Neurological manifestations of Erdheim-Chester Disease

Abstract

Objective: To characterize the spectrum of neurologic involvement in Erdheim-Chester Disease (ECD), a treatable inflammatory neoplasm of histiocytes.

Methods: Sixty-two patients with ECD were prospectively enrolled in a natural history study that facilitated collection of clinical, imaging, laboratory, neurophysiologic, and pathologic data.

Results: Ninety-four percent of the patients had neurologic abnormalities on examination or imaging, and 22% had neurologic symptoms as the initial presentation of ECD. The most common neurologic findings were cognitive impairment, peripheral neuropathy, pyramidal tract signs, cranial nerve involvement, and cerebellar ataxia. Imaging revealed atrophy and demyelination along with focal lesions that were located throughout the nervous system, dura, and extra-axial structures. The BRAF V600E variant correlated with cerebral atrophy. Brain pathology revealed lipid-laden, phagocytic macrophages (histiocytes) accompanied by demyelination and axonal degeneration.

Interpretation: In patients with ECD, neurologic morbidity is common and contributes significantly to disability. Since neurologic symptoms can be the presenting feature of ECD and, given the mean delay in ECD diagnosis is 4.2 years, it is critical that neurologists consider of ECD and other histiocytosis in patients with inflammatory, infectious, or neoplastic-appearing white matter. Furthermore, given the broad spectrum of neurologic involvement, neurologists have an important role in a team of specialists treating ECD patients.

Figure 1

CNS neurodegeneration in Erdheim–Chester Disease. (A) Cerebellar and midbrain atrophy seen on FLAIR imaging. (B) Cerebral atrophy (FLAIR imaging). (C) Spinal cord atrophy (T2‐weighted image).

Figure 2

Examples of CNS parenchymal lesions in ECD. (A) Dural enhancing lesion on gadolinium‐enhanced T1 image. (B) Gadolinium‐enhanced FLAIR image revealing patchy enhancement within the left temporal lesion (right temporal resection is also seen) (C) Non‐enhancing cerebellar and peduncular lesion (D) Subtle bilateral temporal FLAIR lesions with cerebral atrophy. (E) Longitudinal spinal lesion and cord atrophy on short tau inversion recovery (STIR) imaging.

Figure 3

Quantitative MRI reveals demyelination and atrophy in ECD. (A) Purple demarcates white matter regions where fractional anisotropy (FA), mean diffusivity (MD), or radial diffusivity values were significantly different between patients (PT) and controls (CT) (P < 0.05). (B) Brain images were averaged for 15 ECD patients and 15 healthy controls, generating two image maps that were statistically compared on a voxel‐by‐voxel basis. Five clusters of gray matter volume loss were found in ECD patients compared to controls (P < 0.05) and are demarcated in various colors. These clusters are all located on the right hemisphere, within the middle frontal gyrus (1.356 mL/pink), insula and perirolandic cortex (0.699 mL/red), posterior‐parietal cortex (0.411 mL/green), orbitofrontal cortex (0.254 mL/yellow), and perirolandic cortex (0.004 mL/blue).

Figure 4

Histology of ECD brain lesions. Brain biopsy of an ECD lesions revealing (A) lipid‐laden histiocytes on H&E stain. (B) CD163 + reactivity on histiocytes (brown). (C) Neurofilament staining (brown) demonstrating axonal neurodegeneration in the vicinity of cerebral ECD histiocytes (arrowhead is an example). (D) Area of demyelination surrounding histiocytes (myelin is stained blue). (E) ECD macrophage phagocytosing PAS + myelin fragments (arrowhead for examination).