier R; OFSEP and NOMADMUS Study Group. Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study. Neurology. 2018;90:e1858-e1869. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 293] [Cited by in RCA: 445] [Article Influence: 55.6] [Reference Citation Analysis (0)] |
| 30. | Beatty C, Bowler RA, Farooq O, Dudeck L, Ramasamy D, Yeh EA, Zivadinov R, Weinstock-Guttman B, Parrish JB. Long-Term Neurocognitive, Psychosocial, and Magnetic Resonance Imaging Outcomes in Pediatric-Onset Acute Disseminated Encephalomyelitis. Pediatr Neurol. 2016;57:64-73. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 18] [Cited by in RCA: 23] [Article Influence: 2.3] [Reference Citation Analysis (0)] |
| 31. | Javed A, Khan O. Acute disseminated encephalomyelitis. Handb Clin Neurol. 2014;123:705-717. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 25] [Cited by in RCA: 33] [Article Influence: 2.8] [Reference Citation Analysis (0)] |