Differential trigeminal myelinated and unmyelinated nerve fiber involvement in FOSMN syndrome

Facial-onset sensory-motor neuronopathy (FOSMN) first manifests with trigeminal sensory loss and pain, then spreads to bulbopontine and spinal motoneurons, sometimes with a fatal outcome.^1,2

Although a previous study assessed infraorbital nerve pathology in one patient,² no studies have directly aimed at investigating trigeminal nerve fiber damage in patients with FOSMN and assessing the involvement of the different sensory nerve fiber populations in this disease. Having this information might help understand the pathophysiology of FOSMN and thus guide its clinical management.

To find out whether FOSMN damages myelinated as well as unmyelinated trigeminal nerve fibers, we quantified epidermal nerve fibers (ENF) and dermal myelinated nerve fibers (MF) by indirect immunofluorescence and confocal microscopy in supraorbital skin biopsies³ from 5 patients with FOSMN and 10 healthy subjects.

Methods.

We enrolled 5 patients (1 M, 4 F; age 42–69 years, follow-up 8.2 ± 3.9 years) with FOSMN and 10 healthy subjects (5 M, 5 F; age 45–71 years). All patients underwent clinical examination and neurophysiologic testing including trigeminal reflexes,⁴ nerve conduction study, and EMG. We also used a Nd:YAP laser stimulator to quantify supraorbital warm and pinprick sensory thresholds.⁵

The study was approved by the institutional review board and patients gave their written informed consent.

Two-millimeter punch biopsies were taken from patients and controls in an area above the eyebrow and distinct from that used for laser stimulation. The wound healed in a few days without a visible scar.

Specimens were fixed overnight in Zamboni solution, cryoprotected in 20% sucrose in phosphate-buffered saline, and cut into 50-μm-thick sections on a freezing microtome (Leica 2000R, Wetzlar, Germany). Free-floating sections were processed for indirect immunofluorescence using an antibody panel to stain neural and vascular structures.⁶ Digital images were acquired using nonlaser confocal microscopy (Apotome; Zeiss, Jena, Germany).

ENF density was evaluated by applying Neurolucida software (MicroBrightField Bioscience, Williston, VT) to 4 20× z-series confocal images (2 μm × 16 increments) obtained from 4 randomly selected sections for each sample. MF density was calculated following previously published procedures³ as the number of fibers intercepting a calibrated grid in the dermal surface included in 1 mm depth from the basement membrane (intercepts per mm²) of 3 random sections for each sample. A single operator blindly quantified all samples.

Statistical analysis.

We used the Mann-Whitney test to compare differences in non-normally distributed data between patients with FOSMN and healthy subjects. p Values <0.05 were considered to indicate significance. All data are reported as mean ± SD.

Results.

In all patients, clinical examination disclosed bilateral trigeminal tactile sensory deficits, similarly involving supraorbital and perioral regions. Four patients also complained of spontaneous ongoing burning pain. Whereas no difference was found between warm threshold in patients and healthy subjects (25.6 ± 4.9 and 23.6 ± 4.6 mJ/mm²), pinprick threshold was higher in patients than in healthy subjects (114.0 ± 13.0 vs 93.5 ± 12.8 mJ/mm²) (p = 0.02).

Whereas no patients had upper motor neuron, extrapyramidal, or cognitive disturbances, all had severe motor symptoms. Two patients had tongue atrophy and fasciculation. One patient had masseter muscle atrophy. One patient had facial muscle weakness. Three patients had neck flexion weakness. Three patients had dysphagia and 2 had dysarthria. Four patients had upper limb muscle weakness and atrophy accompanied by generalized fasciculations. In one patient, these motor disturbances involved the lower limbs. This patient died of pneumonia after a 6-year disease course.

Neurophysiologic testing showed that all patients had abnormal or absent trigeminal reflexes and severe EMG abnormalities (fibrillation potentials, fasciculation and denervation–reinnervation changes).

No difference was found between groups in ENF density (patients 19.6 ± 10.8/mm and healthy subjects 19.0 ± 3.8/mm) (figure, B vs A). Conversely, MF density was lower in patients than in healthy subjects (1.0 ± 1.0/mm² vs 6.7 ± 1.4/mm²) (p = 0.0003) (figure, D vs C). All findings are detailed in table e-1 on the Neurology® Web site at Neurology.org.

Figure. Confocal images show severe myelinated fiber involvement along with unmyelinated fiber sparing in facial-onset sensory-motor neuronopathy.

Epidermal nerve fibers exhibit a similar number and distribution in patient (B) and control (A) despite severe myelinated fiber loss (D compared with C). Scale bar = 100 µm in A and B, 600 µm in C and D.

Discussion.

Our skin biopsy findings, showing normal ENF and reduced MF densities in patients with FOSMN, indicate that FOSMN is a dissociated neuropathy selectively affecting trigeminal myelinated fibers and sparing unmyelinated fibers.

Our clinical and neurophysiologic data agree with morphologic findings from skin biopsy, showing sensory deficits predominantly affecting tactile and pinprick sensation and trigeminal reflex responses, but sparing unmyelinated fiber-related warm thresholds.

Although most of our patients had ongoing burning pain, the unmyelinated nerve fiber sparing we found argues against the classic notion that ongoing burning pain arises from damage to unmyelinated nerve fibers. A possible reason why neuropathic pain develops in this condition is the unbalanced input from myelinated and unmyelinated nerve fibers onto the second-order neurons.⁷

Our findings on dissociated trigeminal nerve fiber involvement in patients with FOSMN improve current knowledge on this rare disease, and help to define its pathophysiologic mechanisms, thus possibly improving its clinical management.