Treatment of acute demyelinating encephalomyelitis associated with recent rickettsial infection

Summary

Acute disseminated encephalomyelitis (ADEM) is a rare, immune-mediated demyelinating disorder of the central nervous system that typically follows viral or bacterial infections. There are only two known case reports that describe an association with ADEM post rickettsial infection. A female in her 80s presented with progressive neurological decline, including dysarthria, dysphagia and hemiparesis, following recent treatment in Hong Kong for rickettsial infection. Initial CT brain imaging showed a right subcortical infarct. She deteriorated with encephalopathy and respiratory failure, requiring intubation. MRI revealed extensive brain and spinal demyelination. Infectious, autoimmune and paraneoplastic investigations were negative, while serology revealed markedly elevated spotted fever group antibodies. Treatment with high-dose corticosteroids and plasma exchange therapy resulted in significant neurological recovery. She was discharged after rehabilitation with a good recovery at 70%–80% of pre-morbid function. This case supports a possible post-infectious immune-mediated mechanism linking rickettsia and ADEM and underscores the importance of early recognition and treatment of ADEM.

Background

This case highlights an uncommon and diagnostically challenging presentation of acute disseminated encephalomyelitis (ADEM) occurring in the setting of recent rickettsial infection. Our patient, a previously independent female in her 80s, developed focal neurological deficits and encephalopathy, resulting in hypoxic respiratory failure and subsequent intensive care admission. Her diagnosis of ADEM was confirmed through detailed neuroimaging with MRI and CT brain, cerebrospinal fluid (CSF) analysis and extensive exclusion of infectious, autoimmune and para-neoplastic causes. A full multidisciplinary team approach was taken, with extensive consultation from our colleagues in neurology, infectious diseases and radiology. She improved following high-dose corticosteroids and plasma exchange (PLEX), with significant neurological recovery and subsequent radiological improvement on follow-up.

While rickettsial infections are known to cause meningoencephalitis, there are very few published reports linking them with ADEM. Our case not only supports this possible association but also adds to the growing body of evidence calling for broader infectious differential diagnoses, including rickettsial serology, in patients presenting with possible ADEM from endemic areas. Furthermore, our case study emphasises the importance of early recognition of ADEM, as well as success of second line treatment with PLEX.

Case presentation

A female in her 80s was admitted to a metropolitan hospital in Australia with a 1 week progressive decline in her mobility, new dysarthria, dysphagia and lethargy. Her previous medical history included essential hypertension, type 2 diabetes mellitus and previous gastric cancer which had been fully managed with partial gastrectomy 25 years prior. Our patient had no known allergies, and her regular medications included metformin, gliclazide and amlodipine. She had been recently discharged 2 months prior from an East Asian hospital with acute rickettsial infection, as well as acute cholecystitis which was conservatively managed with intravenous ceftriaxone. Her rickettsia was managed with a course of vibramycin, azithromycin and ceftriaxone, and her spotted fever titres were <128 and 512, respectively.

Neurological examination revealed a moderate left-sided hemiparesis, and CT imaging showed a new right subcortical stroke which was deemed to be new. Our patient was loaded with aspirin 300 mg and placed onto atorvastatin 80 mg. Seven days into her admission, our patient deteriorated with progressive encephalopathy and was subsequently intubated due to markedly reduced Glasgow Coma Scale (7/15, E1, V2, M4) and hypoxic respiratory failure (oxygen saturation (SPO2) 75% on room air). An MRI of the brain showed atypical leptomeningeal infection, with multiple lesions suspicious for acute demyelination, including the brainstem and cerebellum (see figure 1, showing initial MRI brain). An MRI spine was subsequently performed, which showed extensive cord signal abnormality with features suggestive of extensive meningitis/leptomeningitis. She was started on intravenous aciclovir, as well as ceftriaxone and benzylpenicillin to cover for meningoencephalitis.

Figure 1. MRI images from day 5 of admission. Reported as showing atypical leptomeningeal infection, with multiple lesions suspicious for acute demyelination.

CSF analysis, performed on day 7 of symptom onset, revealed clear, colourless fluid with minimal cellular content (polymorphs 1 /µL, lymphocytes 5 /µL, erythrocytes 123 /µL).

Biochemical parameters demonstrated elevated protein (3.16 g/L) with reduced glucose homeostasis (CSF glucose 5.7 mmol/L, serum 11.0 mmol/L). Microbiological studies, including routine microscopy and culture, yielded no organism growth. Mycobacterium tuberculosis PCR and culture were negative, although acid-fast bacilli staining could not be performed due to insufficient sample volume.

Comprehensive CSF analysis included negative cryptococcal antigen testing and an extensive molecular diagnostic panel. Meningitis and encephalitis panel returned negative results for common bacterial pathogens (Escherichia coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae and Streptococcus pneumoniae) and viral aetiologies (human herpesvirus 6, human parechovirus, enterovirus, herpes simplex virus 1 and 2 and varicella zoster virus). Cryptococcus species testing for neoformans and gattii was also negative.

Autoimmune and paraneoplastic screening demonstrated absence of classical onconeural antibodies (anti-Yo, anti-Hu, anti-Ri) and neuronal surface antibodies (anti-GAD65, anti-Tr(DNER), anti-amphiphysin). CSF oligoclonal band analysis revealed intrathecal IgG synthesis with additional weak bands present in both CSF and serum specimens. Flow cytometric analysis of lymphocyte subsets demonstrated a CD4:CD8 ratio of 1.67, with gated lymphocytes comprising 88% of white blood cells, without evidence of abnormal lymphoid populations. Extended neuronal antibody screening returned negative for both myelin oligodendrocyte glycoprotein (MOG) antibodies (fluorescence-activated cell sorting (FACS) ratio 0.1) and neuromyelitis optica (NMO) IgG antibodies.

Following multidisciplinary consultations involving critical care, neurology and neuroradiology teams, high-dose intravenous methylprednisolone was initiated at 1000 mg daily for 5 days, based on provisional clinical diagnosis of ADEM. On completion of pulse therapy after 5 days, the patient was transitioned to an oral prednisolone regimen, commencing at 50 mg daily.

Infectious disease consultation broadened the differential diagnosis to include several neuroinfectious aetiologies including endemic mycoses, melioidosis, central nervous system (CNS) tuberculosis, neurocysticercosis, HIV, neurosyphilis and cerebral toxoplasmosis. A systematic diagnostic approach was implemented, encompassing comprehensive serological studies, repeat CSF analysis and targeted pathology. Given the patient’s recent history of rickettsial infection, repeat rickettsial serology was particularly noteworthy, demonstrating markedly elevated spotted fever group antibodies (2048), while both typhus group and scrub typhus group antibodies remained below significant levels (titres<128).

Following serological confirmation of spotted fever, antimicrobial therapy was rationalised to doxycycline 100 mg two times per day, with cessation of empiric ceftriaxone, benzylpenicillin and aciclovir, as CSF analysis did not support meningoencephalitis. While follow-up MRI on day 17 demonstrated a reduction in the previously noted ring enhancing lesions, clinical improvement was noted to be suboptimal despite 5 days of high-dose methylprednisolone.

Given the inadequate response to initial steroid therapy, PLEX was initiated on day 24 of admission with 5% albumin and 3 L acid-citrate-dextrose formula A (ACDA) citrate. There was a noted clinical improvement within 48 hours of PLEX initiation. By day 31, bilateral upper limb movement returned, although our patient remained mildly confused. Successful extubation was achieved on day 33, with subsequent transfer to the ward for further care a few days later.

Our patient remained on a tapering protocol of oral prednisolone, involving weekly dose reductions of 10 mg until a dose of 10 mg was reached, followed by decrements of 2.5 mg each week over the subsequent 4 weeks. The patient completed the corticosteroid taper and discontinued all steroid therapy by day 98 of her initial admission.

Outcome and follow-up

Following 63 days of intensive inpatient rehabilitation, our patient was discharged home, with her immediate family assisting with most activities of daily living on discharge. Outpatient follow-up demonstrated substantial functional improvement, estimated to be 70%–80% of baseline function. Residual deficits included mild confusion and asymmetric lower limb weakness. Detailed neurological examination revealed normal tone with varying degrees of power deficits (left hip flexion 3/5, right hip flexion 3+/5, bilateral hip extension 4/5, right knee extension/ankle plantar flexion 4+/5, knee flexion/ankle dorsiflexion 4−/5). Deep tendon reflexes were brisk at the knees (3+) and normal at the ankles (2+), with an upgoing plantar response on the right and equivocal response on the left. Sensory examination demonstrated intact pin-prick sensation with graduated vibratory loss, most pronounced distally and asymmetrically (right sided predominance).

Follow-up MRI showed significant interval improvement in both supratentorial and infratentorial demyelinating lesions, with resolution of enhancement and residual fluid-attenuated inversion recovery (FLAIR) hyperintensities (see figure 2, showing follow-up MRI brain). Notable improvement was observed in brainstem involvement, particularly surrounding the pons and fourth ventricle, with minimal residual pontine and medullary demyelination. The previously noted longitudinally extensive cord demyelination showed substantial improvement with only mild persistent patchy involvement. Repeat serological testing for MOG and NMO antibodies remained negative.

Figure 2. MRI images from 197 days post initial presentation, showing a reduction in previously noted ring-enhancing lesions.

Discussion

ADEM is an immune-mediated inflammatory disorder, which primarily affects the white matter of the brain and spinal cord leading to demyelination.¹ It has an incidence of 0.07–0.9 per 100 000 and is more common in children. ADEM typically manifests with focal neurological deficits that can progress to encephalopathy if left untreated. It can occur most commonly in the days to months following a viral or bacterial illness; however, there is often no definitive aetiology found. Known causative pathogens include smallpox virus, Epstein-Barr virus, mumps virus, rubella virus, measles virus, varicella-zoster virus, HIV, influenza virus and mycoplasma pneumoniae.² Associations with immunisations have been reported; however, evidence supporting a causative link remains limited (see tables 1 and 2).^{3 4}

Table 1. Causes of ADEM.

Group	Examples (most commonly reported)	Association
Classic childhood viruses	Measles, mumps, rubella, varicella-zoster virus (VZV)	Historically classic post-infectious ADEM triggers, especially measles and VZV, now rare in vaccinated populations1 19–21
Respiratory viruses	Influenza A/B, parainfluenza, RSV, adenovirus	Among the most common antecedent infections in modern paediatric ADEM cohorts1 19 20
Herpesviruses (non-VZV)	EBV, CMV, HHV-6 (± HHV-7), HSV-1/2	Well-described in case series of ADEM/post-infectious demyelination; EBV and HHV-6 particularly frequent in children1 15 19 20
Enteric/systemic viruses	Enteroviruses (eg, EV-71), parvovirus B19, hepatitis A/B	Multiple case reports/series of ADEM or ADEM-like demyelination following these infections19–22
Arboviruses/emerging viruses	Japanese encephalitis virus, West Nile virus, TBEV, dengue, chikungunya, Zika	Usually present first with viral encephalitis; a subset develop post-infectious demyelinating syndromes with ADEM-like MRI1 20 21 23
Retrovirus/HIV	HIV (acute or chronic infection)	ADEM-like demyelination reported in both paediatric and adult HIV cohorts; often part of broader HIV-related CNS disease20 21 24
SARS-CoV-2 and post-COVID	SARS-CoV-2 (COVID-19), MIS-C	Since 2020, numerous paediatric and adult reports of COVID-associated ADEM or ADEM-like imaging patterns20 23 25
Atypical respiratory bacteria	Mycoplasma pneumoniae	One of the best-established bacterial triggers in paediatric ADEM; appears repeatedly in encephalitis/ADEM series1 15 19 20
Other bacteria/zoonoses	Borrelia burgdorferi (Lyme), Bartonella henselae, Leptospira, syphilis, tick-borne ehrlichiae	Less common; ADEM-like demyelination mainly supported by case reports and small series, often after documented CNS infection20 21 24
Very rare parasitic/other	Amoebae (eg, Balamuthia), helminths (eg, Baylisascaris)	Fulminant infections with secondary demyelination; only sporadic ADEM-like case reports21 24

ADEM, acute disseminated encephalomyelitis; CMV, cytomegalovirus; CNS, central nervous system; EBV, Epstein-Barr virus; EV, enterovirus; HHV, human herpes virus; MIS-C, multisystem inflammatory syndrome in children; RSV, respiratory syncytial virus; TBEV, tick-borne encephalitis virus.

Table 2. Possible differential diagnosis of ADEM and key similar features.

Diagnosis	Similar features to ADEM
Relapsing-remitting multiple sclerosis (RRMS)	Multifocal CNS demyelination; MRI white matter lesions9 10
Clinically isolated syndrome (CIS)/ first demyelinating event	Single or multifocal demyelinating event affecting optic nerve, brainstem, cord9 10
MOG-antibody associated disease (MOGAD)	Monophasic encephalitis/encephalomyelitis in children; MRI often indistinguishable; strong ADEM overlap15 21 24
AQP4-positive neuromyelitis optica spectrum disorder (NMOSD)	Transverse myelitis, optic neuritis, brain/brainstem lesions15 21 24
Viral or bacterial meningoencephalitis (eg, HSV, enterovirus and bacterial meningitis)	Fever, headache, seizures, encephalopathy; abnormal CSF; diffuse MRI changes20 23
CNS vasculitis/primary angiitis of the CNS (PACNS)	Multifocal deficits, encephalopathy, white matter lesions, sometimes enhancing20 25
Posterior reversible encephalopathy syndrome (PRES)	Acute encephalopathy, seizures, visual loss; bilateral posterior white matter lesions20 25
Metabolic or mitochondrial encephalopathy (eg, MELAS and urea-cycle disorders)	Acute encephalopathy, seizures, multifocal MRI lesions20 25
Toxic/hypoxic ischaemic leukoencephalopathy (eg, CO poisoning, inhaled heroin and severe hypoxia)	Acute encephalopathy with diffuse white matter changes20 25
Progressive multifocal leukoencephalopathy (PML)	Multifocal neurologic deficits, white matter lesions24 25
Acute necrotising encephalopathy (ANE)	Often post-viral (influenza, COVID-19); encephalopathy, seizures20 23
Brain abscess/septic emboli	Focal deficits, seizures, ring-enhancing lesions20 23
Neoplastic/versus glioma/lymphoma	Mass-like lesions with oedema, enhancement20 25
Autoimmune encephalitis (eg, anti-NMDAR, LGI1 and GABA-A/B)	Subacute encephalopathy, seizures, psychiatric changes20 25

ADEM, acute disseminated encephalomyelitis; AQP4, aquaporin 4; CNS, central nervous system; CO, carbon monoxide; GABA, gamma-aminobutyric acid; HSV, herpes simplex virus; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; NMDAR, anti-N-methyl-D-aspartate receptor.

Rickettsial infections encompass a diverse range of gram-negative, obligate intracellular pathogens, including rickettsia family and following genus: rickettsii, prowazekii, typhi and conorii (see table 3). Typical clinical presentation involves fever, eschar, regional lymphadenopathy and headache,⁵ while potential complications include meningitis, encephalitis, non-cardiogenic pulmonary oedema, cardiac arrhythmias and coagulopathy.⁶ A retrospective study comprising 92 paediatric patients treated for rocky mountain spotted fever found that 13 patients experienced neurological sequelae on discharge, including encephalopathy, blindness and ataxia, which were attributed to delays in diagnosis and subsequent management.⁶ While rickettsial infections are known to cause meningoencephalitis, their association with ADEM is not well described. There are currently two published case reports of ADEM following rickettsial infection. As found in both case reports and our patient, presentation post rickettsial infection was delayed, which has been hypothesised to be a contributory factor in the development of ADEM.

Table 3. Rickettsial infection subtype and classic geographical location²⁶.

Rickettsial infection	Geographic location
Rocky Mountain spotted fever	North and South America
Mediterranean spotted fever	Southern Europe, Africa, India, Western and Southern Asia
African tick bite fever	Sub-Saharan Africa, Caribbean
Epidemic typhus	North and South America, Central Africa, Asia
Murine typhus	Worldwide (especially coastal/tropical and subtropical areas)
Scrub typhus	Southeast Asia, Western Pacific

CT brain imaging can occasionally demonstrate focal or multifocal white matter abnormalities, but it is usually non-diagnostic in the setting of ADEM.^{7 8} MRI of the brain and spinal cord remains the gold standard for diagnosing ADEM and classically reveals hyperintense lesions on T2-weighted and FLAIR sequences.^{7 8} These lesions commonly involve the subcortical and periventricular white matter but can also be seen in the cortical grey matter, basal ganglia and thalami. Notably, spinal cord involvement is observed in approximately one-third of ADEM cases (as exemplified in our patient); however, isolated spinal cord lesions are rare.⁸

Lumbar puncture with CSF analysis frequently reveals evidence of inflammation and serves to exclude other pathologies that may present similarly to ADEM, such as meningoencephalitis and multiple sclerosis.⁹ CSF findings in ADEM are often non-specific with lymphocytic pleocytosis (white cell count <100 cells/µL) and mildly elevated protein concentrations (<70 mg/dL) commonly observed.^{10 11} Meta-analysis of 11 studies comprising 309 patients suggests a low prevalence (23.9%) of oligoclonal bands.^{10 12} Further oligoclonal band profiling can help to distinguish ADEM from multiple sclerosis, as persistent bands are more characteristic of the latter.¹³ In addition to MRI imaging and CSF analysis, serological testing for NMO spectrum disorder (anti-aquaporin-4 immunoglobulin G (AQP4-IgG)) and MOG antibody-associated demyelination (anti-MOG-IgG) is integral to the comprehensive work-up of suspected ADEM.^{14 15}

Methylprednisolone 20 mg/kg/day (to a maximum of 1 g) for 5 days is the currently accepted first-line treatment for suspected ADEM. While ADEM can be highly responsive to initial steroid therapy, this is not always the case and second-line immunomodulation with intravenous immunoglobulin (IVIG) or PLEX should be considered. Patients must also undergo a slow steroid wean over 4 to six weeks.

IVIG has demonstrated efficacy in patients with ADEM who fail to respond to high-dose corticosteroid therapy, with clinical improvement typically observed within the first 7 days of initiation and maximal benefit achieved by week three.¹⁶ PLEX also serves as a recognised second-line therapy and can be particularly beneficial in cases of refractory or fulminant disease. In the presented case, PLEX was initiated in response to persistent severe encephalopathy despite 5 days of intravenous methylprednisolone. Notably, early initiation of PLEX has been associated with favourable neurological outcomes in ADEM, as well as with factors such as male sex and preserved deep tendon reflexes at commencement.^{17 18}

Learning points.

• Comprehensive neuroimaging, including both brain and spinal cord MRI in all patients presenting with unexplained encephalopathy and focal neurological deficits is essential to facilitate early recognition and treatment of acute disseminated encephalomyelitis (ADEM).

• We present a possible diagnosis ADEM secondary to rickettsial infection, without another clear cause found despite extensive investigation and multidisciplinary team involvement. This case report adds to the limited but growing body of literature supporting an association between rickettsial infection and ADEM.

• ADEM remains fundamentally a diagnosis of exclusion, and systematic investigation of post-infectious aetiologies including rickettsial disease is crucial for expanding our understanding of this condition.

• Serological testing for recent rickettsial infection should represent a critical component in the diagnostic evaluation of ADEM, particularly in patients presenting from endemic regions.

• Further research is warranted to elucidate several critical aspects: the temporal relationship between rickettsial infection and ADEM development, the optimal timing of immunomodulatory therapy initiation and comparative efficacy of treatment modalities.