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Erdheim-Chester's Disease: A Case Report and Brief Literature Review

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A 63 year old Caucasian male with no significant PMH presented initially with several episodes of right-sided arm, leg and facial muscle weakness/stiffness and lack of coordination over the preceding 5 weeks.  Each episode lasted for about 30 seconds to 1 minute.  Patient¡¯s neurological exam was essentially normal, however MRI brain showed hyperintensities in the pons with extension to midbrain, and in bilateral medial temporal regions, most of which were contrast enhancing.  CSF studies were non-diagnostic with mild elevation in proteins (71) and no WBC.  Oligoclonal bands suggested non-specific inflammation, as clinical picture did not correlate with MS.  Patient then had two large volume lumbar punctures which were both negative for cytology, and EEG was negative for seizure.  The most likely diagnosis was felt to be primary CNS lymphoma vs. glioma, and it was decided that patient should be started on a trial of outpatient steroids and be followed with serial MRI¡¯s.  The patient was treated as an outpatient with decadron for less than one week and unfortunately he self-discontinued it due to "side effects" and was lost to follow up.     

Two years later the patient presented to neurology clinic with worsening double vision and left sided weakness, now requiring a cane to ambulate.  On exam he was found to have diplopia, dysmetria, ataxia and bilateral up-going toes.  He was admitted for one day to have further laboratory tests and repeat repeat brain MRI showed resolution of temporal enhancement, and improvement in brainstem hyperintensity with mild residual hyperintensity in the belly of the pons.  It was noted it would be unusual for lymphoma or glioma to regress, but that inflammatory lesions like sarcoid, or Behcet Syndrome could be a possibility.  PET scan showed uptake in the pons, at the level of C1 below the cerebellum, thorax uptake of lobar/lobular distribution in the right middle lobe and left lower lobe.  No tracer uptake was found in the brain.  Pt was discharged home and again lost to follow-up.

One year later the patient presented for the third time to neurology clinic with further functional decline over the preceding 6 months due to worsening left leg weakness, now requiring a walker and was only able to ambulate 20 feet.  The patient continued to have left hand clumsiness and diplopia, and had now developed dysphagia and dysarthria.  He had also had two recent falls which he felt to be due to weakness.  He denied loss of consciousness or head trauma.  He was unable to cook, required assistance to dress and bathe, and had not left his home in nearly one year. 

On admission, the patient was afebrile and normotensive, saturating at 97% on room air.  He appeared cachectic with very labile affect and markedly depressed mood.  Mini-mental exam was 30/30.  Speech was spontaneous, slow and dysarthric with comprehension intact.  Several small patches of brown crusted skin lesions were noted over his feet, ears and scalp.  Heart exam was normal.  Decreased bibasilar breath sounds (right worse than left) were heard over his lungs.  Abdomen was soft and benign with no hepatosplenomegaly or other masses noted.  There was no peripheral edema.  Neurological exam was remarkable for a number of abnormalities.  There was incomplete abduction on horizontal gaze to either side consistent with bilateral CN VI palsy.  Cranial Nerves were otherwise intact.  Motor exam revealed 5/5 strength of right upper extremities, 4/5 for right lower and left upper extremities, 3/5 for left hip flexion/knee extension and 2/5 for ankle extension.  No pronator drift or fasciculations were found.  Rapid Alternating Movements were symmetrical but slow in both hands.  Deep tendon reflexes were ¾ diffusely with sustained ankle clonus on left and a few beats on right.  Bilateral upgoing extensor responses were observed again.  Finger to nose and heel to shin tests showed dysmetria bilaterally.  Sensory was diffusely intact including proprioception.  No truncal ataxia was noted when the patient was sitting up, he refused gait testing due to imbalance.                            

The patient was again admitted and underwent extensive diagnostic workup.  Multiple subspecialty consult services were involved.  Routine labatory tests showed a mild anemia of chronic disease and low albumin (2.1).  Extensive serology tests were sent, including HIV, AFB, ACE, RPR, histoplasma Ag, CrAg, lyme screen, AFP, PSA, CEA, C-anca, P-anca, cryoglobulin, complements, RF, anti-dsDNA, anti-Hu/Ri, serum markers for brucellosis, proteus and salmonella.  ESR was mildly high (50) and CRP was markedly elevated (15), suggestive a systemic inflammatory process.  There were mildly elevated levels of serum cocci Ab, anti-Jo, anti-Sm, anti-Sm/RNP, anti-SSA, anti-SSB, anti-Scl-70.

Serial MRI brain over the next few months showed fluctuating enhancement in temporal lobes, persistent hyperintese lesion in the pons and cerebellar/pontine atrophy.  Repeat PET showed hypermetabolism in pons and lung unchanged and new uptake in the pituitary gland.  Chest CT showed right infrahilar irregular soft tissue abnormality measuring 7 x 4.5cm with collapse and infiltration of the RML and RLL, and infrahilar adenopathy.  It also showed sclerotic lesions in the sternum, T10 vertebral body and proximal humoral head.  Patient underwent thoracentesis with results revealing exudative effusion, with negative cytology for malignancy.  Subsequently he had bronchoscopy with biopsies which showed no evidence of granuloma or tumor.  A VATS procedure with multiple biopsies of the right middle lobe mass and pleura was performed next in an effort to provide a definitive diagnosis.  Pathology of these specimen showed ¡°marked fibroplasia, chronic inflammation, organizing pneumonia with sclerosis, aggregates of foamy histiocytes (postive for CD68), hyperplasia of mesothelial cells and type 2 pneumocytes.¡±  Pt underwent brain biopsy of his temporal lobe lesions which showed nonspecific gliosis, and bone marrow biopsy which was non-diagnostic.  Bone scan was done to follow up sclerotic bone lesions found on chest CT, showing diffuse uptake in the clavicles, humeri, proximal forearms, femurs and tibia/fibula, sternomanubrial, T10 ¡°suggestive of peripheral bone marrow expansion¡±.  Skeletal Survey was thus done which showed ¡°sclerosis of the diaphyses and metaphyses of bilateral femurs and humeri, with sparing of epiphyses, consistent with the diagnosis of Erdheim-Chester Disease¡±.

While hospitalized for workup patient continued to have progressive neurologic deterioration with worsening dysarthria and development of bilateral exophthalmos.  After the diagnosis of Erdheim-Chester Syndrome, he underwent a short steroid taper trial w/o improvement.  Due to pt¡¯s poor functional status, he was not felt to be a good candidate for interferon or chemo.  Moreover, patient himself declined interferon therapy.  He agreed to continued treatment with steroids (prednisone 1mg/kg/day) as an outpatient and was enrolled into a hospice program.  He continues to be followed by neurology service to periodically assess response to treatment (serial bone scan, skeletal films of long bones, neurologic assessment q2-3 months).    

Discussion:

Erdheim-Chester Disease (ECD) is a rare sporadic systemic histiocytic disease of unknown etiology.  176 cases have been reported in literature as of 2003 per one review.  First identified by William Chester in 1930, it primarily affects middle-aged and older adults.  The clinical picture runs the spectrum from asymptomatic or minimally symptomatic bone lesions to a severe multisystem disease which significantly reduces lifespan of the patients affected.  The prognosis depends largely on the extent of extraosseous disease with overall 3-year survival rate of 50% per some reports.  Mortality is usually from respiratory distress or cardiac failure. 

ECD predominantly involves the long bones of the extremities, thus it comes as no surprise that bone pain is the most common presenting symptom.  However in up to 50% of patients a variety of other tissues may be involved.  Such involvements have been observed and described in skin (xanthomas), retroorbital/periorbital tissues (exophthalmos), pituitary-hypothalamic axis (diabetes insipidus), heart, kidney, retroperitoneum, skeletal muscle and lung (pulmonary fibrosis).     

Histopathologically, ECD is characterized by a diffuse infiltration of the affected organs by lipid-laden histiocytes (sometimes referred to as xanthogranulomatous infiltration).  In fact, it used to be considered a variant of Langerhands cell histiocytosis (LCH), in particular it was thought to be similar to the subgroup of LCH known as Hand-Schuller Christian Disease (HSC).  However more recent evidence has shown that LCH and HSC are likely two separate identities.  In general, histiocytes are believed to derive from pluripotent stem cells in the bone marrow.  Under the influence of various cytokines (e.g., GM-CSF, TNF-a, IL¨C3, IL-4), these precursor cells can differentiate into specific groups of antigen-processing cells (histiocytes), some with phagocytic capabilities.  These include tissue macrophages, monocytes, dendritic cells, interdigitating reticulum cells, and Langerhans cells.  Each disease category in histiocytosis can be traced to reactive or neoplastic proliferation and disorder of cells in one of the above mentioned cell lineages.  The cells involved in ECD can be differentiated from those in LCH by immunohistological markers.  Specifically, ECD-afflicted histiocytes are CD68+ but negative for CD1a and S-100, while the opposite is true in LCH. 

Furthermore, it has been noted that ECD and HSC have a number of distinct epidemiological/radiological features.  Namely, ECD tends to affect an older patient population (age 21 to 77 with an average of 54) than HSC (the majority of patients are children, adolescent and young adults).  Lytic lesions predominate in HSC associated bone lesions, whereas mixed lytic/sclerotic lesions tend to occur in ECD.              

The diagnostic imaging study of choice is the skeletal survey, which exhibits a striking pattern of bilateral, symmetric, patchy sclerotic lesions of the metaphyses and diaphyses of long bones with epiphyseal sparing.  These changes are considered virtually pathoneomonic for ECD.  A bone scan in such patients would reveal increased tracer uptake in the corresponding areas, as was demonstrated in our case.

Pulmonary Involvement has been observed in approximately 20% of ECD patients with dyspnea as a frequent presenting feature among those affected.  Most patients are found to have diffuse interstitial infiltrates and pleural and/or interlobar septal thickening on imaging.  Histopathology of lung biopsy specimens show the typical accumulation of CD68+ histiocytes with variable amounts of fibrosis and variable lymphoplasmacytic infiltrate. 

CNS involvements in ECD have been well-documented in literature with Diabetes insipidus being the most frequent presenting sign.  There has been an interesting correlation between DI and orbital involvement in some cases, it has been postulated that there might be extension of the disease process from the orbit along the optic nerves and chiasm to the hypothalamic-pituitary axis.  Other CNS presentations include cerebellar symptoms and signs (most commonly gait ataxia), multiple sclerosis and spinal epidural and extradural masses.  Unilateral weakness as in our patient is atypical.  In most cases the evolution of the neurological symptoms and signs is slowly progressive.  Neurological problems may arise in isolation or in association with symptoms and signs of systemic disease.  CSF analysis is usually normal or shows small increases of protein, as is true in this case.  MRI often shows intense gadolinium enhancement which may persist for a prolonged period.  Extra-axial lesions often involve the dura over the convexities or along the falx, while intra-axial lesions usually involve the cerebellum and pons, rarely pituitary gland (even in those patients with clinical DI.  In our patient, DI was not observed, though PET imaging showed some involvement of the pituitary gland.

To date there has been no definitive treatment recognized for ECD.  Studies have been difficult to conduct due to the rarity of the disease and small patient sample sizes.  Various treatment modalities have been tried, mostly on patients with severe cases of systemic ECD, including corticosteroids, chemotherapy, radiation therapy, interferon and cyclosporine among others.  Steroid courses have so far demonstrated only transient clinical improvement.  Other the other hand,  radiation therapy has been shown efficacy mainly with bone lesions.               

References:

1.       Allen TC.  Pulmonary and Ophthalmic Involvement with Erdheim-Chester Disease: A Case Report and Review of the Literature.  Arch Pathol Lab Med 2004; 128: 1428-1431

 2.       Johnson MD, Aulino JP, JagasiaM, Mawn, LA.  Erdheim-Chester Disease Mimicking Multiple Meningiomas Syndrome.  Am J Neuroradiol 2004; 25: 134-137

 3.       Kenn W, Eck M, Allolio B, Jakob F, Illg A, Marx A, Mueller-Hermelink HK, Hahn D.  Erdheim-Chester disease: evidence of a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis.  Hum Pathol 2000; 31(6):734-9

 4.       Veyssier-Belot C, Cacoub P, Capparros-Lefebvre D, Wechsler J, Brun B, Remy M, Wallaert B, Petit H, Grimaldi A, Wechsler B, Godeau P.  Erdheim-Chester disease.  Clinical and radiologic characteristics of 59 Cases.  Medicine (Baltimore) 1996; 75(3): 157-69.

 5.       Wright RA, Hermann RC, Parisi JE.  Neurological manifestations of Erdheim-Chester disease.  J Neurol Neurosurg Psychiatry 1999; 66: 72-75

 


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