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In the Pipeline-Multiple Sclerosis
Neurographic MRI Reveals Peripheral Nerve Lesions in MS Patients



ARTICLE IN BRIEF

Using a highly sensitive magnetic resonance imaging technique, researchers were able to see more peripheral nerve lesions in patients with multiple sclerosis, suggesting that demyelination may be occurring in the peripheral nerve system.

German researchers using magnetic resonance neurography (MRN) — an imaging method that provides high-resolution sequences that visualize peripheral nerves — have detected and quantified lesions suggestive of peripheral nerve demyelination in multiple sclerosis (MS) patients, a team of German investigators reported in the October 10 online publication of Annals of Neurology.

It remains unclear, however, whether or not these are the result of an inflammatory process or related to spinal cord lesions.

Significantly more peripheral nerve lesions were found in a group of MS patients compared to a matched group of healthy controls, according to the study.

Current opinion is that pathological changes in MS are restricted to the central nervous system (CNS) and cranial nerves, but the new proof-of-concept study may offer new insights into the pathophysiology of the disease and help guide new treatment options, said lead author Jennifer Kollmer, MD, a neuroradiologist at Heidelberg University Hospital.

The results might also help explain why CNS MRI scans in some patients show only a few lesions or older, non-enhancing ones, despite severe or new clinical symptoms, she told Neurology Today.

“Although a few studies have suggested that the peripheral nervous system [PNS] might be affected in MS, ours is the first to prove frequent involvement of peripheral nerves in MS patients by high-resolution MRN, regardless of disease duration or medical treatment,” Dr. Kollmer said.

MRN is a modified form of MRI that allows imaging down to the level of single nerve fascicles that can objectify lesions. The technique provides a detailed image of a nerve from the resonance signal in the nerve itself rather than surrounding tissues or from fat in the nerve lining. Regular MRI can show the outline of some nerves but not the intrinsic signal.

“Currently this specialized technique is used at only a few centers around the world,” Dr. Kollmer said. “One of the problems is that it is a relatively time-consuming method. However, I think it is an emerging technique that is becoming increasingly important as an additional diagnostic tool in the workup of unclear focal and non-focal neuropathies or in presurgical planning.”

The finding of a negative correlation between PNS and spinal cord lesions, together with the exclusion of any other potential sources of CNS damage in spinal MRIs in the MS cohort, makes it unlikely that the observed peripheral nerve system lesions occurred as a direct consequence of spinal cord lesions, according to the researchers.

“The clinical relevance of our findings is not completely clear,” Dr. Kollmer said. “In the absence of pathological results in nerve conduction studies, it cannot be ruled out that the nerve lesions detected by MRN are subclinical and do not cause any symptoms. However, as the exact pathomechanism in MS is still unclear, the knowledge of combined CNS and PNS effect and possible peripheral demyelination might help identify potential immunoreactions or antibodies targeting peripheral nerve system antigens in MS, with future implications for therapeutic approaches.”

STUDY METHODS, RESULTS

In the study, findings in 36 patients diagnosed with MS, including 34 with relapsing-remitting disease and two with clinically isolated syndrome, both treated and untreated, were compared with those of 35 healthy volunteers. All patients underwent detailed neurological and electrophysiological examinations, prior to undergoing 3T MRI with coverage of both legs and the lumbosacral plexus.

Nerve lesions were detected in all of the MS patients, with a mean lesion number within the sciatic nerve at thigh level of 151.5±5.7 versus 19.1±2.4 in the healthy control group. Nerve proton spin density (the density of water hydrogen atoms within the tissue, used to calculate nerve damage) was also significantly higher in the tibial and peroneal nerves of the MS patients. In addition, T2-relaxation time was significantly higher in controls in tibial (82.0±2.1) and peroneal nerves (78.3±1.7) compared to the MS group (64.3±1.0/61.2±0.9).

Electrophysiological tests are commonly negative for signs of PNS involvement in MS and are not routinely performed. However, in many patients there is a large and inexplicable gap between the severity of clinical symptoms and a comparably low burden of CNS lesions, Dr. Kollmer noted. Nerve biopsy could probably prove peripheral demyelination, but it is an invasive procedure and could be regarded as unethical in MS patients, she added.

“An explanation might be that PNS involvement is very subtle in many cases and thus may escape detection by regular nerve conduction velocity exams, as in our study.”

The study was supported by the German Research Foundation, the Amyloidosis Foundation, and Alnylam Pharmaceuticals. The study authors reported no conflicts of interest.

EXPERT COMMENTARY

Benjamin M. Jacobs, MD, an MS researcher at the Barts Health NHS Trust, in London, UK, told Neurology Today that the findings, if confirmed, could change the diagnostic and prognostic landscape for MS. Dr. Jacobs won the AAN's 2016 Saul R. Korey Award in Experimental Neurology.

“These findings are incredibly interesting. If they can be followed-up with more definitive evidence of demyelination, such as biopsy evidence, it would require us to radically rethink our view of MS biology,” he told Neurology Today. “To my knowledge this is the clearest evidence yet that MS may directly affect peripheral nerves. This had been suggested previously but there was little robust evidence for it.”

He added that if it turns out that these findings are sensitive and specific, then at some point MRN could become part of routine diagnostic work-up and disease monitoring.

Because no strong evidence of demyelination was found with nerve conduction studies, or in their peripheral nerves using T2-MRI, the changes cannot be explained by compression of the spinal nerve roots, the presence of spinal cord lesions, or disease-modifying therapy, he added.

“Interestingly, nerve width was increased in MS patients for large nerves compared to controls, but there was no such difference in smaller, terminal branches.”

Dr. Jacobs added that it is also worth noting that the healthy controls had quite a few lesions, implying that MRI may pick up very subtle disturbances of peripheral nerve myelin which don't have any functional importance.

“Importantly, the peripheral nerve lesions were not associated with abnormalities of nerve conduction. This means that their functional significance is unclear. It would be useful to know how these people fare in the long-term to see whether these subtle MRI changes pre-empt frank disturbances of peripheral nerve conduction.”

Saud A. Sadiq, MD, FAAN, director of the Tisch MS Research Center of New York, agreed that the findings were unexpected. “The findings are definitely novel and extremely surprising given that peripheral nerve disease is not a clinical feature of early MS, and nerve conduction studies show no peripheral nerve disease in patients with MS,” he told Neurology Today.

Although some early MS patients have sensory findings that cannot be explained on the basis of spinal cord disease, he noted, they do not have diminished reflexes or other clinical manifestations of peripheral nerve involvement.

“It may be that these findings represent a mild degree of pathophysiological involvement of peripheral nerves with no associated clinical manifestations. As a corollary, patients with peripheral nerve demyelinating disorders associated with anti-MAG [myelin associated glycoprotein] antibodies may occasionally have CNS demyelination with a subclinical optic nerve demyelination.”

Unfortunately, given that there are no associated clinical findings, one cannot perform sural nerve biopsies to show demyelination, he added. “Perhaps autopsy of peripheral nerves taken form MS patients can be studied for histological evidence to support these findings.”

EXPERTS: ON PERIPHERAL NERVE INVOLVEMENT IN MS

Figure

DR. BENJAMIN M. JACOBS: “These findings are incredibly interesting. If they can be followed-up with more definitive evidence of demyelination, such as biopsy evidence, it would require us to radically rethink our view of MS biology.”

Figure

DR. SAUD A. SADIQ: “It may be that these findings represent a mild degree of pathophysiological involvement of peripheral nerves with no associated clinical manifestations. As a corollary, patients with peripheral nerve demyelinating disorders associated with anti-MAG [myelin associated glycoprotein] antibodies may occasionally have CNS demyelination with a subclinical optic nerve demyelination.”

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•. Jende JME, Hauk GH, Diem R, et al. Peripheral nerve involvement in multiple sclerosis: Demonstration by magnetic resonance neurography http://onlinelibrary.wiley.com/doi/10.1002/ana.25068/full. Ann Neurol 2017; Epub 2017 Oct 10.