Granuloma, vasculitis, and demyelination in sarcoid neuropathy

Abstract

Background: Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified.

Methods: We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non-caseating epithelioid cell granuloma in their sural nerve biopsy specimens.

Results: Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients.

Conclusions: Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy.

Keywords: conduction block; demyelination; electrophysiology; granuloma; pathology; sarcoid neuropathy.

FIGURE 1

Representative waveform in the ulnar nerve showing a conduction block. The amplitude of the compound muscle action potential at the proximal part was markedly decreased compared with that at the distal part.

FIGURE 2

Representative pathological findings in sural nerve biopsy specimens from patients with sarcoid neuropathy. (a) Distribution of granulomas in the epineurium in association with vessel location. An epineurial vessel indicated by an arrow is surrounded by a granuloma with a multinucleated giant cell (arrowhead). The vascular lumen is occluded. An asterisk indicates the endoneurium. (b) Extensive granuloma formation around a vessel in the epineurium. An arrow indicates the vascular lumen. (c) Fibrinoid necrosis of the epineurial vessel in a patient with extensive granuloma formation. An arrowhead indicates a multinucleated giant cell. (d) On electron microscopy, some epineurial microvessels were surrounded by macrophages (asterisks). The vascular lumen is occluded (arrow). Cross sections. Hematoxylin and eosin staining (a–c). A sample prepared for transmission electron microscopy (d). Scale bars = 30 μm (a–c) and 2 μm (c).

FIGURE 3

Granulomas and myelinated fibers in the endoneurium. (a) Many granulomas in the endoneurium (asterisk) were continuous with or adjacent to perineurial granulomas, as indicated by arrowheads. (b) Myelinated fibers relatively preserved with respect to the extent of granuloma formation. A granuloma in the epineurium is indicated by an asterisk. (c) On electron microscopy, a disproportionately large unmyelinated axon (indicated by a box), considered to have been originally myelinated, in the vicinity of the granulomas indicated by asterisks. (d) High‐powered view of the region within the box in (c). Cross sections of sural nerve biopsy specimens from patients with sarcoid neuropathy. Hematoxylin and eosin staining (a) and toluidine blue staining (b). A sample prepared for transmission electron microscopy (c, d). Scale bars = 50 μm (a, b), 20 μm (c), and 1 μm (d).