Edema Associated With Infarct . . . Or Something Else?

Figure 1. Noncontrast CT scan of the head showing areas of hypodensity in the parieto-occipital regions bilaterally. There is no evidence of intracranial hemorrhage.

Figure 2. Magnetic resonance fluid-attenuated inversion recovery sequence image illustrating abnormally increased signal intensities involving the cortex and subcortical white matter in the bilateral occipital lobes extending into the bilateral parietal and left temporal lobes.

HISTORY

A sharp decrease in visual acuity affecting both eyes developed in a 35-year-old man 3 days after elective abdominal surgery. Six months earlier, acute B cell-type lymphoblastic leukemia was diagnosed in the patient for which he received bone marrow transplantation (BMT). Following BMT, graft-versus-host disease developed in the patient. It was treated with cyclosporine, mycophenolate mofetil (CellCept), sirolimus (Rapamune), and prednisone.

PHYSICAL EXAMINATION

Vital signs were stable. Heart rate was 85 beats per minute, blood pressure was 148/114 mm Hg, and respiratory rate was 14 breaths per minute. The patient was afebrile. He was awake and although he was confused, he was able to name items, to repeat information, and to read and write without difficulty. Dysarthria was not present. Visual acuity in both eyes was decreased significantly. The patient was able to see motion and light but was not able to count fingers. Pupils were 4 mm bilaterally and briskly reactive to light stimulation. Optic discs appeared normal. Ocular movements were intact. Other findings related to cranial nerves and motor and sensory testing were unremarkable. Lung sounds were clear. S₁ and S₂ sounds were present but within normal limits with regular rate and rhythm.

LABORATORY TESTS

Basic metabolic panel values were all within the normal limits. Serum cyclosporine level was markedly elevated. A complete blood cell count was significant for mild anemia and thrombocytopenia. A chest radiograph did not show significant abnormalities. Results of urinalysis were normal.

What is your diagnosis and management plan?

DIAGNOSIS: Reversible posterior leukoencephalopathy syndrome (RPLS) secondary to cyclosporine therapy

The clinical presentation of bilateral vision loss with normal optic discs, high blood pressure, and confusion raises the possibility of RPLS. The MRI findings also are characteristic of RPLS, with increased signals in both fluid-attenuated inversion recovery (FLAIR) and T2-weighted images. The most likely cause for RPLS in this patient was cyclosporine toxicity.

During the hospital stay, cyclosporine was discontinued and blood pressure was controlled with intravenous antihypertensive medications, after which the patient's symptoms resolved. Four weeks later, the patient had normal visual acuities in both eyes, and abnormal signal changes on MRI scans resolved (Figure 3).

RPLS

RPLS was described by Hinchey and colleagues¹ in 1996. They reported on 15 patients who presented with headache; seizures; confusion; and visual disturbances, including cortical blindness. CT and MRI scans showed extensive bilateral white-matter abnormalities suggestive of vasogenic edema in the posterior regions of the cerebral hemispheres. All symptoms resolved once blood pressure was adequately controlled and immunosuppressive medications were discontinued. With advances in neuroimaging technology and widespread understanding of this syndrome, there has recently been an increase in reported incidences of RPLS.

RPLS typically occurs in association with hypertensive encephalopathy; eclampsia; renal failure; or immunosuppression associated with cyclosporine, tacrolimus, cisplatin, and immune globulin therapy. Rare causes include stem cell reinfusion and exposure to bevacizumab (Avastin),² granulocyte-colony stimulating factor, and ephedrine-containing supplements such as ephedra.³ RPLS is the most common severe neurologic complication in the setting of adult and pediatric hematopoetic stem cell transplantation.⁴

Most patients have either acute or subacute presentation, with headache followed by confusion, focal seizures with secondary generalization, and visual changes that range from hemianopia to visual neglect to cortical blindness. Seizures are more common at the onset of RPLS, and multiple seizures are more common than single events. Initial examination frequently reveals hypertension. Other aspects of the neurologic examination can vary from confusion and lethargy to coma. Ocular movement disturbance and hemiparesis may also be seen.

Noncontrast CT of the brain usually shows decreased attenuation in the occipital lobes, posterior parietal lobes, and posterior temporal lobes. Despite the name of this syndrome, the brain stem, cerebellum⁵ and anterior hemispheres also may be affected. However, the hypodensity seen on a CT scan of the brain (Figure 1) is not specific for RPLS and thus CT alone is not sufficient for making the diagnosis.

Figure 3. Magnetic resonance fluid-attenuatedinversion recovery sequence image showingcomplete resolution of vasogenic edema.

MRI of the brain is more sensitive and specific than CT. Occipital and posterior parietal lobes are commonly involved. Contrary to the initial description of RPLS, anterior circulation and gray matter are often involved.

Lesions appear hypointense on T1-weighted images and hyperintense on T2-weighted and FLAIR images (Figure 2). These MRI changes are similar to those caused by cytotoxic edema secondary to cerebral infarction. Diffusion-weighted image (DWI) and apparent diffusion coefficient (ADC) maps are generally used to differentiate cytotoxic and vasogenic edema. Cytotoxic edema associated with cerebral infarction or ischemia appears bright on DWI, with decreased signal on ADC in the corresponding area. Vasogenic edema secondary to RPLS does not usually cause similar brightness on DWI and usually has an increased signal on ADC.^6-8 Lumbar puncture usually reveals high intracranial pressure,⁹ and spinal fluid analysis may show neutrophilic pleocytosis.¹⁰ Magnetic resonance venography may also be needed to rule out the possibility of cerebral venous sinus thrombosis.

Hypertensive encephalopathy is one of the most well-recognized causes of RPLS. Sudden increase in blood pressure exceeds the autoregulatory threshold of the capillaries, leading to breakdown of the blood-brain barrier, transudation of fluid, and even petechial hemorrhages. Vertebral and basilar arteries may receive less sympathetic innervation compared with the anterior circulation arteries, which makes the posterior aspect of the brain more vulnerable to a rapid rise in blood pressure.¹¹

Serious neurotoxicity secondary to calcineurin inhibitors, such as cyclosporin A, occurs in approximately 5% to 6% of patients. Risk factors for the development of neurotoxicity include abnormally elevated drug levels, intravenous administration, hepatic failure, hypomagnesemia, hypercholesterolemia, significant fluid overload, and concurrent steroid therapy.^12,13 Cyclosporine causes a breach in the blood-brain barrier through anoxia, either by an effect on nitric oxide or by inhibiting a drug efflux pump.¹⁴

INTERVENTION

Treatment requires transfer of the patient to an ICU where intravenous antihypertensive therapy can be administered under close supervision. Commonly used agents include intravenous labetalol and nicardipine. Intravenous nicardipine in particular has an advantage of being easily titrated, allowing tight control of blood pressure in either a gradual or rapid fashion. Sodium nitroprusside should be avoided because of the potential for intracranial pressure elevation as well as cyanide toxicity, which may lead to seizures.

The offending immunosuppressive medications must be discontinued immediately. Seizures should be treated with antiepileptic medication, although intravenous magnesium may be sufficient in cases of eclampsia.

PROGNOSIS

With prompt diagnosis and adequate treatment, prognosis is usually good. Clinical recovery is seen within 1 to 2 weeks with complete resolution of MRI signal abnormalities. Most patients do not require antiepileptic medication long-term, but they may require antihypertensive medications long-term.

IN SUMMARY

RPLS remains a relatively uncommon clinical entity, but it is extremely important for clinicians to be able to recognize it clinically and radiographically. Prompt diagnosis is important to avoid potential cerebral ischemia, hemorrhage, and death. Clinicians should be aware of the common causes (including drugs that are associated with this syndrome) as well as the radiographic characteristics.

References:

REFERENCES

1.

Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome.

N Engl J Med

. 1996;334:494-500.

2.

Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and bevacizumab.

N Engl J Med

. 2006;354:980-982.

3.

Moawad FJ, Hartzell JD, Biega TJ, Lettieri CJ. Transient blindness due to posterior reversible encephalopathy syndrome following ephedra overdose.

South Med J

. 2006;99:511-514.

4.

Faraci M, Lanino E, Dini G, et al. Severe neurologic complications after hematopoietic stem cell transplantation in children.

Neurology

. 2002;59:1895-1904.

5.

Chang GY, Keane JR. Hypertensive brainstem encephalopathy: three cases presenting with severe brainstem edema.

Neurology

. 1999;53:652-654.

6.

Schwartz RB, Mulkern RV, Gudbjartsson H, Jolesz F. Diffusion-weighted MR imaging in hypertensive encephalopathy: clues to pathogenesis.

Am J Neuroradiol

. 1998;19:859-862.

7.

Schaefer PW, Buonanno FS, Gonzalez RG, Schwamm LH. Diffusion-weighted imaging discriminates between cytotoxic and vasogenic edema in a patient with eclampsia.

Stroke

. 1997;28:1082-1085.

8.

Ahn KJ, You WJ, Jeong SL, et al. Atypical manifestations of reversible posterior leukoencephalopathy syndrome: findings on diffusion imaging and ADC mapping.

Neuroradiology

. 2004;46;978-983.

9.

Chester EM, Anamanolis DP, Banker BQ, Victor M. Hypertensive encephalopathy: a clinicopathologic study of 20 cases.

Neurology

. 1978;28:928-939.

10.

McDonald CK, Waters ML, Griffin FM Jr. Case report: neutrophilic CSF pleocytosis in hypertensive encephalopathy.

Am J Med Sci

. 1993;306:167-168.

11.

Sadoshima S, Heistad D. Sympathetic nerves protect the blood-brain barrier in stroke-prone spontaneously hypertensive rats.

Hypertension

. 1982;4: 904-907.

12.

Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management.

Transpl Int

. 2000;13:313-326.

13.

Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review.

J Neurol

. 1999;5:339-346.

14.

Wijdicks EF. Neurotoxicity of immunosuppressive drugs.

Liver Transpl

. 2001;7:937-942.