Acute disseminated encephalomyelitis following Campylobacter jejuni gastroenteritis: Case report and review of the literature

Abstract

We describe a case of a 25-year-old male with a diagnosis of acute disseminated encephalomyelitis (ADEM) following infection with Campylobacter jejuni, which is implicated in various human pathologies regarding the central nervous system (CNS) with acute course like Guillain-Barré syndrome (GBS), Miller-Fisher syndrome (MFS), Bickerstaff’s brainstem encephalitis (BEE), acute transverse myelitis (ATM) as well as ADEM. These conditions are caused by cross-reactivity between Campylobacter’s epitopes and cells of the CNS that causes an immunomediated inflammatory demyelination of the CNS. In the acute phase, magnetic resonance (MR) can detect pathologic signal intensity at the CNS with areas of pathologic contrast enhancement at cortical and spinal white matter that normalize over time or can be stable. These findings can be associated with edema in parts of the CNS. The lesions typically appear at different times during the disease course and also can have a different evolution. Our purpose therefore was to describe the clinical course and MR findings of this case and perform a critical review of the literature.

Introduction

Acute disseminated encephalomyelitis (ADEM) is an acute inflammatory demyelinating disease, frequently with a monophasic course, that involves the central nervous system (CNS), particularly frequent in children. Usually it is triggered by infectious or post-vaccination processes. The mechanism of damage is supported by an inflammatory response with edema and perivascular infiltrate by T-cells, macrophages and rarely plasma cells that destroy the myelin coating of CNS neuronal cells. Symptoms are focal or multifocal neurologic deficits with a predominance of motor deficits. It may be associated with seizures and mental status changes to coma. Very common is the onset of ataxia, fever and headache. Magnetic resonance imaging (MRI) shows increased T2 signal intensity in the white matter of the CNS with enhancement after contrast medium in the acute phase. Unusual is the presence of oligoclonal bands in the cerebrospinal fluid (CSF). Therapy is based on high-dose steroids that lead to a gradual resolution of clinical symptoms although MR imaging might be altered for many months or highlight permanent damage.

Case report

A previously healthy 25-year-old man with a recent history of Campylobacter gastroenteritis was admitted to our hospital with a 15-day history of paresthesia of four limbs followed by rapidly progressive hyposthenia, with proximal and distal distribution, ataxic gait and urinary retention. He also developed VII cranial nerve palsy and double vision.

He was fully vaccinated according to the Italian schedule; moreover, there was no history of recent vaccination or toxic drugs abuse. No head trauma or injury was detected.

In the previous 20 days he presented with non-bloody diarrhea, nausea and vomiting that spontaneously recovered in a few days. Seven days later he complained of fever and oral vesicular erythema treated with oral acyclovir. When admitted to the Neurological ward, the patient was bedridden, he presented with tendency to sleepiness, slurring of speech, severe flaccid tetraparesis and four-limb and truncal hypoesthesia, right facial weakness and ophthalmoparesis.

Lumbar puncture revealed clear and colorless CSF with a white cells count of 150 mm³ (100% lymphocytes), total protein of 110 mg/dl (n.v. 10–45 mg/dl), lactates 3.80 mmol/l (n.v. 0.50–2.20 mmol/l), albumin 63.10 mg/dl (n.v. 0.00–35.00 mg/dl), glucose 60 mg/dl (n.v. 40–76 mg/dl) and some erythrocytes. Oligoclonal bands were not detected; there was no intrathecal immunoglobulin (Ig)G production at hospital admission (day 0) but at day 3, 22.70 mg/dl (n.v. 0–4.00 mg/dl) IgG in the CSF were found. Polymerase chain reaction (PCR) was negative for enterovirus and herpesvirus.

Blood count, C-reactive protein and erythrocytes sedimentation rate (ESR) were normal. Also, serology for cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus (HHV), human immunodeficiency virus (HIV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), West Nile virus, flu virus, Coxsackie virus and Treponema Pallidum results were negative. Anti-gangliosides antibodies (Ab), anti-aquaporin-4 Ab and screening for other immune disorders were performed and were also negative. IgA anti-Campylobacter jejuni (C. jejuni) was detected in serum.

Nerve conduction studies showed the absence of “F” waves from the upper and lower limbs, according to polyradiculitis.

The first MR examination performed at hospital admission showed an area of increased T2 signal intensity with focal area of contrast enhancement at the left periventricular white matter (Figure 1). Another singular finding that we found was an area of altered signal intensity at the right side of the medulla oblongata (Figure 2), that placed suspicions, according to the clinical and laboratory data, on pathological involvement of the spinal cord. At day 8 we extended the study to the spinal cord and found an increase in the number and the extension of the lesions in the periventricular white matter and also a widespread T2 hyperintensity of the spinal cord with diffuse contrast enhancement (Figure 3). The MR study at day 23 showed a diffuse and bilateral increase of T2 signal intensity at the frontal, temporal, and parietal lobes, with associated linear and focal areas on contrast enhancement to the gray and white matter junction, in the hippocampal and para-hippocampal cortex, and at the left periventricular white matter. The signal intensity on T2 and T1 after contrast media was decreased slightly compared to the previous examination (Figure 4).

Figure 1.

Brain magnetic resonance at hospital admission. T2 FLAIR ((a), (c)), T1 after gadolinium ((b), (d)). The examination showed an area of altered signal intensity (arrows) at the periventricular white matter with contrast enhancement referred to an acute lesion. FLAIR: fluid-attenuated inversion recovery.

Figure 2.

A magnification at the level of the medulla oblongata. The examination showed a high SI on T2 (a) and low SI on T1 pre- (b) and post-gadolinium (c) at right bulbar olive (arrows). SI: signal intensity.

Figure 3.

MR examination at day 8. (a), (b): T2 FLAIR; (c), (d): T1 after gadolinium; T1 (e) and T2 (f) after gadolinium at spinal cord. Note the increased area of altered signal intensity at periventricular deep white matter with contrast enhancement (arrows). The spinal cord examination also showed altered T2 and T1 signals with spinal cord swelling in particular from C2 to C5 level (arrows). MR: magnetic resonance; FLAIR: fluid-attenuated inversion recovery.

Figure 4.

MR examination at day 23. (a), (b): T2 FLAIR; (c), (d): T1 after gadolinium; T1 (e) and T2 (f) after administration of contrast medium at the spinal cord. The examination showed an increase of number of areas of altered signals at both cerebral hemispheres (arrows) with evidence of widespread areas of contrast enhancement with a “ribbon-like” course (arrows in (c) and (d)). Areas of contrast enhancement and edema at the spinal cord also appear minimally reduced. MR: magnetic resonance; FLAIR: fluid-attenuated inversion recovery.

The clinical and instrumental assessments were consistent with ADEM and spinal radiculitis. The patient therefore was treated with plasma exchange, acyclovir, and linezolid, meropenem and doxycycline.

At day 21 of illness his neurological conditions progressively worsened; he developed generalized seizures. Also, thoracic computer tomography documented a right basal bronchial pneumonia. The patient needed mechanical ventilation and he was transferred to the intensive care unit. He was started with a high dose of intravenous Ig followed by intravenous methylprednisolone. At day 30 he was extubated because his clinical condition slowly improved and he was discharged at day 34 and sent to a neurological rehabilitation center, where he presented a gradual recovery of neurologic symptoms. During the last neurological examination only a minimal delay at neurological tests and minimal anesthesia to the distal areas of the lower limbs persisted.

Discussion

Campylobacter is a Gram-negative bacillus. Usually it causes gastroenteritis and septicemia. C. jejuni is the most common cause of bacterial gastroenteritis in the United States. It causes the development of gastroenteritis, septicemia, meningitis, miscarriage, proctitis and a variety of neurological diseases, foremost of which is Guillain-Barré syndrome (GBS), in which it has been reported in almost 4%–66% of cases.¹

Campylobacter can also affect the CNS with various diseases with acute course such as GBS, of which it is the main cause, as well as acute transverse myelitis (ATM), Miller Fisher syndrome (MFS), ADEM and Bickerstaff's brainstem encephalitis (BEE). All these forms, except ADEM, are characterized by a progressive demyelinating peripheral neuropathy.

It also has a prominent role in the development of some pathologies with a chronic course affecting the CNS such as multifocal motor neuropathy (MMN) or chronic inflammatory demyelinating polyradiculoneuropathy (CDIP), although the mechanisms that cause these diseases are less clear than the acute forms.

Usually these kinds of diseases are preceded by an infection of the gastrointestinal tract supported by C. jejuni, which causes watery diarrhea and abdominal pain.

ADEM is a monophasic disease characterized by demyelination of the CNS associated with edema and perivascular inflammation.² The main causes of ADEM are systemic viral infections (such as measles, mumps, rubella, influenza virus A and B, herpes simplex virus (HSV), EBV, varicella zoster virus (VZV)) or bacterial infections (such as Mycoplasma pneumoniae, Chlamydia, Legionella, Streptococcus) or after immunizations for smallpox, diphtheria, tetanus, pertussis and rabies.³ The disease appears to be mediated by a mechanism that involves T-cells, macrophages, and rarely, plasma cells.⁴ Furthermore, the high titer of antiganglioside GM1 IgG Ab can be associated with development of demyelination on the inflammatory basis of the CNS;^5,6 these Ab recognize particular protein sequences shared between the bacterial antigens and epitopes of myelin due to a molecular mimicry. To strengthen this hypothesis is the fact that Ab against gangliosides are found in patients with neurological symptoms post-C. jejuni enteritis while they are not found in patients with enteritis by C. jejuni without neurological involvement.

Edema and inflammation during ADEM can be evidenced on MR with an increase of T2 and T2 fluid-attenuated inversion recovery (FLAIR) signals in correspondence with white matter, which has a characteristic course along the bundles of fibers affected. The inflammation also causes an increase in permeability of the blood-brain (BBB) and blood-myelo barrier (BMB) with areas of pathological contrast enhancement. These findings appear less evident after the beginning of corticosteroid therapy, although may remain as sequelae of pathogenetic mechanism.

After a prodromal period of about 7–28 days after infection, characterized by fever, malaise and myalgia, multifocal lesions of the CNS⁷ appear, associated with worsening of neurological symptoms that are initially very mild.

We found only six studies in the literature, mainly as isolated case reports, about ADEM-Campylobacter related cases, using the keywords “ADEM” and “Campylobacter” without adding additional filters (Table 1), the first described by Huber et al.⁵ in 1999. What emerges considering the population concerned is that the disease mainly affects children or young adults, immediately after an episode of gastroenteritis and the initial symptoms are rather unspecific; also it does not seem to be a clear distinction by sex. A constantly present symptom is the acute retention of urine in patients with ADEM associated with the presence of a gradual worsening of the neurological symptoms in the critical period. Recovery also appears valid after the start of high-dose steroid therapy. In two cases, however, it was necessary to implement plasmapheresis.

Table 1.

The table, sorted by data, shows a review of literature of ADEM related to Campylobacter infection. In none of these articles is there the presence of oligoclonal bands in the CSF.

References	Age/gender	CSF analysis	Antibodies profile	MRI findings	Therapy	Outcome
Huber et al.5 (1999)	23/M	Normal cell count, high protein level, high albumin CSF/serum ratio	IgG anti-GM1 positive in acute phase. Unchanged after six months	HSI on T2W at cerebellar peduncle bilaterally, pons, basal ganglia, deep white matter. Slight enhancement in left cerebellar peduncle	Steroids + Acyclovir +  Amoxicillin	Mild distal paresis in legs, slight frontal lobe disturbances
Orr et al.8 (2004)	24/M	Lymphocytis pleocytosis, high protein level	NA	HSI on T2W along white matter of CNS specially in the subcortical white matter of both hemispheres, which enhance after gadolinium	Methylprednisolone	No sequelae
Gaig et al.6 (2005)	38/F	Mononuclear pleocytosis, elevated protein level	IgG anti-GM1 positive in acute phase. Negative after five months	HSI on T2W in dorsal pons that extended to the medulla, dorsal cord (T6 to T11) without gadolinium enhancement.	Corticosteroids and plasma exchange	Neurologic bladder dysfunction
Young et al.2 (2008)	20/F	Lymphocytic pleocytosis, high total protein	IgG anti-GM1 positive. Follow-up NA	HSI on T2W in the dorsal pons extending into the base of the left middle cerebellar peduncle, cervical and thoracic cord.a	Methylprednisolone, Plasmapheresis	Urinary urgency at discharge (46 days)
Guison et al.9 (2016)	32/M	Lymphocyte predominance, moderate protein level	IgG anti GT1A, IgG anti GT1B, IgG anti-GQ1B in acute phase. Follow-up NA	HSI on T2W in cervical and thoracic cord associated to brainstem. These areas showed moderate enhancement.	Methylprednisolone, Cefotaxime, Amoxicillin	Only minimal residual after urination (10–20 cm3)
Present case report	25/M	Lymphocytic pleocytosis, high total protein, high albumin level	IgA serum positive. High IgG in liquor. All negative at follow-up	HSI on T2W in fronto-tempo-parietal white matter bilaterally and in the spinal cord, especially at cervical tract, with high contrast enhancement. HSI on T2 in medulla oblongata.	Methylprednisolone, Acyclovir, plasma exchange, Linezolid, Meropemen, Doxycycline	Minimal delay at neurological tests and anesthesia to the distal areas of the lower limbs. Low residual after urination

M: male; F: female; CSF: cerebrospinal fluid; MRI: magnetic resonance imaging; Ig: immunoglobulin; HSI: high signal intensity; T2W: T2-weighted; NA: not available. ^aContrast medium was not administrated.

The differential diagnosis should be placed against MFS, a variant of GBS, which is characterized by the presence of ophthalmoplegia with acute onset, ataxia and areflexia (due to a generalized abolition of deep tendon reflexes); the CSF shows albuminocytologic dissociation present in 84% of patients during the third week.¹⁰ In addition, MFS is characterized by the presence of cross-reactivity between the GQ1b ganglioside, an antigen of human neurons, and of the lipo-oligosaccharides (LPS) of Campylobacter ssp. Anti-CQ1b antibody is a powerful diagnostic marker for MFS but there are a small sample of anti-GQ1b-negative MFS cases.

Also the BBE was excluded; it is characterized by ataxia, symmetrical ophthalmoplegia with disorders of consciousness, drowsiness, coma and hyperreflexia, conversely to MFS, and no facial paralysis. It is associated with the presence of anti-GQ1b antibodies and anti-GM1 IgG. MR shows increased T2 signal mainly in the brainstem, thalamus, cerebellum and the CNS white matter; CSF also shows an albuminocytologic dissociation.¹¹

This case report highlights the ability of MR to detect early the areas of CNS involvement by inflammatory disease, including the spinal cord and brainstem. MR, in relation to its high spatial and contrast resolution, together with clinical data, can allow an early diagnosis of this inflammatory disease allowing us to evaluate the asynchrony of the inflammatory lesions in ADEM.

Conclusion

From the analysis of the literature it seems that the main symptom of post-infection ADEM, in particular following C. jejuni gastroenteritis, although not specific, is represented by acute retention of urine in young patients who may present with various degrees of neurologic deficiency and fever immediately after an infectious episode or in the post-vaccination period, without evidence of acute urological causes. Evidence strengthening the presence of this disease are Ab directed against the protein GM1 that are the cause of the damage at the level of the myelin of the CNS cells due to a phenomena of cross-reactivity with epitopes of myelin and bacteria cells. We have to remember, however, that some cases have negative Ab profiles. MR can detect the presence of a hyperintense T2 signal early with some areas of contrast enhancement not only in deep and cortical white matter but also in the spinal cord, especially in the acute phase of the disease; the signals normalize with time or can be stable. Another important criterion to evaluate is the swelling of the white matter, particularly evident at the level of the spinal cord. A singular finding in this case was the hyperintensity of T2 at the medulla oblongata in the first MR examination that did not have contrast enhancement, to be related to the asynchrony of the presentation and evolution of lesions related to ADEM. These findings, correlating with the presence of a clinical history, are very reliable in establishing an early diagnosis of post-infectious ADEM.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.