0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Observation |

Cerebral Arteriolar Thromboembolism in Idiopathic Hypereosinophilic Syndrome FREE

Mikayel Grigoryan, MD; Scott D. Geisler, MD; Erik K. St. Louis, MD; Gary L. Baumbach, MD; Patricia H. Davis, MD
[+] Author Affiliations

Author Affiliations: Departments of Neurology (Drs Grigoryan, Geisler, St. Louis, and Davis), and Pathology (Dr Baumbach), University of Iowa Hospitals and Clinics, Iowa City.


Arch Neurol. 2009;66(4):528-531. doi:10.1001/archneurol.2009.36.
Text Size: A A A
Published online

ABSTRACT

Objective  To describe imaging findings as well as postmortem brain and cardiac pathology in a patient with fulminant idiopathic hypereosinophilic syndrome.

Design  Case report.

Setting  University hospital.

Patient  A 48-year-old right-handed man with hypereosinophilia, rapidly progressive encephalopathy, and focal neurological deficits who died 22 days after presentation.

Main Outcome Measures  Physical examination, radiologic, and neuropathologic examination results.

Results  Imaging of the brain revealed bihemispheric ischemic changes in and beyond the watershed distributions. Pathology review demonstrated mural cardiac thrombus that likely caused cardioembolism as well as diffuse microangiopathy despite resolution of the hypereosinophilia.

Conclusions  Timely recognition of idiopathic hypereosinophilic syndrome may enable aggressive treatment prior to widespread cardioembolism and degranulation that result in devastating cerebrovascular complications.

Figures in this Article

Idiopathic hypereosinophilic syndrome (IHES) is characterized by a persistent eosinophilia greater than 1500/μL (to convert to ×109/L, multiply by 0.001) for more than 6 months, causing systemic dysfunction of multiple organs without evidence of associated allergic reactions, parasitic infections, connective tissue diseases, or malignancies.1 Neurologic involvement is common in IHES.2 Moore et al3 documented neurologic dysfunction in 65% of their 52 patients with IHES. Of these, 50% had peripheral neuropathy, 12% had cerebrovascular ischemia, and 10% had encephalopathy. We report postmortem brain and cardiac pathology from a patient with a rapidly progressive encephalopathy due to IHES.

REPORT OF A CASE

A 48-year-old right-handed man with a history of hypertension and obesity presented to his primary care physician with a 5-month history of an unintentional 60-pound weight loss and a 5-day history of distal lower extremity paresthesias and fatigue. His fasting blood glucose concentration was 388 mg/dL (to convert to millimoles per liter, multiply by 0.0555). He was treated with glyburide. The next day, the patient had brief episodes of disorientation and unsteadiness and was admitted to another hospital. Neurological and general medical examination results were normal. Laboratory testing demonstrated a white blood cell count of 17 900/μL with hypereosinophilia of 4100/μL (normal range, 0-200/μL), or 23% of all white blood cells. Head computed tomography (CT) showed an old left internal capsule lacunar infarct.

On the third day following presentation, the patient became more somnolent and disoriented and developed left-sided hemiparesis and hemispatial neglect. Results of a repeated head CT were unchanged. An electroencephalogram demonstrated mild generalized background slowing without epileptiform activity. Carotid duplex study results were unremarkable.

The next day, the patient developed dysarthria and right hemiparesis. Another head CT showed new ischemic changes in the centrum semiovale. He was transferred to our hospital.

On admission, the patient was somnolent and could not follow commands. No cranial nerve deficits were noted. Motor examination showed diffuse hypotonia and weakness, worse in the arms. Muscle stretch reflexes were normal in the upper extremities and reduced in the legs with bilateral extensor plantar signs.

Hematologic studies showed persistent leukocytosis and eosinophilia (peaking at 5700/μL). Troponin I and creatine kinase–MB concentrations were significantly elevated. The patient's erythrocyte sedimentation rate was 58 mm/h (normal, 0-15 mm/h) and C-reactive protein concentration was 9.3 mg/L (normal, <0.5 mg/dL) (to convert to nanomoles per liter, multiply by 9.524). Liver enzyme levels were moderately abnormal. Hemoglobin A1C was 8.2% (normal, 4.8%-6.0%). Abnormal indices of immune function included an IgE concentration of 3168 μg/L (normal, 0-1500 μg/L) (to convert to milligrams per liter, multiply by 0.001), an IL-4 (interleukin 4) count of 4000 (normal, 0), and an IL-5 (interleukin 5) count of 250 (normal, 0). A peripheral blood smear demonstrated increased eosinophils with rare immature and partially degranulated forms. Results of other tests, including those for cytoplasmic antineutrophilic cytoplasmic antibody, perinuclear antineutrophil cytoplasmic antibodies, IgG, thyroid-stimulating hormone, free T4, free T3, and rheumatoid factor, were normal.

Contrast-enhanced magnetic resonance imaging revealed ischemic changes in and beyond the watershed distributions (Figure 1). Catheter cerebral angiography results were normal. A head CT performed 3 days after magnetic resonance imaging showed new lesions outside of the watershed distribution.

Place holder to copy figure label and caption
Figure 1.

Diffusion-weighted magnetic resonance imaging showing multiple bilateral ischemic lesions both in and beyond the watershed zones.

Graphic Jump Location

On cardiac evaluation, an electrocardiogram showed sinus tachycardia with diffuse anterolateral ST segment depression. A transesophageal echocardiogram demonstrated mild left ventricular dysfunction (ejection fraction, 40%) with segmental inferior and posterior hypokinesis and biventricular enlargement, without evidence of cardiac or aortic mural thrombus or vegetations.

Cerebrospinal fluid analysis demonstrated an elevated protein concentration (138 mg/dL; normal range, 15-45 mg/dL) with a normal cell count and glucose concentration. Bacterial, fungal, and acid-fast bacilli cultures and cryptococcal antigen analysis results were negative. Electromyography documented an axonal polyneuropathy with acute denervation of the patient's distal leg muscles.

Bone marrow aspirate revealed hypercellular marrow and marked eosinophilia (30%) without evidence of clonality or karyotypic abnormalities. Results of CT of the chest, abdomen, and pelvis and cultures of blood and stool were normal.

Treatment with intravenous methylprednisolone was initiated. The patient's eosinophil count normalized within a day while his troponin I concentrations decreased but remained mildly elevated. Despite 12 days of treatment, the patient remained unresponsive and quadraparetic. He received palliative care and died 22 days following presentation.

The autopsy was limited to the brain and heart. Multifocal subcortical regional softening and hemosiderin staining were seen in the frontal, parietal, and left temporal lobes. On microscopic examination (Figure 2), there were multifocal small-vessel ischemic infarctions of varying ages with fibrin and platelet occlusion of small-caliber arterioles. No intravascular eosinophils or parenchymal eosinophilic infiltrates were noted.

Place holder to copy figure label and caption
Figure 2.

Low-magnification (A) and high-magnification (B) photomicrographs of an infarct in cerebral white matter. Several small arterioles contain fibrin and platelets.

Graphic Jump Location

Examination of the heart showed multifocal myocardial infarction of the anterior and posterior ventricles and septum. Careful gross inspection of the endocardium revealed no lesions. However, several organizing thrombi on the endocardial surface were identified in microscopic sections (Figure 3). In addition, several small arterioles were occluded with platelets. No eosinophilic infiltrates were seen.

Place holder to copy figure label and caption
Figure 3.

Low-magnification (A) and high-magnification (B) photomicrographs of an organizing thrombus on the endocardial surface.

Graphic Jump Location

COMMENT

To our knowledge, there are only 3 previous reports of brain pathology in IHES. Surgical biopsy findings from 1 patient demonstrated infarction with abundant intravascular eosinophils.4 Autopsy cases have shown acute and chronic ischemic brain lesions in borderzone areas as well as endocardial fibrosis and a mural thrombus in the left ventricle, suggesting cardioembolism as an etiology of cerebrovascular complications.5,6

Pathologic investigation in our patient demonstrated endocardial mural thrombosis that was only identified after a careful review of microscopic sections; it was not detected by echocardiography or gross visualization of the heart in the autopsy. This endocardial mural thrombosis was likely the etiology of the borderzone infarctions identified early on; however, multiple lesions, identified by repeated CT, were outside the watershed distribution. Pathologic examination of the vessels did not reveal whether the endothelial changes were due to in situ thrombosis or tiny emboli. There were no intraluminal or parenchymal eosinophils in the brain or heart. Furthermore, the patient failed to improve clinically despite normalized eosinophil counts following immunosuppressive treatment, implying that steroids were given at a time when damage may not have been reversible. This suggests that cerebrovascular endothelial injury and neurotoxicity from eosinophilic degranulation could also have directly contributed to the encephalopathy in our patient. With this mechanism of clinical deterioration, antithrombotic therapy could be considered in similar cases in the future.

The characteristic manifestations of cerebral eosinophilic neurotoxicity were initially described as the Gordon phenomenon from intraventricular injection of Hodgkin disease aspirates into rabbit cerebrospinal fluid. Eosinophil-derived neurotoxin, a ribonuclease, was later identified as the primary mediator.2 Two eosinophil ribonucleases with deleterious effects on axons have been identified: major basic protein and eosinophilic cationic protein. Major basic protein toxicity is nonspecific and damages multiple cell types and organs.7 Intravascular release of major basic protein damages endothelial cells, causing thrombosis and embolic infarctions.2 Eosinophilic cationic protein has been shown to be responsible for a hypercoagulable state, which may further potentiate thromboembolic phenomena.7 Endothelial damage in peripheral nerves causes edema and axon loss.7

The etiology of IHES has not been elucidated. Interleukin 5, which has a selective role in eosinophil maturation, differentiation, mobilization, activation, and survival, appears to contribute to the pathogenesis of some phenotypes of the IHES,8 thus making its inhibition a logical therapeutic target.9,10 Recently, a randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of an anti–IL-5 monoclonal antibody enabling clinically significant corticosteroid-sparing in patients with IHES.11 Complete hematological and cytogenetic remission with interferon alpha treatment has also been reported, further supporting an immune-mediated pathogenesis for IHES.12

Cardiac and neurologic complications may be fulminant in IHES. The pathology in our patient demonstrated mural cardiac thrombus that likely caused cardioembolism as well as diffuse microangiopathy despite resolution of the hypereosinophilia. Prompt recognition of IHES may enable physicians to provide 2 aggressive treatments prior to widespread cardioembolism, which could result in irreversible cerebrovascular complications.

ARTICLE INFORMATION

Correspondence: Mikayel Grigoryan, MD, Department of Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242 (mikayel-grigoryan@uiowa.edu).

Accepted for Publication: December 8, 2008.

Author Contributions:Study concept and design: Grigoryan, Geisler, St. Louis, and Davis. Acquisition of data: Grigoryan, Geisler, St. Louis, and Baumbach. Analysis and interpretation of data: Grigoryan, Geisler, St. Louis, Baumbach, and Davis. Drafting of the manuscript: Grigoryan, Geisler, and St. Louis. Critical revision of the manuscript for important intellectual content: Grigoryan, Geisler, St. Louis, Baumbach, and Davis. Administrative, technical, and material support: Grigoryan, Geisler, St. Louis, and Baumbach. Study supervision: Davis.

Financial Disclosure: None reported.

REFERENCES

Chusid  MJDale  DCWest  BCWolff  SM The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975;54 (1) 1- 27
PubMed
Fauci  ASHarley  JBRoberts  WCFerrans  VJGralnick  HRBjornson  BH NIH conference: the idiopathic hypereosinophilic syndrome: clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 1982;97 (1) 78- 92
PubMed
Moore  PMHarley  JBFauci  AS Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Ann Intern Med 1985;102 (1) 109- 114
PubMed
Kwon  SUKim  JCKim  JS Sequential magnetic resonance imaging findings in hypereosinophilia-induced encephalopathy. J Neurol 2001;248 (4) 279- 284
PubMed
Volle  ESarazin  MBaudrimont  et al.  Hypereosinophilia and multiple embolic brain infarctions in the distal fields in idiopathic hypereosinophilic syndrome and Schistosoma Mansoni infestation [abstract]. Neurology 1999;52S2A285
Sarazin  MCuames  ECohen  AAmarenco  P Multiple microembolic borderzone brain infarctions and endomyocardial fibrosis in idiopathic hypereosinophilic syndrome and in Schistosoma mansoni infestation. J Neurol Neurosurg Psychiatry 2004;75 (2) 305- 307
PubMed
Monaco  SLucci  BLaperchia  N  et al.  Polyneuropathy in hypereosinophilic syndrome. Neurology 1988;38 (3) 494- 496
PubMed
Simon  HUPlotz  SGDummer  RBlaser  K Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. N Engl J Med 1999;341 (15) 1112- 1120
PubMed
Simon  HU The neutralization of interleukin-5 as a therapeutic concept in allergic inflammation. Sarcoidosis Vasc Diffuse Lung Dis 2002;19 (1) 25- 28
PubMed
Foster  PSHogan  SPYang  M  et al.  Interleukin-5 and eosinophils as therapeutic targets for asthma. Trends Mol Med 2002;8 (4) 162- 167
PubMed
Rothenberg  MEKlion  ARoufosse  ME  et al. Mepolizumab HES Study Group, Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med 2008;358 (12) 1215- 1228
PubMed
Malbrain  MLVan den Bergh  HZachee  P Further evidence for the clonal nature of the idiopathic hypereosinophilic syndrome: complete haematological and cytogenetic remission induced by interferon-alpha in a case with a unique chromosomal abnormality. Br J Haematol 1996;92 (1) 176- 183
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Diffusion-weighted magnetic resonance imaging showing multiple bilateral ischemic lesions both in and beyond the watershed zones.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Low-magnification (A) and high-magnification (B) photomicrographs of an infarct in cerebral white matter. Several small arterioles contain fibrin and platelets.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Low-magnification (A) and high-magnification (B) photomicrographs of an organizing thrombus on the endocardial surface.

Graphic Jump Location

Tables

References

Chusid  MJDale  DCWest  BCWolff  SM The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975;54 (1) 1- 27
PubMed
Fauci  ASHarley  JBRoberts  WCFerrans  VJGralnick  HRBjornson  BH NIH conference: the idiopathic hypereosinophilic syndrome: clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 1982;97 (1) 78- 92
PubMed
Moore  PMHarley  JBFauci  AS Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Ann Intern Med 1985;102 (1) 109- 114
PubMed
Kwon  SUKim  JCKim  JS Sequential magnetic resonance imaging findings in hypereosinophilia-induced encephalopathy. J Neurol 2001;248 (4) 279- 284
PubMed
Volle  ESarazin  MBaudrimont  et al.  Hypereosinophilia and multiple embolic brain infarctions in the distal fields in idiopathic hypereosinophilic syndrome and Schistosoma Mansoni infestation [abstract]. Neurology 1999;52S2A285
Sarazin  MCuames  ECohen  AAmarenco  P Multiple microembolic borderzone brain infarctions and endomyocardial fibrosis in idiopathic hypereosinophilic syndrome and in Schistosoma mansoni infestation. J Neurol Neurosurg Psychiatry 2004;75 (2) 305- 307
PubMed
Monaco  SLucci  BLaperchia  N  et al.  Polyneuropathy in hypereosinophilic syndrome. Neurology 1988;38 (3) 494- 496
PubMed
Simon  HUPlotz  SGDummer  RBlaser  K Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. N Engl J Med 1999;341 (15) 1112- 1120
PubMed
Simon  HU The neutralization of interleukin-5 as a therapeutic concept in allergic inflammation. Sarcoidosis Vasc Diffuse Lung Dis 2002;19 (1) 25- 28
PubMed
Foster  PSHogan  SPYang  M  et al.  Interleukin-5 and eosinophils as therapeutic targets for asthma. Trends Mol Med 2002;8 (4) 162- 167
PubMed
Rothenberg  MEKlion  ARoufosse  ME  et al. Mepolizumab HES Study Group, Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med 2008;358 (12) 1215- 1228
PubMed
Malbrain  MLVan den Bergh  HZachee  P Further evidence for the clonal nature of the idiopathic hypereosinophilic syndrome: complete haematological and cytogenetic remission induced by interferon-alpha in a case with a unique chromosomal abnormality. Br J Haematol 1996;92 (1) 176- 183
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
JAMAevidence.com

Users' Guides to the Medical Literature
Thromboembolism or Acute Pulmonary Embolism