Multiphasic Acute Disseminated Encephalomyelitis with a Temporal Gap of 26 Years: A Case Report with Novel Presentation

Acute disseminated encephalomyelitis (ADEM) is an acute multifocal demyelinating disease of the central nervous system that typically follows an infectious illness. A contagious disease can be seen in 50–85% of ADEM cases [1]. It predominantly occurs in children; however, adult cases can be seen [2]. Its pathogenesis has been linked to an autoimmune response to myelin autoantigens, which leads to the demyelination [3].

ADEM is usually a monophasic illness. Based on the IPMSSG criteria, the diagnosis of ADEM must include both encephalopathy (altered mental status, confusion, psychosis) and polyfocal neurological abnormalities (brain stem deficits, seizures, motor and sensory problems, etc.) [1]. The diagnosis of ADEM is usually made using an MRI. It demonstrates T2-weighted hyperintense lesions; however, some extensive lesions can also be seen on T1-weighted MRI as hypointense lesions [4]. Sometimes, the lesions on the MRI do not appear at the onset of the symptoms and may occur weeks after the initial presentation. Moreover, a CT scan can also be used as an imaging modality in case of emergencies [4]. ADEM can also present as a multiphasic illness as well. Literature review showed that ADEM in adults has varying temporal gaps between symptoms. Losavio et al. [5] have described a case report of a patient with multiphasic ADEM with a temporal gap of 8 years. Shah et al. [6] have described a patient with a symptom-free period of 10 years, while Numa et al. [7] have reported a patient with a symptom-free period of 33 years, diagnosed initially at 4 years of age. We are reporting a 59-year-old adult male who was diagnosed with two episodes of ADEM occurring with a temporal gap of 26 years in the absence of any recent viral infection, vaccination, or other classical etiologies.

Our patient, a 59-year-old male, with a history of hypertension and ischemic heart disease taking losartan, aspirin, and atorvastatin, developed sudden-onset progressive lethargy and slurring of speech within a day. This was followed by upper and lower limb weakness and speaking difficulties. He progressively deteriorated and developed an altered state of consciousness.

His neurological examination revealed right pronator drift and right upper motor neuron facial palsy. The remainder of the neurological and systemic examination was normal.

MRI brain (Fig. 1) showed multiple (>20) punctate and confluent foci of abnormal signal intensity in the deep white matter of the centrum semiovale and periventricular regions including the genu of the corpus callosum. These appeared hypointense in the T1-weighted scan and hyperintense in the T2 and fluid-attenuated inversion recovery-weighted scans. No post-contrast or DWI imaging was performed.

His CSF analysis showed lymphocytic pleocytosis with high protein as detailed in Table 1. Further immunological workup was done, which is shown in Table 2.

After excluding the possibility of stroke and other demyelinating diseases, a diagnosis of “multiphasic” ADEM was established considering a similar episode 26 years back where he was diagnosed with ADEM based on clinical picture and magnetic resonance imaging (MRI) brain (Fig. 1). He was managed with intravenous methylprednisolone (1 g daily for 8 days), which showed marked improvement in clinical condition. His symptoms showed dramatic improvement and reported no residual symptoms on follow-ups. The patient was recommended a follow-up MRI; however, they were noncompliant.

In the current episode, he was similarly treated with intravenous methylprednisolone (1 g daily for 5 days) and showed complete resolution without any neurological symptoms. The patient had no recurrence upon follow-up of up to 3 months.

This case report involves the case of an adult male with multiphasic ADEM having a temporal gap of 26 years. There are no diagnostic criteria for ADEM, especially in adults and the elderly. ADEM is a demyelinating disease of the brain and spinal cord that follows an infection or inflammation. It has been proposed that it occurs due to the formation of autoantibodies that react against the myelin autoantigens leading to the destruction of the myelin sheath around the neurons [3]. However, there is also another alternative proposed mechanism, which includes an increase in the vascular permeability in the central nervous system [3]. It is believed to occur due to the inflammation caused by the vaccination or viral infection. The mononuclear cell influence has been linked to the necrosis, gliosis, edema, and hemorrhage that occurs in ADEM [3, 8]. This leads to the slowing of the progression of nerve impulses and results in the characteristic demyelination symptoms including fatigue, somnolence, slurring of speech, confusion, sexual dysfunction, and urinary incontinence [2].

ADEM is more prevalent in children, but it can also be present in the adult population (such as in our case of a 59 years old person) as well. The median age of onset in children is 4–8 years and in adults, it ranges from 18 to 82 years of age, with median age between 33 and 41 (2). ADEM can be referred to as a type of myelin oligodendrocyte glycoprotein antibody disease, but a person does not need to have positive anti-MOG antibodies for the diagnosis of ADEM [9], and there are reports for ADEM with negative titer for anti-MOG antibodies (5, 6). Our patient also had negative anti-MOG antibodies. ADEM may also look like an acute attack of multiple sclerosis (MS), except for ocular involvement [2]. Many pathogens have been linked with ADEM. Some of the most common ones include herpes viruses, cytomegalovirus, varicella zoster, measles, etc. Moreover, some nonviral pathogens including Rickettsia, Borrelia, Leptospira, and Mycoplasma have been linked with ADEM too [10]. However, in some cases, an illness or a recent vaccination history is absent. And such was the case in our patient as well. Having a history of illness or vaccination certainly aids in making the diagnosis; however, it is not necessary [1].

ADEM generally presents as a monophasic illness, but recent reports have suggested that it may recur later in life. Terms such as recurrent disseminated encephalomyelitis [11] and multiphasic disseminated encephalomyelitis (MDEM) [11] have also been used to describe the disease. However, Shah et al. [6] report that the term recurrent disseminated encephalomyelitis was recently deleted from major publications. ADEM can present with a variety of symptoms, including motor, sensory, seizures, balance, or brain stem problems [12]. Almaghrabi et al. [13] reported a case of a patient with the symptoms of agitation, delirium, and seizures. Mazzola et al. [14] present the case with symptoms of expressive aphasia and right hemiparesis. These occurred after an attack of mycoplasma pneumonia. Our patient had the symptoms of speaking difficulties along with upper and lower limb weakness. Moreover, the patient progressed to develop altered mental status as well. The temporal gap in multiphasic ADEM is also quite unpredictable. Our patient had a gap of 26 years. Losavio et al. [5], Shah et al. [6], and Numa et al. [7] have reported multiphasic ADEM with varying temporal gaps ranging from 8 years to 33 years. There are many explanations (such as immune response variability, individualized immune memory and regulation, nature of the initial pathogen, the chronic inflammatory state of the body, and environmental factors) provided for the variance in the temporal gap among the patients; however, they are not very satisfactory and further research is warranted [15].

Investigations for the diagnosis of ADEM include clinical picture evaluation as well as neuroimaging. CSF analysis usually shows a high level of protein and lymphocytosis [13]. Our patient also had similar CSF laboratory results. MRI is usually the first line of investigation used for imaging and diagnosis; however, CT scan has also been used in emergencies [2]. T2-weighted and fluid-attenuated inversion recovery MRI techniques show high-signal lesions [14]. Bilateral asymmetrical hyperintense ovoid or elliptical lesions are usually seen in the white matter. These lesions are usually present in the basal ganglia and the periventricular areas [16]. Our case also showed similar lesions, with multiple bilateral punctate lesions in the deep white matter in the genu of the corpus callosum. The differentials of MDEM include MS and other encephalopathies such as progressive reversible encephalopathy syndrome, progressive multifocal leukoencephaly, adult-onset leukodystrophies, etc. However, MRI alone cannot differentiate between MDEM and these differentials; a detailed clinical history and physical exam are needed [13]. In the case of our patient, MS was ruled out based on complete recovery on follow-up, a temporal gap of 26 years, negative oligoclonal bands, and noncharacteristic MRI findings.

Treatment for the disease includes high-dose steroids (particularly glucocorticoids) administered over 3–5 days, followed by an oral steroid taper over 6–9 weeks [12]. The steroids work by inhibiting the inflammatory cytokines (such as IL-1, IL-2, IL-6) and reducing leukocyte infiltration. Moreover, they also suppress immune hyperactivity by T-cell modulation and restoring the blood-brain barrier integrity [16]. Our patient responded well to steroids with complete disease remission and no neurological disability on follow-up. In other cases, steroids alone may not be sufficient for the management of ADEM. Here, the use of plasmapheresis, intravenous immunoglobulins, and immunosuppressive drugs prove to be successful [17, 18].

The importance of reporting this case is the fact that there can be a variably long gap between episodes of multiphasic ADEM, which can cause a delay in diagnosis and can lead to the permanent disability of the patient. Also, there can be a possibility of underlying autoimmune disorder or association with autoimmune diseases like neuromyelitis optica spectrum disorders or anti-MOG antibody syndrome. In the future, there can be the possibility of using immunomodulating agents to treat MDEM with associated autoimmune diseases.

Rarely, ADEM can present with recurrence or multiple phases, which need prompt diagnosis and management to prevent morbidity and mortality. These phases may or may not be preceded by an identifiable trigger. Most patients respond well to steroids. However, further studies are required to evaluate the underlying causes, association with autoimmune disorders, and use of long-term immunomodulating agents.

ADEM can rarely present with multiple phases (even after many years), and this can cause a delay in diagnosis leading to permanent neurological disability. Prompt diagnosis with MRI and clinical history and initiation of high-dose glucocorticoids can cause disease remission completely.

The authors would like to acknowledge the team of clinicians who managed the patient.

The study protocol was reviewed and the need for approval was waived by the Institutional Review Board of Rawalpindi Medical University. Written informed consent was obtained from the patient to publish the details of their medical care and any accompanying images. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (see https://doi.org/10.1159/000540951).

The authors would like to declare no conflicts of interest.

This manuscript has no funding from external sources.

The authors’ contributions have been added according to the ICJME criteria. The manuscript has been read and critically reviewed by all authors. Conception and data acquisition, conception and writing, writing and review, writing and data acquisition, and final approval of the manuscript: Muhammad Hamza Asif, Armeen Butt, Khadija Riaz, and Faizan Shahzad. Study conception, writing and review, writing and data acquisition, editing and supervision, and final approval of the manuscript: Maimoonah Asif, Muhammad Farhan, Waqas Ahmed, and Besher Shami.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.