The Dentate Nucleus Is the Clue: Erdheim–Chester Disease as a Cause of Cerebellar Syndrome

Erdheim–Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis, most commonly affecting bones, skin, retroperitoneum, heart, orbit, lung, and brain. Clinical manifestations are mediated by local effects of the histiocytic infiltration, as well as by chronic systemic inflammation and cytokine release. The heterogeneity, low prevalence and its variable clinical presentations make this disease one of the most difficult entities to diagnose.1 We present a case report of a patient affected with this disorder with special emphasis on his magnetic resonance imaging (MRI) abnormalities. A 59-year-old male was admitted to hospital because of gait instability and a behavioral disorder. He had a personal history of hypertension and dyslipidemia in medical treatment. None of the family members was affected of ataxia, and the parents were not consanguineous. The patient had developed progressive gait impairment with instability for 2 years, associated with difficulty in coordinating manual movements. In addition, he presented disinhibition, aggressiveness, and a delusional episode with paranoid ideation without visual or auditory hallucinations. The patient presented a clinical progressive worsening with dysarthria, dysphagia to solids and liquids, and urinary incontinence. Clinical examination showed a disinhibition, logorrhea, and bilateral palmomental reflex. The Montreal Cognitive Assessment (MoCA) test was 18/30. He had bilateral gaze-evoked nystagmus, but no square waves nor saccadic intrusions. These symptoms were associated with bilateral dysmetria, head titubation, Stewart Holmes rebound sign, mild truncal ataxia that does not worsen with suppression of visual stimuli, and ataxic gait (Video 1). Blood levels of TSH (Thyroid Stimulating Hormone), vitamin B12, folic acid, vitamin E, antinuclear antibody, liver enzymes, and electrolytes were normal, and urine, serum sodium, and osmolality were within normal limits. The cerebrospinal fluid (CSF) study was normal (no cellularity, proteins: 40 mg/dL, glucose: 59 mg/dL). Immunophenotyping did not show atypical cells. Tuberculosis culture and Tropheryma whipplei polymerase chain reaction (PCR) were all negative. Oligoclonal bands, anti-neuronal, and anti-neuropil antibodies in CSF and serum were also negative. The brain MRI presented T2 hyperintense lesions involving the dorsal part of the pons, lower midbrain tegmentum, middle cerebellar peduncles, and bilateral dentate nuclei, without gadolinium enhancement (Fig. 1). No spinal cord involvement was observed. Given the finding of MRI a suspicion ECD was raised. Thoracic abdominal computed tomography (CT) was performed showing an increase in soft tissue density surrounding both kidneys (corresponding to typical “hairy kidneys”) and at the aortoiliac bifurcation, suggesting a possible periaortitis (Fig. 2). Bone scintigraphy showed an increased activity in the ulnar, radius epiphyses, right tibial epiphyses, left distal tibial, femoral proximal metaphyseal region (Fig. 2). Both the radiological and clinical findings were compatible with a possible ECD affecting bones, vascular (periaortitis) and central nervous system (CNS). Therefore, an ultrasound-guided fat perirenal biopsy was analyzed by immunohistochemistry showing an infiltration of the perirenal adipose tissue by abundant lymphoplasmohistiocytic inflammatory infiltrate, predominantly of histiocytes with clear and foamy cytoplasm. These histiocytes are positive with the immunohistochemical technique for CD68 (Fig. 2) and negative for IgG4, CD1a, S100 confirming ECD diagnosis. Because of the possibility somatic mosaicism, several analyses were done in bone marrow tissue to exclude BRAF mutations, Video 2. Patient with uninhibited speech and intelligible scandic dysarthria. He presents a frontal syndrome with uninhibited behavior and frontal release reflexes (palmomental). Confrontational visual fields, oculomotricity and saccades are normal while horizontal nystagmus type gaze-evoked is present. Lower cranial nerves are not altered and there is no motor or sensory deficit. He has diminished deep muscle reflexes in lower limbs. Hypotony with Stewart Holmes rebound sign. Dysmetria is observed in finger-nose and heel-spine tibial maneuver. Axial and appendicular ataxia is present. He has head tremor with low amplitude and frequency. No rigidity or bradykinesia are shown. Gait is altered with an increased base of support, unstable, tandem walk is impossible. Video content can be viewed at https://onlinelibrary.wiley.com/doi/10.1002/mdc3.13526 Full video from the 2021 video challenge discussion of this case. Video content can be viewed at https://onlinelibrary.wiley.com/doi/10.1002/mdc3.13526 ECD affects adults between their 5th and 7th decades of life. The multi systemic form is associated with significant morbidity. The most common CNS alteration is diabetes insipidus, orbital infiltration, and cerebellar syndrome.1 The role of the cerebellum in affects and cognitive processing has been extensively studied both through structural and functional neuroimaging in the last three decades.2 This entity was termed “cerebellar cognitive affective syndrome” (CCAS).3 Cognitive deficits observed in CCAS are characterized by a dysexecutive syndrome, visuospatial deficits, language abnormalities (dysprosodia, agrammatism, and anomia) and emotional dysfunction (disinhibition or flattening of affect).3 The anatomic substrate of these cognitive symptoms is the disruption of the connections between the posterior lobe of the cerebellum and cerebral association areas, especially prefrontal, parietal, and frontotemporal regions. In a retrospective review of 33 patients with biopsy-proven ECD, cerebral MRI revealed a hypothalamic–pituitary involvement 53%, orbital involvement 30% and bilateral symmetric T2 hyperintensity in dentate nuclei in only 10%.4 In our patient, neuroradiological presentation was characterized by symmetrical T2 hyperintensities in the dentate nuclei and middle cerebellar peduncles. Middle cerebellar peduncle hyperintensities have been associated with other disorders (such as multiple system atrophy, fragile X tremor ataxia syndrome or leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation), which do not associate with dentate hyperintensities. The symmetry of cerebral lesions and the absence of gadolinium enhancement were atypical for cerebral lymphoma, inflammatory, or paraneoplastic syndromes, which were finally discarded following CSF results. Other than ECD, dentate nucleus T2 hyperintensities have been found in genetic disorders such as SPG7(Spastic paraplegia type 7), Alexander's disease, POLG1, and cerebrotendinous xanthomatosis, but none of these entities could explain the systemic clinical features found in the case of this patient. Both 99mTc bone scintigraphy and radiologic studies contribute to the diagnosis of this disease.5 Retroperitoneal involvement, periaortic (“coated aorta”) and perirenal (“hairy kidney”) can be observed. These abnormalities were present in our patient. Histopathological confirmation is necessary for ECD diagnosis. A biopsy obtained from bone, skin, retro-orbital, or retroperitoneal soft tissue confirms the diagnosis on detection of CD68(+), CD1a(−) non-Langerhans histiocytes.6 These findings in the retroperitoneal tissue biopsy, confirmed the diagnosis in our patient (Fig. 2). In 77% it occurs in a context of inflammatory stroma induced by BRAFV600E, and mitogen-activated protein kinase pathway mutations in lesional tissue.6 Different treatments have been administered, interferon α (IFN-α) and PEG-IFN-α(Peginterferon-alfa) such as anakinra, infliximab, and tocilizumab that have shown variable efficacy. Imatinib and particularly vemurafenib (an inhibitor of BRAF) have been used with unprecedented clinical and radiographic improvement in patients harboring V600E BRAF mutation.7 Because of the possibility somatic mosaicism, in our patient several analyses were done in bone marrow tissue to exclude BRAF mutations. The negative results of these tests led to the choice of IFN-α therapy. This treatment was started with initial poor outcome, but with improvement and clinical stability after increasing the dose of this treatment. Control MRI shows stability without progression. In summary, despite ECD being a rare neurological disease, neurologists must consider this entity as a putative cause of the cerebellar syndrome with dentate nuclei involvement in cerebral MRI, which is potentially treatable (Video 2). (1) Research Project: A. Conception, B. Organization, C. Execution. (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique. (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. S.T.D: 1A, 1B, 1C, 3A, 3B. G.V: 1B, 1C, 3B. L.G.A: 3B. G.D.M.A: 3B. H.V.J: 1B, 1C, 3B. Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. Informed consent was obtained from the patient. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for Previous 12 Months: We confirm no funding was received for this work in the last 12 months. The authors declare that there are no conflicts of interest relevant to this work.