Ancillary tests found hyperleukocytosis (13,000/mm3, with 8890 neutrophils/mm3), biological inflammation (C-reactive protein was 24 mg/L), with no monoclonal gammopathy. Viral and bacterial serologies, immunological (antinuclear, anticardiolipin, and anti-β2-glycoprotein 1 antibodies) and metabolic (cholesterol, triglyceride, glycosylated hemoglobin, homocysteine, thyroid stimulating hormone, and transaminases) tests were unremarkable. Cerebrospinal fluid analysis was normal (1 white cells/mm3; protein level at 46 mg/dL, for a normal value <45 mg/dL; normal glucose level). A bone marrow biopsy showed no abnormality.
Plain radiographs showed bilateral and symmetric cortical osteosclerosis of the diaphyseal and metaphyseal regions of the lower limbs; 99Technetium bone scintigraphy revealed a symmetric tracer uptake by the long bone of lower extremities (and also in maxillary and frontal bones) suggestive of the diagnosis of ECD (Fig. 3). After a second biopsy of the maxillary sinus, pathological study finally demonstrated a xanthogranulomatous infiltrate mainly composed by foamy histiocytes accompanied by fibrosis (stains for CD1a and S-100 were negative), confirming the diagnosis of ECD.
She was treated with interferon-α (3 million IU 3 times weekly, then a gradual increase of the dose up to 9 million IU 3 times weekly over the following months), with not only an improvement of the cognitive function (particularly visual function and memory) but also of headaches. A treatment by clopidogrel (75 mg/d) was proposed for stroke. After 3 months of treatment with interferon-α, we observed reduction of the stenosis of the basilar artery (50%) on MR-angiography (with a quite total recanalization 2 years after the onset of the treatment; Fig. 1). After 4 years, the neurological examination was still stable, but she developed insipidus diabetes (successfully treated with desmopressin).
Most of patients with ECD are men (75%), mostly affecting during the fifth and sixth decades. Patients with ECD carry the V600E mutation of the BRAF gene in 54% of cases (as 57% of patients with Langerhans cell histiocytosis). ECD is not only associated with skeletal involvement in all patients, but is also a multisystemic disease with high mortality due to many extraskeletal manifestations: diabetes insipidus, xanthelasma, interstitial lung disease, bilateral adrenal enlargement, retroperitoneal fibrosis (with perirenal and/or ureteral obstruction), renal impairment, testis infiltration, cardiovascular disorders, and CNS involvement.[7,8]
In fact, CNS involvement is frequent in ECD, reported in 30% to 50% of cases.[9,16,17] On 27 patients with ECD, diencephalic involvement was found in 23 patients, cerebellar involvement in 11 patients, and meningeal involvement in 9 patients. In 2006, in the largest review of medical literature (66 patients), the most frequent neurological manifestations were cerebellar (41%) and pyramidal (45%) signs, the other features being seizures, headaches, neuropsychiatric manifestations or cognitive impairment, sensory disturbances, and cranial nerve paralysis. In addition, systematic cranial MRI in 33 patients with ECD was normal in only 3 of them: most patients have 2 or more anatomical sites affected (hypothalamic-pituitary axis, brain, meninges, facial and skull bones, and orbits), even if they were asymptomatic. These neurological involvements lead to severe functional disability in almost all patients, and CNS involvement appears to be a major prognostic factor for ECD.
Among these neurological manifestations, strokes are of rare occurrence, reported in only 1% of cases. With our patient, we have found only 8 observations of cerebrovascular disorder in ECD (Table 1).[10–14,20,21] We have secondarily excluded the observation of Black et al because the patient also suffered from a familial hemiplegic migraine (probably the cause of the neurological deficit). Choi et al and Gauvrit et al reported transient ischemic attack; for the 5 other patients, the diagnosis of ECD was established after the diagnosis of stroke. However, three of these 5 observations are questionable. In the case of Amezyane et al a focal stroke was discovered on brain MRI, but was probably asymptomatic and did not explain the neurological deficit (due to a brain pseudonodular lesion of ECD); in the case of Mergancova et al, there were incomplete criteria of ECD; finally, Mélé et al described a patient with mixed histiocytosis (with both Langerhans and non-Langerhans forms in the same patient). Interestingly, in the other cases (as in the case of Mergancova et al), vascular involvement (periarterial infiltration and sometimes stenosis) was observed in the supra-aortic arteries, whereas patients had no cardiovascular risk factors. However, in the radiological series of Drier et al, if 3 patients (on a total of 30) had such lesions, a stroke was observed in only one (corresponding to our patient). In patients with stroke/transient ischemic attack (Table 1), vascular involvement of other arteries was found in four patients (aorta in 4 cases, renal arteries in 2 cases, and coronary arteries in 1 case). This observation is consistent with other studies that found periaortic fibrosis in more than half of the patients with ECD (aorta branches and other arteries being affected in only one fifth of the patients). Nevertheless, if cardiovascular involvement (heart failure, renovascular hypertension, and pericarditis possibly leading to tamponade) are also quite frequent in ECD (found in a third of the patients), stroke are surprisingly unusual in this disease.
The pathophysiological processes explaining stroke in ECD are uncertain. Few patients have the classical cardiovascular risk factors: arterial hypertension in 2 patients, and type 2 diabetes mellitus in 2 patients. Even if a coincidence is not excluded, 1 evident explanation could be the periarterial infiltration of some supra-aortic arteries, such as in our patient.[10,12] It is probable that the slowness of the narrowing of the cerebral and/or cranial arteries could facilitate the adaptation of the blood circulation in the circle of Willis, except in some particular cases such as the severe stenosis of the basilar artery observed in our case. Finally, another explanation may be a decompensation of one of the potential cardiovascular involvements due to the disease (ECD can provoke renovascular hypertension or cardiopathy); our patient has renovascular hypertension but was treated by surgery 4 years earlier.
This wide clinical spectrum of ECD makes its management and treatment complicated. Many therapeutics have been tried in ECD (steroids, interferon-α, cladribine, recombinant human interleukin-1 receptor antagonist, tyrosine kinase inhibitors, bisphosphonates, and autologous hematopoietic stem cell transplantation), but interferon-α seems to be a more efficient means by improving survival in ECD patients.[18,23] Recently, it has been demonstrated that vemurafenib may be also an efficient treatment in BRAF-mutated histiocytosis. In our case (partially described in another study), it is interesting to highlight the clinical long-term improvement (and also the dramatic recanalization of the basilar artery) after treatment (confirming that stroke was a direct consequence of the infiltration of the basilar artery). Finally, it is of the utmost importance for internists, cardiologists, and neurologists to know that stroke is a treatable and potentially reversible complication of ECD, particularly in the case of periarterial stenosis of cerebral arteries (on brain imaging) with contrast enhancement on 18FDG PET.
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Keywords:Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
basilar; Erdheim–Chester disease; histiocytosis; infiltration; stroke