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A question of persistently enhancing lesions

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Introduction and objectives

A 54-year-old man with a past medical history of hypertension and hyperlipidemia presented after developing a sudden sense of imbalance and feeling as if he would fall to either side.  According to his wife, his gait appeared normal.  About the same time, he noticed mild weakness of his abdominal and leg muscles, right worse than left, most evident when rising from a seated position or going up or down stairs. He denied sensory, cognitive, visual, and bowel/bladder symptoms. 

Two weeks prior to developing these symptoms, he had a dental implant for which he was given amoxicillin prophylactically. One week post-procedure, he developed a sore throat, and pain and decreased hearing in the L ear.  He was treated for an ear infection and pharyngitis, and symptoms resolved within a week.

An MRI of his brain upon presentation is shown below.  

Case presentation

Many, though not all, of the lesions enhanced with either a partial ring or nodular appearance.  

Imaging

Spinal imaging and MR angiography of the head were normal.  CSF was acellular with normal glucose and protein levels.  CSF viral, bacterial, Lyme, Toxoplasma, and cytological studies were negative.  There were two oligoclonal bands (OCBs) unique to the CSF but a normal IgG synthetic rate.  

HIV testing and serum rheumatologic testing was negative.

His symptoms improved almost entirely within several weeks

Subsequent scans two and four months later showed significant improvement.

Laboratory studies

Four months after the initial event, the patient denied any symptoms other than a possible vague “sense of pelvic weakness” that was so subtle he couldn’t be sure of it. His neurologic exam was normal. 

Discussion: The differential diagnosis of this monophasic neurologic episode includes acute disseminating encephalomyelitis (ADEM) or the initial presenting event of multiple sclerosis (MS).  The bilateral, diffuse, “fluffy” appearing lesions seen on initial MRI and the extent of enhancement argued in favor of ADEM, as did the clinical history of a preceding infection.  The mild nature of the clinical episode (with the subtle changes imperceptible to his wife, and lack of encephalopathy) argued in favor of MS, as did the acellularity and OCBs seen in the CSF.  Indeed, on subsequent MRIs, lesions contracted to appear more typical of MS lesions, with oblong lesions radiating from the callososeptal interface, oriented perpendicular to the lateral ventricle. 

The patient was diagnosed with MS: CIS that met McDonald 2010 diagnostic criteria for dissemination in space and time based on radiologic changes (T2 lesions in at least 2 MS-typical regions and enhancing asymptomatic and non-enhancing lesions).  It was recommended that he begin a disease-modifying therapy; however, he preferred to remain off therapy and continue to be monitored clinically and via MRI.  

Over the ensuing 18 months he continued to feel well and ultimately attributed the very subtle, vague sense of pelvic weakness to “just getting a bit older”.  His neurologic exam remained normal.  His next MRI showed several lesions with nodular enhancement.  The two subsequent MRIs showed no change – the previously enhancing lesions continued to enhance.  These areas of enhancement clearly persisted for at least 14 months.  Below one can see lesions in the R insula and R anterior temporal lobe seen on scans 14 months apart.  

T1-weighted sequence with contrast at time point A:

Diagnosis

T1-weighted sequence with contrast 14 months later:

Current treatment

Discussion: MRI enhancement in MS is a transient phenomenon due to acute inflammation resulting in breakdown of the blood-brain barrier.  Typical MS lesions enhance for under one month.  One study in which MRIs were performed weekly in 26 patients found that the mean period of enhancement was 3 weeks (median was 2 weeks) (Cotton et al, 2003).  MS lesions that persistently enhance with gadolinium are rare; in the aforementioned study only one lesion enhanced beyond 6 weeks.  In another study of 301 gadolinium enhancing lesions in 25 MS patients, 2% of gadolinium enhancing lesions persisted for longer than 6 months (He et al, 2001).  Persistently enhancing lesions should raise concern for etiologies other than MS; the differential diagnosis for persistently enhancing brain lesions includes infection, malignancy, and granulomatous disease.  (Vascular malformations may also persistently enhance, though in this case the enhancement was associated with T2 lesions and the areas of enhancement were not present on initial scans).

Further evaluation consisted of repeat CSF testing, including viral studies, cytology and flow cytometry, all of which were unremarkable other than a finding of three unique OCBs.  A CT of the chest, abdomen and pelvis was normal.  The patient had a normal quantiferon.  ACE level was normal. RPR was non-reactive. The patient remained asymptomatic and his neurologic exam remained normal.  Spinal imaging remained unremarkable.  

The explanation for the persistently enhancing lesions remains unclear.  

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Comments

MRI enhancement is not just a BBB breakdown issue, it is also the cornerstone of the definition of a relapse. However, even to this date, an actual definition of what consitutes an acute relapse in MS eludes us all in the MS world and NOT one single study has evaluated phase 3 clinical trials that have no MRI evidence of a relapse but a clinical relapse is recorded. Without MRI evidence, is a relapse a true event ? Why CSF studies were repeated in this case, for an 'MS profile' beats me. Clearly, the dx is MS, based on radiological criteria. There is zero explanation as to why the gad enhancement has stuck around. We don't do biopsies in general (at least outside of a large Univ setting, in a manner of speaking) and so for now, nothing will reveal the nature of the enhancement.
Yes I agree that, following the acute relapse, the T2 lesion burden settled into a pattern very classic for MS. The persistent enhancement was just concerning enough to raise suspicion of an alternate diagnosis, which is why CSF studies were repeated.