What you should know about edema

American Family Physician

June 1, 2005

What is edema?

Edema (say: eh-DEE-mah) is swelling or puffiness of parts of the body. Edema usually happens in the feet, ankles, and legs. It also can affect the face and hands. Pregnant women and elderly people often get edema, but it can happen to anyone.

What causes edema?

Edema happens when water gets trapped in the tissues in your body. Many things can cause this to happen. Sometimes gravity pulls water down into your legs and feet. Sitting in one place for too long can cause edema of the legs. Eating food with too much salt can make the problem worse.

Congestive heart failure and liver, kidney, and thyroid diseases can cause edema. You cannot catch edema from other people. It does not run in families.

How do I know if I have edema?

Your doctor can tell by examining you whether you have edema. The skin over the swollen area may be stretched and shiny. Pushing gently on the swollen area for about 15 seconds will leave a dimple. If this happens, your doctor might want to do tests to see what is causing the edema.

What can I do to treat my edema?

Edema cannot be "cured." The only way to treat edema is to treat the condition that is causing it. But there are some things you can do to keep the swelling down. Put a pillow under your legs when you are lying down. Wear support stockings, which you can buy at most drugstores. Support stockings put pressure on your legs and keep water from collecting in your legs and ankles. Do not sit or stand for too long without moving. Follow your doctor's orders about limiting how much salt you eat. Your doctor might want you to take a medicine called a diuretic (say: di-yoo-RET-tik, also called a water pill).

It is important to see your doctor if you have edema. If it is not treated, your skin may keep stretching, which can lead to other problems. If you are pregnant and you notice edema, see your doctor as soon as you can. See your doctor right away if you start to have trouble breathing.

COPYRIGHT 2005 American Academy of Family Physicians

Diabetic Macular Edema trial with Retisert; Positive Results for pSivida

2/21/2006 12:47:40 PM

Diabetic Macular Edema trial with Retisert; Positive Results for pSivida

Global bio-nanotech company pSivida Limited today announced the publication of preliminary three year follow-up data from Bausch and Lomb's multi-center, randomized, controlled clinical trial of Retisert for the treatment of diabetic macular edema (DME). Global eye health company, Bausch and Lomb, exclusive licensee of Retisert from pSivida, conducted the study in hospitals in the United States in which 197 patients were randomized to receive either standard of care (repeat laser or observation) or a Retisert implant. The study concluded that significantly more patients receiving a Retisert implant had improved visual acuity (of three or more lines on an eye chart) than those receiving standard of care.

DME, a common complication of Diabetic Retinopathy (DR), is the leading cause of vision loss in people under the age of 65 in the United States with an estimated 500,000 treatable cases. DME is characterized by swelling of the retina and loss of vision. Currently the only FDA approved treatment is laser therapy in which holes are burned into the macula with a laser. This treatment is often ineffective or generally provides only temporary benefit. There are no approved drug therapies for the treatment of either DME or DR. Retisert for DME is surgically implanted into the eye and releases a constant amount of the drug, fluocinolone acetonide. Retisert is FDA approved for the treatment of posterior uveitis with a duration of 30 months and is licensed to Bausch & Lomb and co-promoted by Novartis.

Medidur is pSivida's next generation product. It is a tiny, injectable device that can release the same drug as Retisert. Unlike Retisert, which is surgically implanted, Medidur is injected into the eye during an office visit. Medidur is in Phase III clinical trials in DME in collaboration with Alimera Sciences Inc., a specialty pharmaceutical company focused on the ophthalmic industry.
"As Retisert and Medidur can deliver the same drug, at a similar rate, to the back of the eye, we hope the Medidur trials in DME show a very similar improvement in visual acuity to that shown in the Retisert DME trial. Medidur differs from Retisert in that it is a smaller device that can be inserted without the need for surgery," said Mr Gavin Rezos, CEO of pSivida Limited.

Results of the Bausch & Lomb study has shown that a statistically significant number of eyes treated with Retisert had an improvement of visual acuity of three or more lines on an eye chart compared to eyes receiving standard of care (28% versus 15%, p less than 0.05). Additionally, a statistically significant number of eyes treated with Retisert showed an improvement in their diabetic retinopathy severity score, a measure of the severity of their disease (13% versus 4% p less than 0.001). More eyes receiving Retisert also showed a reduction in their edema and there was also no evidence of edema in 58% of eyes receiving the implant versus 30% of eyes receiving standard of care (p less than 0.001).

Side-effects of Retisert in patients with DME were similar to those reported in patients with uveitis for which Retisert is approved. Of the patients with DME receiving Retisert, at three years 33% required an operation to relieve elevated intraocular pressure (IOP) and 95% required cataract surgery. Cataract surgery is a relatively uncomplicated and established procedure with a high success rate. The abstract (#5442) detailing the DME data is available on the website of the Association for Research in Vision and Ophthalmology http://www.arvo.org. The three year uveitis data is available at the same website (abstract #1523). Fuller data will be presented at the ARVO conference in May 2006.

pSivida receives royalties from sales of Retisert for chronic non-infectious posterior segment uveitis, a sight threatening condition that affects an estimated 175,000 people in the United States and an estimated 800,000 people worldwide. The product is presently priced at US$18,250 and is approved as a 30 month treatment. Covered in the United States by Medicare and Medicaid, Retisert is co-marketed in the United States by Bausch & Lomb and Novartis. In the event that Retisert is approved for DME and Bausch & Lomb decide to market Retisert for DME, then pSivida will receive royalty payments from Bausch & Lomb for Retisert sales for DME.

Article

Imaging of Cauda Equina Edema in Lumbar Canal Stenosis

American Journal of Neuroradiology 27:346-353, February 2006

Imaging of Cauda Equina Edema in Lumbar Canal Stenosis By Using Gadolinium-Enhanced MR Imaging: Experimental Constriction Injury S. Kobayashia, K. Uchidaa, K. Takenoa, H. Babaa, Y. Suzukib, K. Hayakawac and H. Yoshizawada

Department of Orthopaedics and Rehabilitation Medicine, Fukui University School of Medicine, Matsuoka, Fukui, Japanb Suzuki Orthopaedic Clinic, Toki, Gifu, Japanc Department of Radiology and Orthopaedics, Aiko Orthopaedic Hospital, Midori, Aichi, Japand Department of Orthopaedics, Tachikawa Kyousai, Hospital Tachikawa, Tokyo, Japan

Address correspondence to Shigeru Kobayashi, MD, PhD, Department of Orthopaedics and Rehabilitation Medicine, Fukui University School of Medicine, Shimoaizuki 23, Matsuoka, Fukui, 910-1193, Japan

BACKGROUND AND PURPOSE: It has been reported that disturbance of blood flow arising from circumferential compression of the cauda equina by surrounding tissue plays a major role in the appearance of neurogenic intermittent claudication (NIC) associated with lumbar spinal canal stenosis (LSCS). We created a model of LSCS to clarify the mechanism of enhancement within the cauda equina on gadolinium-enhanced MR images from patients with LSCS.

METHODS: In 20 dogs, a lumbar laminectomy was performed by applying circumferential constriction to the cauda equina by using a silicon tube, to produce 30% stenosis of the circumferential diameter of the dural tube. After 1 and 3 weeks, gadolinium and Evans blue albumin were injected intravenously at the same time. The sections were used to investigate the status of the blood-nerve barrier function under a fluorescence microscope and we compared gadolinium-enhanced MR images with Evans blue albumin distribution in the nerve. The other sections were used for light and transmission electron microscopic study.

RESULTS: In this model, histologic examination showed congestion and dilation in many of the intraradicular veins, as well as inflammatory cell infiltration. The intraradicular edema caused by venous congestion and Wallerian degeneration can also occur at sites that are not subject to mechanical compression. Enhanced MR imaging showed enhancement of the cauda equina at the stenosed region, demonstrating the presence of edema.

CONCLUSION: Gadolinium-enhanced MR imaging may be a useful tool for the diagnosis of microcirculatory disorders of the cauda equina associated with LSCS.

Case Report: Optic Disc Edema without Hydrocephalus in Acoustic Neuroma

Skull Base. 2005 February; 15(1): 83–86.

doi: 10.1055/s-2005-868165.

Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Joseph Grainger, M.R.C.S.1 and Palitha S. Dias, F.R.C.S.1

1Department of Neurosurgery, University Hospital of North Staffordshire, Royal Infirmary, Stoke-on-Trent, Great Britain, United Kingdom

Address for correspondence and reprint requests: Palitha S. Dias F.R.C.S. Department of Neurosurgery, University Hospital of North Staffordshire, Royal Infirmary Princes Road, Hartshill, Stoke-on-Trent ST4 7LN, Great Britain, United Kingdom Palitha.Dias@uhns.nhs.uk

Abstract

Traditionally, visual disturbance and optic disc edema are regarded as late manifestations of acoustic neuromas indicating increased intracranial pressure as a result of obstructive hydrocephalus or a sizeable mass lesion. We report the case of a 56-year-old man who presented with visual disturbance and bilateral optic disc edema. Classic features of hydrocephalus were absent. Magnetic resonance imaging showed a large acoustic neuroma. However, there was no ventriculomegaly and at surgery intracranial pressure was normal. We suggest that cerebrospinal fluid protein may have a role in the formation of optic disc edema through a normal pressure communicating type of hydrocephalus. Furthermore, patients with acoustic neuromas and a visual disturbance related to optic disc edema may be inappropriate for treatment with stereotactic radiosurgery and should be offered early surgery to prevent visual deterioration.

Keywords: Acoustic neuroma, papilledema, hydrocephalus

Acoustic neuromas, also known as vestibular schwannomas, account for about 8% of intracranial tumors and are the most common lesion of the cerebellopontine angle.1

The presentation of an acoustic neuroma is related to the size of the lesion and the presence of an intrameatal component. However, hearing loss and tinnitus are by far the most common presenting symptoms, occurring in more than 95% and 63% of patients, respectively.1,2 Ophthalmic symptoms are less common, occurring in as many as 16% of patients, and include diplopia, blurring of vision, obscurations, and tunnel vision.1 Ophthalmic findings may be related to the effect of the expanding mass on adjacent cranial nerves or to increased intracranial pressure (ICP). They tend to occur with larger lesions. At presentation, optic disc edema may be present in as many as 8% of patients with acoustic neuromas.1 The edema is usually related to intracranial mass effect or compression of the fourth ventricle resulting in obstructive hydrocephalus. It is well recognized that untreated optic disc edema may cause deterioration of visual function.3,4 Therefore, the presence of optic disc edema has significant implications for management.

Over the past two decades, the management of acoustic neuromas has changed significantly with the introduction of stereotactic radiosurgical techniques. These procedures may be used in patients with normal ICP and offer high rates of tumor growth control often with regression.5 Open surgical techniques are favored in patients with increased ICP to provide rapid decompression.

We present the case of a patient who presented with visual disturbance and optic disc edema with no evidence of obstructive hydrocephalus or increased ICP.

Case Report

A 56-year-old man had a 6-month history of blurred vision. The blurred vision, which was worse in the left eye but affected both eyes, was increasing. Headache had been present initially but had gradually resolved. On further questioning he admitted that 4 months earlier he had become deaf in his left ear and since then had had tinnitus. When he noticed the tinnitus, he had experienced several episodes of dizziness and described symptoms of vertigo. However, these symptoms also had improved by the time he was examined. He had no nausea, vomiting, or incontinence and complained of no memory problems.

On examination he was alert and oriented. His visual acuity was 6/9 bilaterally. Fundoscopy revealed gross bilateral optic disc edema (Fig. 1). His visual field testing demonstrated enlarged blind spots. Sensation in the distribution of the left ophthalmic and maxillary divisions of the trigeminal nerve was reduced to light touch. The left corneal reflex was absent. The facial nerve was intact. Sensorineural deafness in the left ear was confirmed by pure tone audiometry. Hearing in the right ear was normal. His gag reflex was intact and he had no cerebellar signs. His gait was normal.

A supratentorial mass lesion was suspected. Computerized tomography revealed no mass lesion. The size of the ventricles was normal, but the fourth ventricle was shifted to the right (Fig. 2). Magnetic resonance imaging showed a large mass lesion at the left cerebellopontine angle entering the internal auditory meatus, consistent with a large acoustic neuroma. The mass had displaced the contents of the posterior fossa to the right, but again the size of the ventricle was normal (Fig. 3).

Management options were discussed with the patient. To prevent further visual deterioration, surgical excision was advised. He underwent posterior fossa craniectomy and excision of the mass lesion. Before the lesion was removed, an external ventricular drain and an ICP monitor were placed. Opening ICP was 14 cm H2O. Ventricular cerebrospinal fluid (CSF) protein concentration was 0.45 g/dL. CSF protein concentration from the basal cisterns was significantly raised at 4.05 g/dL.

Postoperatively, the patient had a facial nerve palsy. Follow-up at 3 months revealed no optic disc edema and the facial nerve was recovering. The patient was independent in his activities of daily living.

Discussion

Visual disturbance and optic disc edema are unusual presenting features of acoustic neuromas. They usually indicate increased ICP as a result of obstructive hydrocephalus or a sizeable mass lesion. In this case, however, optic disc edema was present even though these other findings were absent. The cause of optic disc edema in this case remains unclear. ICP recorded during surgery was normal. However, this finding does not exclude intermittently increased ICP as is thought to occur in normal pressure hydrocephalus.6 Normal pressure hydrocephalus typically causes gait ataxia, memory loss, and incontinence, but these findings were absent in this case. Furthermore, general anesthesia may have reduced the patient's ICP before it was measured.

Sporadic cases of optic disc edema in the absence of increased ICP have been reported in the world literature in patients with leukemia7 and iron-deficiency anemia.8 Local mechanisms have been proposed for these cases. In this case, a high protein concentration was found in the CSF around the neuroma. We suggest that this high protein concentration may have impaired reabsorption of CSF, albeit intermittently, resulting in a type of communicating hydrocephalus. This mechanism has been suggested to underlie increased ICP and normal pressure hydrocephalus associated with spinal cord schwannomas.9 Local protein concentrations were found to be high and symptoms resolved after excision of the lesion. Harada and colleagues10 reported optic disc edema without hydrocephalus in a patient with neurofibromatosis II and bilateral acoustic neuromas. They also suggested high protein concentration as a possible mechanism. In their case, however, CSF protein concentration was not measured.

In this case, early surgical decompression was favored to prevent optic atrophy from prolonged optic disc edema. We would advocate this approach in preference to stereotactic radiosurgery in patients with optic disc edema, even in the absence of evidence of increased ICP.

Commentary

Aiello, Peter (Private practice, Scottsdale, Arizona).

This interesting case suggests that papilledema may result from intracranial pathology provoking high cerebrospinal fluid (CSF) protein without the hallmark of increased intracranial pressure (ICP). The authors speculate that the increased CSF protein impaired reabsorption of CSF in their patient, causing communicating hydrocephalus that produced papilledema and visual deterioration.

Traditionally, disc edema with normal ICP has been associated with local ophthalmologic processes such as central vein obstruction, hypertension, optic neuritis, ischemic neuropathy, compressive neuropathy, scleritis, uveitis, diabetes, toxicity, or infection. Bilateral disc edema with increased ICP is characteristic of pathology beyond the optic nerve itself. The level of protein in this patient's CSF was quite high, a condition known to be caused by a variety of intracranial and intraspinal tumors. An increase in the level of protein in the CSF has been postulated to increase ICP by decreasing absorption of CSF by blocking all semipermeable membranes of the arachnoid granulations. This mechanism was described by Gardner and colleagues1 in 1954. Given this hypothesis, the absence of hydrocephalus in this patient indicates rather mild cerebral edema from the elevated CSF protein levels. Furthermore, all previous descriptions of the complications related to elevated CSF protein have included papilledema associated with increased ICP. This report now suggests the undescribed entity of papilledema associated with normal ICP.

The authors concede that the true opening pressure could have been lowered iatrogenically during general anesthesia. They also speculate that ICP might have been elevated intermittently as in normal pressure hydrocephalus. It is important to point out that disc edema may develop in a gradual, stepwise process that may proceed within a time frame of normal ICP. The authors also suggest that intermittent blockage of the fourth ventricle might have served as a mechanism for the stepwise development of papilledema without being associated with an obvious increase in ICP.

This patient's visual complaints, disc appearance, and ophthalmologic details were rather vague. The visual deterioration to 6/9 or 20/30 Snellen acuity is mild. Although patients with papilledema initially may have mild degrees of visual loss, the authors do not exclude simple refractive errors. The authors describe an enlarged blind spot but failed to investigate this visual field change with a more enlightening full-threshold static perimetry. Had this study been performed, it may have shown a defined scotomatous field defect rather than simple enlarged blind spots. Enlarged blind spots also can be associated with simple optic nerve drusen (congenital anomalous disc elevation), which can mimic disc edema. Furthermore, there is no mention that the visual field defects ever resolved after resection of the acoustic neuroma. Finally, the photographs of the optic nerve are not revealing enough to exclude the possibility of simultaneously present disc drusen. Intravenous fluorescein angiography would have been very useful to distinguish the perfusion patterns of drusen, papilledema, and inflammatory or infiltrative processes. Likewise, contrast sensitivity could have been useful to identify diseases that depress nerve conduction as opposed to nonpathologic anatomic variants with normal conduction.

Despite the limited ophthalmologic details, magnetic resonance imaging showed the large acoustic neuroma compressing the fourth ventricle, and the lesion was removed expeditiously.

This case is important because it highlights possible causes of disc edema associated with normal ICP other than local ophthalmologic processes. This is a unique departure from accepted thinking. Therefore, any patient with a swollen disc should be evaluated thoroughly. This evaluation should include comprehensive neuro-ophthalmologic investigations with full-threshold static perimetry. Although the demise of optic neurons with papilledema is a relatively slow process, space-occupying masses should be treated promptly to minimize optic nerve morbidity. When deciding to forego the use of stereotactic neurosurgical technology in lieu of more immediate surgical decompression, however, the physician should consider all variables, including the degree and duration of papilledema, level of surgical expertise, and finally, the availability of stereotactic technology, rather than the mere presence of disc edema itself.

References

Gardner W J, Spitler D K. Whitten C, Increased intracranial pressure caused by increased protein content in the cerebrospinal fluid; an explanation of papilledema in certain cases of small intracranial and intraspinal tumors, and in the Guillain-Barré syndrome. N Engl J Med. 1954;250:932–936. [PubMed]

Commentary

Newman, Steven A. (Department of Ophthalmology, University of Virginia Health System, Charlottesville, Virginia).

It isn't just roses that raise the issue of semantics. With the advent of the ophthalmoscope in 1851, the appearance of a swollen disc was initially referred to as “optic neuritis.” These early descriptions of optic neuritis included many cases undoubtedly related to intracranial mass lesions and therefore to increased intracranial pressure (ICP). It was not until 1908 that Parsons1 first used the term papilledema to refer to optic disc swelling associated with ICP. Despite this definition, there has been substantial confusion about the implications of papilledema ever since. It has been a problem, particularly because both inflammation (papillitis) and ischemia (anterior ischemic optic neuropathy) may appear identical to disc swelling from increased ICP. Local ocular problems, including vitreoretinal traction, hypotony, and intermediate uveitis (pars planitis), also may cause disc swelling that cannot immediately be distinguished from disc edema caused by increased ICP.

The authors present a single case report of a patient with an acoustic neuroma presenting with disc edema. As the authors point out, disc edema has potential implications for visual function. Patients with papilledema may have long-term disc swelling without progressive deterioration in central acuity. However, disc swelling from increased ICP will cause progressive optic nerve damage in a substantial portion of patients, as demonstrated by worsening arcuate visual field defects, the eventual loss of central visual function, decreased acuity, and optic atrophy. Such an outcome was demonstrated fairly dramatically in the case of pseudotumor cerebri or “benign increased intracranial pressure” when Corbett and associates2 reported a 70% incidence of optic nerve damage. From an ophthalmic perspective, it is therefore imperative that optic nerve function be assessed quantitatively in any patient with disc swelling. The assessment should include best corrected central acuity, quantitative perimetry (usually automated static perimetry), quantitation of afferent pupillary defect, and analysis of the nerve fiber layer. Although past authors have attempted to follow papilledema by measuring the size of the blind spot, this variable does not correlate with optic nerve function and therefore probably is not particularly helpful. Quantitative perimetry must be performed to quantitatively assess the level of optic nerve pathology. Only quantitative assessment can reveal the subtle changes that can indicate progressive damage.

In this particular case, the authors found no evidence of obstructive hydrocephalus, and reported that ICP was normal. Cerebellopontine angle tumors may increase ICP in several ways. They can block ventricular outflow from the fourth ventricle, resulting in hydrocephalus. They also can produce problems with cerebrospinal fluid (CSF) absorption from protein leaking into the CSF, causing an obstruction at the level of the pacchionian granulations. It is not surprising to find patients without evidence of ventriculomegaly who still have significant increased ICP. The lack of elevated pressure at surgery, however, does not preclude the possibility that patients still had increased ICP previously, even without ventriculomegaly. ICP can be quite variable, particularly in syndromes such as pseudotumor cerebri where intermittent plateau waves can cause disc swelling despite random measurements of normal pressure on spinal taps. As early as 1939, the following statement was made: “One determination of intracranial pressure in a case of disease of the central nervous system is no more instructive than one determination of a patient's temperature during the course of a fever.”3

I would agree with the authors that the most likely scenario was that elevated protein in the CSF related to their patient's acoustic neuroma was responsible for problems with CSF outflow and thus papilledema. I would suggest, however, that the only way that the elevated protein is going to cause papilledema is through increased ICP. Therefore, the term “normal pressure hydrocephalus” is inappropriate because pressure, by definition, is not elevated in normal pressure hydrocephalus and there is no evidence of disc edema. I further agree with the authors that in the setting of advanced optic nerve pathology, especially with evidence of progressive optic nerve damage, surgical excision offers a much more rapid way of normalizing ICP than treatment with the Gamma knife. The presence of papilledema alone, however, is not necessarily an indication for emergent surgery. Only evidence of progressive optic nerve damage (advancing visual field defects) would constitute a neuro-ophthalmic indication for urgent treatment. Clinical decisions on treatment modalities must include as much quantitative information about the clinical status of the patient as possible. Thus neuro-ophthalmological input can be exceedingly helpful in decision-making and management issues in similar cases.

References

Parsons, J H.; GP Putnam's Sons. New York, NY: 1908. The Pathology of the Eye, Vol. 4, Part 2. pp. 1349–1365.
Corbett J J, Savino P J. Thompson H S, et al. Visual loss in pseudotumor cerebri. Follow-up of 57 patients from 5 to 41 years and a profile of 14 patients with permanent severe visual loss. Arch Neurol. 1982;39:461–474. [PubMed]
Ford F R. Murphy E L, Increased intracranial pressure: clinical analysis of the causes and characteristics of several types. Bull Johns Hopkins Hosp. 1939;64:369–398.

Additional References

Meter, W S van.; Younge, B R.; Harner, S G.; Ophthalmic manifestations of acoustic neurinoma. Ophthalmology. 1983;90:917–922. [PubMed]
Matthies C, Samii M, Management of 1000 vestibular schwannomas (acoustic neuromas): clinical presentation. Neurosurgery. 1997;40:1–9. discussion 9–10. [PubMed]
Bouzas E A, Parry D M, Elridge R, et al. Visual impairment in patients with neurofibomatosis 2. Neurology. 1993;43:622–623. [PubMed]
Thomas D A, Trobe J D, Cornblath W T, et al. Visual loss secondary to raised intracranial pressure in neurofibromatosis type 2. Arch Ophthalmology. 1999;117:1650–1653.
Kondziolka D, Nathoo N, Flickinger J C, et al. Long-term results after radiosurgery for benign intracranial tumours. Neurosurgery. 2003;53:815–821. [PubMed] [Full Text]
Vanneste J A. Three decades of normal pressure hydrocephalus: are we wiser now? J Neurol Neurosurg Psychiatry. 1994;57:1021–1025. [PubMed]
Mayo G L, Carter J E. McKinnon S J, Bilateral optic disc edema and blindness as initial presentation of acute lymphocytic leukaemia. Am J Ophthalmol. 2002;134:141–142. [PubMed] [Full Text]
Forster H S. Optic disc edema due to iron deficiency. Conn Med. 1985;49:290–292. [PubMed]
Feldmann E, Bromfield E, Navia B, et al. Hydrocephalic dementia and spinal cord tumour: report of a case and review of the literature. Arch Neurol. 1986;43:714–718. [PubMed]
Harada T, Sawamura Y, Ohashi T, et al. Severe optic disc edema without hydrocephalus in neurofibromatosis 2. Jpn J Ophthalmol. 1998;42:381–384. [PubMed] [Full Text]
Article

Impact of edema on recovery after major abdominal surgery

Impact of oedema on recovery after major abdominal surgery and potential value of multifrequency bioimpedance measurements.

Itobi E, Stroud M, Elia M.

Department of Surgery, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.

BACKGROUND:

The consequences of generalized oedema following major abdominal surgery are under-recognized, and its causes are poorly understood.

METHODS:

Thirty-eight patients (21 men and 17 women) were observed for the occurrence of oedema after major abdominal surgery. Oedema formation was related to fluid balance, changes in whole-body bioimpedance (Z) measured at four frequencies (5, 50, 100 and 200 kHz), and clinical outcome.

RESULTS:

The 20 patients who developed oedema were older than those who did not (mean(s.d.) 73(9) versus 63(14) years; P = 0.007). Fluid intake over the first 5 days after surgery was similar in both groups, but those with oedema excreted less total fluid (16.9(2.4) versus 19.7(3.5) litres; P = 0.022). Oedema was associated with a delay in tolerating solid food (P = 0.001) and opening bowels (P = 0.020), a prolonged hospital stay (median 17 (range 8-59) versus 9 (range 4-27) days; P = 0.001) and more postoperative complications (13 of 20 versus four of 18 patients; P = 0.011). The preoperative ratio of whole-body impedance at 200 kHz to that at 5 kHz was higher in those who subsequently developed oedema (0.81(0.03) versus 0.78(0.02); P = 0.015).

CONCLUSION:

The development of oedema after major abdominal surgery is associated with increased morbidity. Age and reduced ability to excrete administered fluid load are significant aetiological factors and bioimpedance analysis can potentially identify patients at risk. Copyright (c) 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.PMID: 16463271

[PubMed - as supplied by publisher]

*** Editor's Note***

This is an interesting article because edema from abdominal surgeries has long been overlooked by the medical community. There is also a high risk of acquiring secondary lymphedema from the surgeries as well. As early as 1962, doctors from the Oregon Health Sciences University were reporting this.

Pedal Edema Associated with Clozapine Use

Rimona Durst MD1, Sergey Raskin MD1, Gregory Katz MD1, Josef Zislin1 and Ronen Durst MD2

1The Jerusalem Mental Health Center, Kfar Shaul Hospital (affiliated with Hebrew University Hadassah Medical School) and 2Department of Internal Medicine, Hadassah University Hospital, Jerusalem, Israel

Key words: clozapine, side effects, pedal edema

Clozapine, widely recognized as an efficient agent for treating nonremittent schizophrenic patients, is associated with well-established adverse effects such as sedation, weight gain, sialorrhea, palpitations, seizures, and agranulocytosis. We report a case in which an additional possible negative side effect of clozapine was observed, namely pedal edema.

Case Description

This 24-year-old patient was known to suffer from schizophrenia for 6 years. Previous treatment by a variety of neuroleptics (including mood stabilizers) failed to produce longterm amelioration. In view of her frequent relapses, it was decided to initiate clozapine treatment as a sole anti-psychotic agent while maintaining her long-term valproic acid treatment. Clozapine was gradually increased to 400 mg/day with satisfactory results. However, 6 weeks after the commencement, the patient began to show signs of pedal edema and peri-orbital puffiness. No polydipsia was apparent.

Physical examination revealed no other abnormal signs. Albumin blood level, and thyroid and liver function tests indicated normal levels. No proteinuria was detected. Other laboratory tests including electrolytes yielded normal results, except for eosinophilia. Echocardiogram showed normal systolic and diastolic functions.

In view of the apparent association between the development of the edema and the initiation of clozapine, the clozapine dosage was reduced to 200 mg/day over a period of 10 days. Parallel to clozapine diminution, eosinophilia subsided and the pedal edema gradually diminished.

Comment

There have been reports of an association between clozapine and a host of
general medical conditions. These include: de novo onset or exacerbation
of preexisting diabetes mellitus, paradoxical hypertension, lactic acidosis
with fatal myocardial failure, acute pancreatitis [1], and pheochromocytoma-
like syndrome suggesting clozapine-induced sympathetic hyperactivity [2]. Eosinophilia has been attributed to clozapine treatment but whether it can serve as a reliable predictor for neutropenia — the main hazardous side effect of clozapine — remains controversial [3].

The attribution of the onset of pedal edema to clozapine treatment in our patient seems to be substantiated by the gradual development of the edema parallel to the initiation of the clozapine treatment, peaking after 6 weeks at 400 mg/day. Diminution of the dosage to 200 mg/day for 10 days led to the gradual disappearance of the edema. Although this may have been
purely coincidental, association between the two is indicated. The
possibility of water dysregulation — also known as the syndrome of psychosis,
intermittent hyponatremia, and polydipsia — is doubtful due to the absence of polydipsia or hyponatremia in the patient.

Moreover, clozapine has been shown to be effective for both the polydipsia and sodium dysregulation associated with water dysregulation syndrome [4]. Lack of any other explanation for the edema, as well as its resolution following dosage diminution supports our hypothesis that the edema was drug induced.

Although the possibility of clozapine-induced angio-edema is supported by the eosinophilia, the dose-related effects suggest otherwise. Clozapine affinity is mainly related to dopamine D1, D2 (relatively weak) and D4, 5HT2, α1 and α2, muscarine and histamine H1 receptors. Thus, the edema may reflect an antagonistic effect of clozapine on renal dopamine receptor type 4 (D4). This receptor, activated by dopamine and the sympathetic system, has natriuretic and diuretic effects. Clozapine has been shown to block this effect in animals [5]. The dose-related edema in this case could be attributed to increased blockage of the D4 receptor, the reduced natriuresis becoming clinically significant at high dosage levels.

A Medline search through January 2000 did not reveal similar cases of clozapine-associated pedal edema. It may be too early to determine whether the edema in this case is exclusively attributable to the clozapine treatment. However, pending further information regarding this side effect and its underlying mechanism, we feel that it is important that clinicians be alerted to the possibility of such a phenomenon.

References

1. Martin A. Acute pancreatitis associated with
clozapine use [Letter]. Am J Psychiatry 1997;
149: 714.
2. Li JK, Yeung VT, Leung CM, Chow CC, Ko
GT, So WY, Cockram CS. Clozapine: a mimicry
of phaeochromacytoma. Aust N Z J
Psychiatry 1997;31: 889–91.
3. Ames D, Wirshing WC, Baker RW, Umbricht
DS, Sun AB, Carter J, Schooler NR, Kane JM,
Marder SR. Predictive value of eosinophilia for
neutropenia during clozapine treatment. J Clin
Psychiatry 1996;57:579–81.
4. Spears NM, Leadbetter RA, Shutty MS JR.
Influence of clozapine on water dysregulation.
Am J Psychiatry 1993;150:9.
5. Sun D, Schafer JA. Dopamine inhibits AVPdependent
Na+ transport and water permeability
in rat CCD via a D4-like receptor. Am J
Physiol 1996;271:391–400.

Correspondence: Dr. R. Durst, Jerusalem
Mental Health Center, Kfar Shaul Hospital,
Jerusalem 91060, Israel. Tel: (972-2) 655
1559; Fax: (972-2) 642 6057; email:
rimona@isdn.net.il

Chaperone selection
Secretory and plasma membrane proteins begin their life
with co-translational translocation into the endoplasmic
reticulum (ER). Inside the ER, the correct folding of
newly synthesized proteins is assisted by a group of chaperone
molecules including binding protein (BiP) and the
lectins calnexin and calreticulin. Molinari and Helenius found
that chaperone selection occurs co-translationally and
describe some of the criteria that select for a particular
chaperone. The position of carbohydrate chains in the
nascent chain of the protein diverted it from an interaction
with BiP to an interaction with calnexin and caireticulin.
Science 2000:288:331.

Isreali Medical Association

Angioedema and Complement 1 (C1) Inhibitor

Angioedema and Complement 1 (C1) Inhibitor

REFERENCE ABSTRACTS

* * * * * * *

Angioedema from angiotensin-converting enzyme (ACE) inhibitor treated with complement 1 (C1) inhibitor concentrate.

January 2006
Nielsen EW, Gramstad S.

Department of Anesthesiology, Nordland Hospital and University of Tromso, Tromso, Norway.

Background:

Up to seven in every 1000 patients experience angioedema from angiotensin-converting enzyme (ACE) inhibitors, even after many years of use. In 2003, every 20th Norwegian used an ACE inhibitor.

Case report:

A 61-year-old woman with chronic obstructive pulmonary disease and a past acute myocardial infarction had used 7.5 mg of ramipril daily for the past 7 years. She also used acetylsalicylic acid, simvastatin, theophylline and salmeterol. One night she woke up with edema of the tongue. On hospital arrival, 250 mg of hydrocortisone and 5 mg of dexchlorpheniramine were given intravenously (i.v.) and 0.3 mg of epinephrine was given subcutaneously (s.c.). The edema of the tongue progressed over the next 8 h and made the tongue protrude. Fiberscopy revealed glassy edema of the arytenoids. Inspiratory stridor was heard and the patient could not speak. She became increasingly uneasy and restless. Berinert((R)) complement 1 (C1) inhibitor concentrate (1500 units) was administered i.v. Over the following 20 min, stridor gradually subsided, the patient calmed and she was able to talk.

Discussion:

ACE inhibitor-provoked angioedema shares many clinical features with hereditary angioedema (HAE), including a limited effect of steroids, antihistamines and epinephrine. HAE, caused by excess bradykinin formation as a result of C1 inhibitor deficiency, usually has its laryngeal edema effectively reversed by C1 inhibitor in less than 0.5 h. Although patients experiencing ACE inhibitor-provoked angioedema have normal C1 inhibitor values, as in our patient, excess bradykinin is probably important as ACE breaks down bradykinin. It is unknown why ACE inhibitor-provoked angioedema appears in some and sometimes after many years of use

Conclusion:

We believe that C1 inhibitor was effective in reversing the ACE inhibitor-induced angioedema in our patient.

PMID: 16451161

[PubMed - as supplied by publisher]

........

Normal C1 inhibitor mRNA expression level in type I hereditary angioedema patients: newly found C1 inhibitor gene mutations.

Feb 2006

Kang HR, Yim EY, Oh SY, Chang YS, Kim YK, Cho SH, Min KU, Kim YY.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background:

C1 esterase inhibitor (C1INH) plays a key role in the classical pathway of the complement cascade. Mutations in this gene cause a decreased level of antigenic (type I hereditary angioedema, HAE) or functional (type II HAE) C1INH.

Objective:

To find novel mutations in C1INH and evaluate the expression of C1INH gene in HAE patients.

Methods:

Direct sequencing mutation analysis was performed for genomic DNA from three unrelated families (14 HAE patients and 18 family members). Genomic DNA from one family was also analyzed for larger genomic rearrangements, using Southern blotting analysis. We used real-time quantitative polymerase chain reaction (PCR) to evaluate C1INH mRNA expression level.

Results:

Four mutations in exons (2311 T-->C, 14 034 G-->A, 16 830 G-->A, and 16 979-16 980 G insertion) and four in introns (738 G-->A, 8531 A-->G, 14 254 A-->G, and 14 337-14 378 TT deletion) were found. Interestingly, all of the nine patients in one family share the same mutation of Gly345Arg (14 034 G-->A) in the seventh exon. In another family, a single base mutation near the splice site (14 254 A-->G) was found in all of the three patients. In the last family, although a significant mutation was not found by direct sequencing, patients showed an abnormal 16 kb fragment in addition to the normal allele (21 kb Bcl I fragment). The C1INH mRNA expression of HAE patients in two families was not significantly different compared with that of normal controls.

Conclusion:

The two novel exonal mutations (G-->A and A-->G) and one large gene deletion were associated with the clinical phenotypes of HAE. Considering the normal C1INH mRNA levels but below normal protein levels in two families, their phenotypes would be associated with the post-translational defect.

PMID: 16409206

[PubMed - in process]

........

Recombinant human C1-inhibitor is effective in the treatment of acute attacks of hereditary angioedema--case report

Porebski G, Bilo B, Obtulowicz K, Obtulowicz P, Nuijens J.

Zaklad Alergologii Klinicznej i Srodowiskowej, Collegium Medicum Uniwersytetu Jagiellonskiego, Krakow. mmobtulo@cyf-kr.edu.pl

Hereditary angioedema (HAE) is a rare condition, resting on attacks of edema in various localizations, potentially life-threatening if in facial, laryngeal, pharyngeal or gastrointestinal area. The disease is caused by deficiency or impaired activity of C1 inhibitor, therefore C1 inhibitor infusion is the the essential treatment and the only efficient method in an acute attack of HAE. Nowadays C1 inhibitor applied in our patients is obtained from human plasma, what restricts the availability of the drug and carries relevant risks. After many years of research it came to the synthesis of the recombinant protein with features of human C1 inhibitor. Its first usage in Poland took place-in two HAE patients with severe edema in 2004. The course and efficiency of this treatment is reported in the paper. Recombinant human C1 inhibitor occurred efficient and safe in presented case of severe angioedema.

Publication Types:Case Reports

PMID: 16334540

[PubMed - indexed for MEDLINE]

........

Acquired C1-inhibitor deficiency in a patient with systemic lupus erythematosus: a case report and review of the literature.

Nettis E, Colanardi MC, Loria MP, Vacca A.

Department of Medicine, Immunology and Infectious Diseases, Service of Allergy and Clinical Immunology, University of Bari Medical School, Bari, Italy

e.nettis@allergy.uniba.it

The C1-inhibitor (C1-INH) is an important member of the serpin family which inhibits the first component of the human complement system and controls contact activation of the coagulation and kinin system. An acquired form of C1-INH deficiency was recognized and classified as type I, which is characterized by accelerated catabolism of C1-INH, whereas type II is defined by the presence of an autoantibody directed against the C1 inhibitor molecule. This study reports the case of a 32-year-old woman with systemic lupus erythematosus (SLE) who experienced recurrent angioedema because of an acquired C1-INH deficiency. The relevant literature is reviewed.

PMID: 16313255

[PubMed - in process]

........

C1 inhibitor: molecular and clinical aspects.

Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B.

Department of Internal Medicine, San Giuseppe Hospital, University of Milan, Milan, Italy.
C1 inhibitor (C1-INH) is a serine protease inhibitor (serpins) that inactivates several different proteases in the complement, contact, coagulation, and fibrinolytic systems. By its C-terminal part (serpin domain), characterized by three beta-sheets and an exposed mobile reactive loop, C1-INH binds, and blocks the activity of its target proteases. The N-terminal end (nonserpin domain) confers to C1-INH the capacity to bind lipopolysaccharides and E-selectin. Owing to this moiety, C1-INH intervenes in regulation of the inflammatory reaction. The heterozygous deficiency of C1-INH results in hereditary angioedema (HAE). The clinical picture of HAE is characterized by bouts of local increase in vascular permeability. Depending on the affected site, patients suffer from disfiguring subcutaneous edema, abdominal pain, vomiting and/or diarrhoea for edema of the gastrointestinal mucosa, dysphagia, and dysphonia up to asphyxia for edema of the pharynx and larynx. Apart from its genetic deficiency, there are several pathological conditions such as ischemia-reperfusion, septic shock, capillary leak syndrome, and pancreatitis, in which C1-INH has been reported to either play a pathogenic role or be a potential therapeutic tool. These potential applications were identified long ago, but controlled studies have not been performed to confirm pilot experiences. Recombinant C1-INH, produced in transgenic animals, has recently been produced for treatment of HAE, and clinical trials are in progress. We can expect that the introduction of this new product, along with the existing plasma derivative, will renew interest in exploiting C1-INH as a therapeutic agent.

PMID: 16267649

PubMed - in process]

........

A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema.

van Doorn MB, Burggraaf J, van Dam T, Eerenberg A, Levi M, Hack CE, Schoemaker RC, Cohen AF, Nuijens J.

Centre for Human Drug Research, Leiden, The Netherlands.

mdoorn@chdr.nl

BACKGROUND:

Hereditary angioedema (HAE) is a congenital disorder with recurrent attacks of localized swelling of submucosal tissue, subcutaneous tissue, or both caused by a deficiency of the plasma protein C1 inhibitor (C1 esterase inhibitor [C1INH]).

OBJECTIVE:

We sought to evaluate the effects of recombinant human C1INH (rhC1INH) isolated from the milk of transgenic rabbits in 12 asymptomatic patients with HAE.

METHODS:

rhC1INH was intravenously administered at doses of 6.25 to 100 U/kg on 2 occasions.

RESULTS:

rhC1INH appeared safe and was well tolerated. The course of functional C1INH in plasma showed a full initial recovery (dose-normalized maximum concentration of about 0.02 U/mL/U/kg) and a dose-dependent clearance of rhC1INH. After infusion of rhC1INH at 100 U/kg, a clearance of approximately 13 mL/min, a half-life of approximately 3 hours, and a volume of distribution of approximately 3 L were observed. Infusion at this dose led to functional C1INH levels in plasma of at least twice the normal level for about 2 hours and greater than 0.4 U/mL for about 9 hours. rhC1INH displayed dose-dependent biologic activity by increasing the C4 level, which was about 2-fold at 12 hours after rhC1INH at 100 U/kg, and decreasing levels of cleaved C4.

CONCLUSION:

The observed safety profile and biologic activity of rhC1INH warrants further clinical studies to assess its efficacy in treating HAE attacks.

Publication Types:Clinical Trial Clinical Trial, Phase I

PMID: 16210064

[PubMed - indexed for MEDLINE]