Reversible cortical blindness after lung transplantation. (Case Report).

Abstract

Cyclosporine (GYA) is a calcineurin inhibitor widely used in immunosuppressive regimens after organ transplantation. Several neurologic side effects are frequently associated with CYA use; however, reversible cortical blindness is a rare manifestation of CYA toxicky traditionally seen after liver and bone marrow transplantation. This report presents a case of reversible cortical blindness after lung transplantation, then details the risk factors and clinical course of 28 previously well-documented cases of CYA-induced cortical blindness after transplantation. Identification of known risk factors, clinical clues, and typical radiographic findings may aid in the diagnosis of CYA-induced cortical blindness, since reduction in CYA dose or cessation of CYA therapy usually permits resolution of the neurologic effects.

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The introduction of cyclosporine (CYA) made lung transplantation a therapeutic option for patients with end-stage lung disease. (1) CYA produces numerous side effects, the most common of which are hypertension and chronic renal insufficiency. Also, CYA causes a variety of central nervous system effects in approximately 10 to 35% of solid organ recipients, ranging from tremors, paresthesias, and occasional headaches to seizures, paralysis, blindness, and (2-19) These effects are potentially reversible by lowering the dose or discontinuing CYA therapy. Therefore, a high index of clinical suspicion for the neurologic effects of CYA and early diagnosis are important to minimize the development of permanent deficits. Herein, we report a case of reversible CYA-induced cortical blindness and seizure after lung transplantation.

Discussion

In one series, central nervous system complications after lung transplantation were reported to occur in 26% of patients. (20) Headaches were the most common complication (38%), followed by seizure (27%), stroke (12%), and confusion (8%). (20) In another series, 22% of lung allograft recipients were affected by seizures. (6) CYA is the single most common etiologic agent identified for such neurologic symptoms (10-35% of patients), while other causes include sepsis, rejection, primary graft nonfunction, cerebral anoxia, renal failure, hepatic failure, stroke, and electrolyte abnormal-ities (2-5,7,9,14,15,17,21,22) Our report describes one case of CYAinduced cortical blindness, which is exceedingly rare after lung transplantation. At least 28 well-documented cases of CYA-induced cortical blindness have been reported in the English literature, mainly after bone marrow or liver transplantation. (3-5,9,10,12,17,23-33 Table I summarizes these cases. In addition, numerous authors have documented cortical blindness w ith CYA use not only in transplant recipients but also in patients being treated for other disorders such as leukemia and aplastic anemia. (34-36)

The presentation of CYA-induced cortical blindness is variable, and diagnosis relies on a high index of clinical suspicion. Clearly, exclusion of other etiologic possibilities is paramount before a diagnosis of CYA-induced neurotoxicity is considered. Cortical blindness seems to occur more often among patients receiving bone marrow or peripheral stem cell transplants (64% of cases) and liver transplant recipients (18% of cases), with a predilection for females (64% of cases. (3-5,9,10,12,17,23-33) Onset of symptoms occurred within the first 2 months of transplantation in 26 (93%) of 28 previous cases (Table 1). The most common CYA-induced neurologic effects associated with cortical blindness may be grouped into the triad of encephalopathy, white matter changes, and seizures; 17 (61%) of 28 previous patients had seizures. (3-5,9,10,12,17,23-33) This presentation has been termed the posterior leukoencephalopathy syndrome. (35)

The results of diagnostic testing for CYA-induced cortical blindness are variable. Funduscopic examination is commonly unremarkable, though scattered yellow exudates were found in the retina of one patient. (4) The retinal examination is essential to exclude primary peripheral explanations for the visual changes such as retinal artery branch occlusion, retinal hemorrhage, and macular hyperpigmentation. (8) Examination of the cerebrospinal fluid is usually unremarkable, (28,29) the most common reported finding being an elevated protein value (3 patients). (4) EEG may show diffuse slowing consistent with a diffuse encephalitic or metabolic process or dysrhythmias of the frontal or occipital lobes. (4,5,28,29,37) Focal epileptiform findings are rare. (5,28).

Imaging of the brain is generally more helpful and consistent in patients with CYA-induced cortical blindness. The predominant CT finding is edema of the subcortical white matter involving the parieto-occipital lobes. (38) This predilection for the parieto-occipital lobes may be explained by the sparse sympathetic innervation of the vertebrobasilar system, resulting in increased perfusion during periods of hypertension and breakthrough of autoregulation affecting these areas. (38) Findings on MRI usually parallel those of CT, with high T2-weighted signal changes involving the white and/or gray matter of the cerebral hemispheres. (33,39) Of the 28 reviewed patients with cortical blindness, 24 (86%) had abnormalities on cranial CT or MRI at presentation (Table 1). (3-5,9,10,12,17,23-33) In the future, reversible perfusion abnormalities in the brain discovered by single photon emission computed tomography (SPECT) may provide a sensitive monitor of CYA-induced neurotoxicity. (18,30)

Gross pathology of the posterior lobes seems to correlate well with these noninvasive techniques. Wilson et al (10) described the pathologic findings of a 55-year-old woman who had CYA toxicity 5 days after liver transplantation and died 8 months later of severe rejection. Mild pallor of the posterior lobes was seen on myelin staining, and there was focal swelling of myelin sheaths with scattered macrophages. Mild astrocytosis was present, and the cerebral white matter showed multiple scattered foci of resolving petechiae. These findings are consistent with hypertensive damage to the posterior hemispheres and edema of myelin sheaths.

Because the blood-brain barrier is thought to be impermeable to CYA, several precipitating factors have been identified that may predispose patients to CYA neurotoxicity (Table 2). To date, the mechanism by which CYA causes neurotoxicity has not been elucidated. Previous hepatic failure may damage the blood-brain barrier, allowing easier influx of CYA and resulting in increased central nervous system toxicity after liver transplantation. (17,21) CYA inhibits P-glycoprotein, an ATPase-dependent transport channel protein that could serve to eliminate CYA from brain tissue, further increasing the risk for neurologic effects. (40) Intuitively, patients with supratherapeutic CYA levels are more susceptible to toxicity. (3,5) Among previous cases of cortical blindness with documented CYA levels, 77% were more than 300 ng/ml, and 64% were more than 400 ng/ml (Table l). (3-5,9,10,12,17,23-33) However, normal CYA levels do not exclude a diagnosis of CYA neurotoxicity, as evidenced by our case. It has been suggested th at CYA neurotoxicity may be mediated through an active metabolite, possibly explaining the lack of correlation between toxicity and CYA levels in some cases. (41)

Our patient initially complained of daily tremors occurring several hours after her morning CYA dose. These symptoms, however, abated when oral metoclopramide therapy was discontinued. The effect of metoclopramide on CYA levels has been studied, and the major drug interaction appears to be an increase in CYA absorption and bioavailability, with a decreased time to reach maximum concentration. (42) CYA metabolism is unaffected. (42) This may explain our patient's predictable daily tremors as CYA levels peaked soon after a morning CYA dose, with resolution of the tremor when metoclopramide was stopped. Presumably, CYA absorption became more uniform. Several other commonly used drugs affect CYA metabolism via the cytochrome P-450 mixed function oxidase system. Prednisone, ketoconazole, erytliromycin, clarithromycin, calcium-channel blockers, oral contraceptives, and androgens increase CYA levels while phenobarbital, phenytoin, valproic acid, carbamazepine, and rifampin decrease CYA levels. Every effort must be m ade to maintain therapeutic CYA levels, and a thorough understanding of CYA drug interactions is mandatory to adjust CYA dosing before clinical toxicity or graft rejection.

CYA is highly lipophilic, and its active form is tightly bound to lipoproteins and chylomicrons in the serum. Hypocholesterolemia may permit more CYA to remain free in the serum, thus increasing its likelihood to pass through the blood-brain barrier. (3,12,17,43-45) Hypocholesterolemia with mean levels of 2.43 mmol/L (94 mg/dl) have been found in patients symptomatic from CYA toxicity as opposed to 3.41 mmol/L (132 mg/dl) in an asymptomatic group. (17) A mean level of 2.90 mmol/L (112 mg/dl) (range, 1.58-8.52 mmol/L) was found among previous cases of cortical blindness (Table l). (3-5,9,10,12,17,23-33) Again, normal or elevated cholesterol levels do not exclude a diagnosis of CYA-induced neurotoxicity, as seen in our patient.

CYA-induced neurologic effects and seizures have been associated with uncontrolled hypertension. (46) While the relationship between CYA and hypertension is universally known, the pathophysiology of this relationship is unclear. Some researchers favor a CYA effect on the renin-angiotensin-aldosterone axis. (47,48) Direct endothelial damage from prolonged CYA exposure resulting in elevated endothelin levels and vasospasm is another possible explanation. (49) This vasospasm may lead to a microangiopathic hemolytic anemia, possibly establishing a cause-and-effect relationship between CYA and neurotoxicity. (12,28)

Hypomagnesemia lowers the seizure threshold and causes tremors, weakness, ataxia, and fasiculations. (12,50) CYA alone has been shown to lower the seizure threshold in a rat model of electroshock-induced seizures. (51) The accelerated renal wasting of magnesium induced by CYA could exacerbate both these effects. (50) Aluminum overload has been identified as a risk factor for seizure and encephalopathy in renal transplant recipients, and high-dose methylprednisolone therapy concurrent with CYA use may lower the seizure threshold by raising CYA levels. (5,7,52-55) Unfortunately, as exhibited by our case, these factors are not always present, and their absence does not preclude the diagnosis of CYA-induced neurotoxicity. Identifiable risk factors such as hypertension, hypomagnesemia, and aluminum overload should be aggressively treated, and hypocholesterolemia should alert the physician to the increased likelihood of toxicity with CYA use.

Definitive treatment of CYA-induced cortical blindness involves reduction or discontinuance of CYA therapy. Rechallenge with CYA after a toxic event may result in a reappearance of neurologic symptoms prohibiting further CYA use, though a lower dose can sometimes be safely maintained. (3,5,28,37) Replacing CYA with tacrolimus remains a therapeutic option, though the reported incidence of neurologic effects with tacrolimus is similar to that of CYA, and the incidence of tremor is even greater. (56-59) Recovery time may be directly proportional to the severity of the presenting symptoms. (17) Complete recovery of vision is the rule (Table 1). However, CYA toxicity has resulted in two cases of permanent blindness. (4,32) The lack of CT or MRI findings as well as the loss of pupillary reflexes and diminished amplitudes on EEG seen in one of these two previous patients may point to a retinal rather than cortical etiology for the blindness. (4) Abnormalities on CT, MRI, and EEG can be expected to resolve after with drawal of CYA, although improvement may lag behind clinical resolution. (4,33,38) The onset of any neurologic complication, regardless of cause, is associated with a poorer prognosis after transplantation despite the almost universal disappearance of CYA-induced symptoms upon removal of the drug. (15)

Conclusion

Transplantation is becoming an increasingly successful treatment for end-stage organ dysfunction. Because more allograft recipients are being managed by primary care physicians and subspecialists, it is important for all internists to be aware of the common and more rare neurologic effects of CYA, especially in the setting of the appropriate clinical, laboratory, and radiographic findings. The clinical triad of encephalopathy, seizures, and white matter changes often heralds CYA-induced cortical blindness, and physicians should expect resolution of these findings after withdrawal of the drug. Risk factors for CYA-induced cortical blindness should be aggressively sought and corrected. A thorough knowledge of CYA drug interactions is necessary to avoid nontherapeutic CYA levels and subsequent graft rejection or drug toxicity.

Table 1

Previously Reported Cases (n = 28) of Cyclosporine-Induced Cortical
Blindness *

                               Onset                   CYA
Age/                       (Postoperative             Level
Sex         Transplant          day)       Seizures  (ng/mL)

7/M             BMT              6           Yes      >1000
30/F            BMT              5           Yes       325
37/M          Kidney            28           Yes       518
33/M            BMT            149           Yes       422
55/F           Liver             5            No        NA
50/F           Liver            11            No        NA
60/F           Liver            10            No        NA
5/F             BMT            >30           Yes       1704
18/F            BMT             43           Yes       2091
55/F           Liver             5            No     199-240
39/F            BMT              3           Yes       327
28/F            BMT             11            No       220
27/F            BMT             22           Yes       350
33/M      Kidney/pancreas       21            No       495
19/F            BMT             60            No        NA
62/M           Heart            22            No       401
25/F            BMT             54           Yes       745
20/M            BMT             18           Yes       683
47/F            BMT             46           Yes        NA
44/M            BMT              4            No        NA
32/F            BMT             41            No       1159
22/F            BMT             50           Yes       632
23/F            BMT             80            No       425
40/F           APSCT            19           Yes       688
53/M           Liver            60           Yes       212
48/M          Kidney            37           Yes       223
11/M          Kidney             7           Yes       221
40/F           APSCT            19           Yes       668

             Cholesterol Level                            CYA
Age/                                                   Dose
Sex         (mmol/L)     (mg/dL)   Imaging            Change

7/M            NA          NA      NA                Decreased
30/F          2.59         100     MRI, abnormal     Unchanged
37/M          4.58         177     CT/MRI, abnormal    Held
33/M           NA          NA      CT, normal           NA
55/F          2.43         94      CT/MRI, abnormal    Held
50/F          3.08         119     CT/MRI, abnormal  Decreased
60/F          1.58         61      CT/MRI, abnormal  Decreased
5/F            NA          NA      CT, abnormal        Held
18/F        1.76-2.27     68-88    CT, abnormal        Held
55/F           NA          NA      CT/MRI, abnormal    Held
39/F          4.09         158     CT/MRI, abnormal    Held
28/F          4.74         183     CT/MRI, abnormal    Held
27/F          3.34         129     MRI, abnormal       Held
33/M           NA          NA      CT/MRI, normal      Held
19/F           NA          NA      NA                  Held
62/M           NA          NA      CT/MRI, abnormal  Decreased
25/F          8.52         329     CT, abnormal        Held
20/M          3.78         146     CT, abnormal        Held
47/F          3.34         129     MRI, abnormal       Held
44/M          3.32         128     CT, abnormal        Held
32/F           4.6         178     MRI, abnormal       Held
22/F           NA          NA      MRI, abnormal       Held
23/F          6.21         240     CT/MRI, abnormal    Held
40/F           NA          NA      MRI, abnormal       Held
53/M           NA          NA      MRI, abnormal       Held
48/M           3.2         124     MRI, abnormal       Held
11/M           NA          NA      CT/MRI, abnormal    Held
40/F           NA          NA      MRI, abnormal       Held


Age/
Sex            Response

7/M               NA
30/F           Reserved
37/M           Reserved
33/M       Death/pneumonia
55/F           Reserved
50/F           Reserved
60/F           Reserved
5/F            Reserved
18/F           Reserved
55/F           Reserved
39/F           Reserved
28/F           Reserved
27/F           Reserved
33/M          Blindness
19/F           Reserved
62/M      Partially reversed
25/F           Reserved
20/M           Reserved
47/F           Reserved
44/M           Reserved
32/F           Reserved
22/F           Reserved
23/F           Reserved
40/F           Reserved
53/M           Blindness
48/M           Reserved
11/M           Reserved
40/F           Reserved

* Adapted from Ghalie et al. (9)

CYA, cyclosporine; BMT, bone marrow transplant; APSCT, allogeneic
peripheral stem cell transplant; NA, not available.

Table 2

Risk Factors for Cyclosporine Neurotoxicity


Hypocholesterolemia
Hypomagnesemia
Hypertension
Aluminum overload
Previous hepatic failure (damage to
 blood-brain barrier)
Supratherapeutic cyclosporine levels
Intravenous cyclosporine
High-dose steroids

Acknowledgments

We thank Steve Nelson, MD, and Donnie Dunagan, MD, for critical review of the manuscript.

Accepted June 18, 2002.

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RELATED ARTICLE: Key Points

* Cortical blindness is a rare manifestation of cyclosporine (CYA) toxicity.

* The most common CYA-induced neurologic effects associated with cortical blindness have been termed the "posterior leukoencephalopathy syndrome": encephalopathy, white matter changes, and seizures.

* Hypocholesterolemia, hypomagnesemia, hypertension, aluminum overload, pervious hepatic failure, supratherapeutic CYA levels, intravenous CYA, and high-dose steroids are all risk factors for CYA-induced cortical blindness.

* Complete recovery of vision is the rule, in the majority of cases, after lowering the dose or discontinuing CYA therapy.

Case Report

A 52-year-old white woman received a right lung allograft for end-stage emphysema related to smoking. She had no history of seizures, stroke, hypertension, alcohol abuse, or other medical problems. Her perioperative course was unremarkable, and she was discharged home with an immunosuppressive regimen of CYA, azathioprine, and prednisone.

Four months postoperatively, the patient had a tremor that resolved after the discontinuance of metoclopramide therapy. One morning several days later, she awoke with blindness. Over the course of the day, she had several seizures and was brought to the emergency department. Her medical regimen included CYA, 150 mg twice daily; azathioprine, 100 mg at night; prednisone, 12 mg daily; trimethoprim-sulfamethoxazole, 1 double-strength tablet twice weekly; ganciclovir, 500mg twice daily; nystatin, 5 ml four times daily; clarithromycm, 500 mg daily; furosemide, 40 mg twice weekly; cisapride, 10 mg four times daily; nizatidine, 150 mg twice daily; folic acid, 1 mg twice daily; and potassium chloride, 40 mEq twice weekly. For the preceding 3 months, her CYA levels ranged from 171 to 392 ng/ml (therapeutic level, 100-300 ng/ml).

At arrival in the emergency department, she was awake but confused and unable to follow commands. Her temperature was 36.8[degrees]C (98.2[degrees]F), pulse 100/min, blood pressure 151/88mm Hg, and respiration 24/min. Her pupils were 3 mm, equal, and reactive to light, and extraocular movements were intact, without nystagmus. She was unable to cooperate with the funduscopic examination. Lung fields were clear and heart sounds were regular, without murmur or gallop. Neurologic examination showed equal movement of all extremities with normal motor tone. Tendon reflexes were equal and brisk, bilateral Babinski responses were absent, corneal and oculocephalic reflexes were preserved, meningeal signs were absent, and she did not blink to confrontational stimuli.

Initial laboratory values were white blood cell count of 13,700/mm (3) with 88% segmented neutrophils and 3% band forms; hemoglobin, 10.3 g/dl; platelet count, 160,000/mm (3) magnesium, 4.0 mg/dl; blood urea nitrogen, 36 mg/dl; creatinine, 2.1 mg/dl; and cholesterol, 9.37 mmol/L (362 mg/ dl). The CYA level at admission was 244 ng/ml. Urinalysis showed trace protein and moderate occult blood with 1 WBC/hpf and no red blood cells. Pulse oximetry was 94% on room air, and arterial blood gas analysis showed a pH of 7.45, partial pressure of oxygen (Pa[O.sub.2]) of 69 mm Hg, and partial pressure of carbon dioxide (Pa[Co.sub.2]) of 36 mm Hg. Findings on electrocardiography and chest x-ray were normal. Computed tomography (CT) of the head without contrast medium showed bilateral posterior occipital white matter hypoattenuation with mild hypoattenuation of the white matter anterior to the frontal horns (Fig. 1). There was no evidence of hydrocephalus, mass effect, or hemorrhage. Electroencephalography (EEG) was not do ne.

A presumptive diagnosis of CYA-induced neurotoxicity was made, and CYA was withheld. Ophthalmologic evaluation showed no orbital, retinal, or optic nerve disease. Over the next 48 hours, mental status improved to baseline without further seizures. Over time, the patient was able to distinguish colors, count fingers, and read a clock on the wall. Her CYA level had decreased to 131 ng/ml, and CYA therapy was restarted at 50 mg twice daily on hospital Day 2. Symptoms did not recur after 5 days of observation. CYA levels were 156 ng/ml on hospital Day 4 and 143 ng/ml on hospital Day 7. Losartan, 50 mg daily, was added, and furosemide was increased to 40 mg three times per week to optimize blood pressure control. The patient was discharged on hospital Day 7, with nearly complete resolution of visual symptoms.

Eleven days later, she was readmitted with weakness, dizziness, blurred vision, episodic confusion, right frontal headache, urinary incontinence, and "staring spells" lasting several minutes during which time she was unresponsive. The CYA level 4 days earlier had been 158 ng/ml. The patient was found to be orthostatic. Supine blood pressure was 180/100 mm Hg, and standing blood pressure was 150/90 mm Hg. Findings on physical and neurologic examinations were unchanged from those at recent discharge. Hemoglobin value was 8.6 mg/dl, and two units of packed red blood cells were given. The remaining laboratory data were normal. Magnetic resonance imaging (MRI) of the brain with and without contrast medium showed periventricular and subcortical small vessel ischemia disproportionate for the patient's age (Fig. 2). However, there was no evidence of occipital white matter disease or evidence of abnormal intracranial enhancement after the administration of contrast material. Vertebrobasilar magnetic resonance angiogra phy (MRA) showed normal flow without evidence of vascular abnormality.

CYA therapy was discontinued, and tacrolimus therapy was started. Dizziness resolved after blood transfusion and substitution of clonidine for losartan. Seizures were considered as a cause of the mental status changes, and neurology consultation was obtained. However, her mental status gradually improved over the next 5 days after the medication changes. No further seizure activity occurred, and EEG was deferred. The patient was discharged on hospital Day 5, with only minimal blurred vision. A repeat ophthalmologic evaluation 2 months after CYA therapy was discontinued showed complete restoration of vision. Currently, more than 4 years after lung transplantation, the patient has no residual CYA-induced neurologic effects except for intermittent headaches.

From the Department of Multi-Organ Transplant, Ochsner Clinic Foundation, New Orleans, LA.

Reprint requests to Mark T. Knower, MD, Ochsner C]inic Foundation North Shore, 804 Heavens Drive, Suite 105, Mandeville, LA 70471.

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