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Research Letters |

Research Letters FREE

John C. Moore, MD; Zuhair K. Ballas, MD
Arch Intern Med. 2009;169(2):199-205. doi:10.1001/archinternmed.2008.580.
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Published online

There is a broad differential to consider when evaluating a patient with angioedema, which can include capillary leak syndrome and lymphedema. Systemic capillary leak syndrome typically presents with hypotension, hemoconcentration, hypoalbuminemia, monoclonal gammopathy, and marked plasma leakage resulting in diffuse edema.1 Prophylactic treatment with terbutaline sulfate and theophylline has been found to be effective for the prevention of systemic capillary leak syndrome exacerbations.2

The other unusual consideration is lymphedema, which is notoriously resistant to therapy, and only supportive measures are available (physical therapy, external compression, and surgery). We describe herein a patient with lymphedema who benefited from treatment with theophylline and terbutaline.

A 53-year-old woman was referred for evaluation of recurrent angioedema that did not respond to several therapeutic modalities, including diuretics. Unusual features in her history included involvement of her abdominal wall and all 4 extremities with no pulmonary edema. Physical examination revealed nonpitting edema of her lower and upper extremities, as well as an indurated abdominal wall. Systemic capillary leak syndrome was considered in the differential diagnosis. Pending the outcome of her testing, the prophylactic regimen for idiopathic capillary leak syndrome was initiated: terbutaline sulfate, 5 mg 5 times daily, and theophylline, 200 mg twice daily.1 Evaluation included a normal C1 esterase inhibitor level; serum immunofixation electrophoresis showed a monoclonal IgGκ band (commonly seen in systemic capillary leak syndrome), which was eventually diagnosed as monoclonal gammopathy of unknown significance. Given the abnormal appearance of her abdominal wall, amyloidosis was considered. Results from a fine-needle aspiration were negative for amyloid. Findings from an abdominal wall punch biopsy were consistent with lymphedema, with scattered dilated capillary lymphatic spaces in the superficial and deep dermis. Evaluation for a cause of lymphedema included an evaluation for malignant neoplasms with a full-body computed tomographic scan showing axillary lymphadenopathy. An axillary lymph node biopsy specimen was negative for malignant cells. One week after the initiation of terbutaline and theophylline therapies, there was a marked improvement of her lymphedema. Her weight decreased by 14 kg after 10 months of treatment (Figure, A and B). There was a direct correlation identified between the dose of terbutaline and the degree of lymphedema. Attempts to wean the terbutaline from 5 tablets to less than 3 tablets daily resulted in increased edema and weight, which would resolve by resuming the higher dose (Figure, C).

Figure.

Clinical response to terbutaline sulfate and theophylline. A, The patient at presentation. B, The patient after several weeks of therapy. C, The patient's weight as a function of the terbutaline sulfate dose.

Graphic Jump Location

Lymphedema is caused by insufficient lymph transport owing to lymphatic hypoplasia, impaired lymphatic function, or obstruction of lymph flow.3 Increased lymphatic endothelial cell permeability is probably an important contributor. An increased cyclic adenosine monophosphate (cAMP) level is known to decrease endothelial cell permeability.4 Terbutaline increases cAMP level by stimulating adenyl cyclase.5 Theophylline increases intracellular cAMP by inhibiting phosphodiesterase.6 With both medications contributing to an increase in cAMP level, this likely resulted in decreased endothelial cell permeability. We propose the use of this therapeutic modality for patients with idiopathic lymphedema.

Correspondence: Dr Moore, Department of Internal Medicine, University of Iowa Hospitals and Clinics, C42/E-13, GH, 200 Hawkins Dr, Iowa City, IA 52242 (john-c-moore@uiowa.edu).

Author Contributions:Study concept and design: Moore and Ballas. Acquisition of data: Ballas. Analysis and interpretation of data: Ballas. Drafting of the manuscript: Moore. Ballas. Critical revision of the manuscript for important intellectual content: Ballas. Administrative, technical, and material support: Ballas. Study supervision: Ballas.

Financial Disclosure: None reported.

Previous Presentation: This study was presented as a poster at the 2007 American College of Allergy, Asthma & Immunology meeting, November 10-11, 2007; Dallas, Texas.

Dhir  VArya  VMalav  ICSuryanarayanan  BSGupta  RDey  AB Idiopathic systemic capillary leak syndrome(SCLS): case report and systematic review of cases reported in the last 16 years. Intern Med 2007;46 (12) 899- 904
PubMed Link to Article
Tahirkheli  NKGreipp  PR Treatment of the systemic capillary leak syndrome with terbutaline and theophylline: a case series. Ann Intern Med 1999;130 (11) 905- 909
PubMed
Cueni  LNDetmar  M New insights into the molecular control of the lymphatic vascular system and its role in the disease. J Invest Dermatol 2006;126 (10) 2167- 2177
PubMed Link to Article
Fischmeister  R Is cAMP good or bad? depends on where it's made. Circ Res 2006;98 (5) 582- 584
PubMed Link to Article
Brogden  RNSpeight  TMAvery  GS Terbutaline: a preliminary report of its pharmacological properties and therapeutic efficacy in asthma. Drugs 1973;6 (5) 324- 332
PubMed Link to Article
Vassallo  RLipsky  J Theophylline: recent advances in the understanding of its mode of action and uses in clinical practice. Mayo Clin Proc 1998;73 (4) 346- 354
PubMed Link to Article

Figures

Figure.

Clinical response to terbutaline sulfate and theophylline. A, The patient at presentation. B, The patient after several weeks of therapy. C, The patient's weight as a function of the terbutaline sulfate dose.

Graphic Jump Location

Tables

References

Dhir  VArya  VMalav  ICSuryanarayanan  BSGupta  RDey  AB Idiopathic systemic capillary leak syndrome(SCLS): case report and systematic review of cases reported in the last 16 years. Intern Med 2007;46 (12) 899- 904
PubMed Link to Article
Tahirkheli  NKGreipp  PR Treatment of the systemic capillary leak syndrome with terbutaline and theophylline: a case series. Ann Intern Med 1999;130 (11) 905- 909
PubMed
Cueni  LNDetmar  M New insights into the molecular control of the lymphatic vascular system and its role in the disease. J Invest Dermatol 2006;126 (10) 2167- 2177
PubMed Link to Article
Fischmeister  R Is cAMP good or bad? depends on where it's made. Circ Res 2006;98 (5) 582- 584
PubMed Link to Article
Brogden  RNSpeight  TMAvery  GS Terbutaline: a preliminary report of its pharmacological properties and therapeutic efficacy in asthma. Drugs 1973;6 (5) 324- 332
PubMed Link to Article
Vassallo  RLipsky  J Theophylline: recent advances in the understanding of its mode of action and uses in clinical practice. Mayo Clin Proc 1998;73 (4) 346- 354
PubMed Link to Article

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