Timeliness is an important factor when treating patients with inflammatory sensory neuronopathy (SNN), also known as sensory ganglionopathy, a type of peripheral polyneuropathy. SNNs are characterized by primary involvement of sensory neurons in the dorsal root ganglion (DRG), and follow an acute, subacute, or chronic course, depending on disease etiology. Acute and subacute courses involve dysregulation of the immune system, as demonstrated by an inflammatory cell reaction in the DRG, and involvement of specific autoantibodies.

SNN may be the a manifestation of an underlying systemic automimmune rheumatic disease, commonly Sjogren Syndrome (SS).  Core clinical diagnostic symptoms of SS include xerophthalmia and xerostomia (sicca syndrome), but visceral involvement such as pneumonitis, renal tubular acidosis, and pancreatitis can also occur. SS-related peripheral nerve damage may present as cranial neuropathy, radiculoneuropathy, painful small fiber neuropathy, autonomic neuropathy, and SNN.

Using sensory nerve action potentials (SNAPs) as a surrogate marker for DRG neuron loss, Jean-Christophe Antoine, MD, and colleagues from the French Neuromuscular Network found that the therapeutic window for SNN stabilization was 8 months from disease onset. Improvement of disease required treatment within 2 months.


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“This means that the main endpoint for future clinical trials should aim at stabilizing the neuropathy rather than improving it within this period. Treatments within two months, the period in which SNAPs undergo maximal reduction, might improve the disease process but needs an early [electromyography] testing of the ulnar and radial nerves, which are the most sensitive to the neuropathic process in the upper limbs,” the authors write.

Evolution of Neuronal Loss

Although patients with inflammatory SNN may benefit from immunomodulatory or immunosuppressive therapies, prior studies have not demonstrated a strong response in this patient population, said Arun Varadhachary, MD, PhD, an assistant professor of neurology from the division of neuromuscular disease at Washington University in St. Louis, Missouri in an interview.

Postulating that treatment had to be administered before the occurrence of irreversible damage, researchers used SNAPs to determine the evolution of neuronal loss in 86 patients with all types of acute/subacute inflammatory SNN. SNAPs were recorded in the median, ulnar, radial, sural, and peroneal nerves, and monthly reductions were normalized with the lower limit of normal (LLN).

Results showed that the monthly SNAP reductions were most severe within the first 2 months of evolution, began to slow after 7 months, and stabilized after 10 months. Reductions in SNAP were highly correlated with progression of disability, as measured by modified Rankin score (P < .001).

Kaplan-Meier analysis revealed that the median time from onset to matching the electrophysiological criteria for SNN diagnosis was 8.5 months (95% CI, 3.2 – 13.8 months). SNN diagnostic criteria was more quickly achieved in older patients (odds ratio [OR] = 1.02; 95% CI, 1.01 – 1.04, P < .01), and those with paraneoplastic SNN (OR = 2.06; 95% CI, 1.05 – 4.00, P < .05).

After 8.5 months, 42% of the sensory nerves were still excitable, and 18% and 11% had a SNAP value above 30% and 50% LLN, respectively.

“Knowledge of the temporal profile of neuronal degeneration and of the time lapse until matching the diagnostic criteria is crucial for future therapeutic developments for SNN. Any future treatment must be applied before too many neurons are lost or before the ongoing process leading to neuronal degeneration cannot be reverted,” the authors point out.

Summary and Clinical Applicability

Inflammatory SNN/ganglionopathies can be associated with good clinical outcomes if treatments are administered in a timely manner. In this study, the therapeutic window to improve patient symptoms is 2 months after onset.

“Being alert to the clinical distinction between neuropathies versus neuron/ganglionopathy will help limit exposing patients to potentially dangerous medications only in cases where the drugs could be helpful,” Dr Varadhachary added, noting that the study is limited by lack of individualized time-course data, physical exam findings, and pathologic information for the sensory nerves or ganglion.

Further research is needed to determine whether SNAP amplitudes can be used as markers of DRG degeneration, and whether timing treatment administration can improve outcomes in patients with an SNN.

This study was supported by a grant from the French Ministry of Health.

Reference

Antoine JC, Robert-varvat F, Maisonobe T, et al. Identifying a therapeutic window in acute and subacute inflammatory sensory neuronopathies. J Neurol Sci. 2016;361:187-91.