Introduction

The optimal treatment at present for children with end-stage renal failure is kidney transplantation. Young patients awaiting a transplant and patients with transplant failure, especially if uremic, are best treated by peritoneal dialysis or, when unfeasible (e.g., loss of peritoneal function due to recurrent episodes of peritonitis or rejection of intraperitoneally transplanted kidneys), by hemodialysis. In hemodialysis in children, the creation of a permanent vascular access can be technically challenging because of the small native vessel size [1].

The guidelines of the Kidney Disease Outcomes Quality Initiative (K/DOQI) stipulate that fewer than 10% of patients be dialyzed through a central catheter and at least 40% via a native arteriovenous fistula. Nevertheless, studies have shown that, in 79% of children starting hemodialysis, a cuffed catheter is used for vascular access [1, 2]. The major cause of catheter failure is venous thrombosis, which can ultimately lead to stenosis or complete occlusion of the vein, even after excision of the central catheter [3, 4]. Rates of central venous stenosis range from 27% to 38% for cuffed and uncuffed central catheters, respectively [5].

The risk of widespread vascular stenosis or complete obliteration arises in patients receiving prolonged chronic hemodialysis [6, 7], which mandates the intensive use of blood vessels for the creation of a new vascular access or for transient insertion of central venous catheters to bridge the maturation of a new access. In this context, patients may acquire superior vena cava (SVC) syndrome, characterized by facial and arm swelling, cyanosis, dyspnea, chest pain, dysphagia, and, sometimes, headache [7]. Indeed, the long-term use of central venous catheters has displaced malignancy (bronchogenic carcinoma in adults and non-Hodgkin lymphoma in children) as the major cause of SVC syndrome [7].

The aim of this report is to describe the first case of intracranial hypertension and blindness in a child on prolonged hemodialysis with multiple vascular interventions. The literature on the neurological and ophthalmologic complications of hemodialysis vascular access is reviewed.

Case report

A 13-year-old girl who had been treated with hemodialysis for 10.5 years complained of sudden loss of vision in her right eye. Past medical history showed that end-stage renal failure had developed at age 8 months secondary to familial hemolytic uremic syndrome (HUS). The parents were unrelated Ashkenazi Jews of Hungarian origin. Another son had died in infancy of the same disease. The patient was started on peritoneal dialysis, but had to be switched to hemodialysis because of peritoneal failure induced by recurrent peritonitis. She underwent cadaveric kidney transplantations at ages 3.5 years, 5 years, and 10 years, which failed within 2 weeks, 10 months, and 1 week, respectively, owing to the recurrence of HUS. Genetic analysis revealed heterozygosity for membrane co-factor 1 mutation.

Efficient hemodialysis was performed (KT/V 1.6, hemoglobin up to 11.6 g%, ferritin 660 ng/ml). Intensive dietary supplementation, together with 8 years’ treatment with growth hormone (GH), had resulted in improved but still suboptimal growth. However, despite the prolonged dialysis sessions, only partial phosphate control was achieved, and severe hyperparathyroidism necessitated several courses of calcitriol pulse therapy and temporary discontinuation of GH therapy. At age 11 years, she underwent right tibial osteotomy for the correction of severe angulation of the right lower limb.

Hypertension was treated with three or, intermittently, four drugs with relatively good control (blood pressure 115–125/70 mmHg).

Three vascular accesses had been created during the patient’s 10.5 years on hemodialysis. The first, in her left arm, failed within a short time, and the second, in her right arm, failed after multiple interventions for venous outflow stenosis, including stent insertion. Venography performed before creation of the third access revealed occluded left innominate, left and right brachiocephalic trunks and calcified right subclavian stent protruding into a stenosed SVC. The left upper limb veins drained into an anomalous left hemiazygos vein and into the SVC above the stenotic segment. A two-step procedure was performed to create a left brachio-basilic arteriovenous fistula.

Within 2 months, progressive left facial edema was observed, together with mild transient hoarseness and orthopnea, which subsided spontaneously. Findings on otolaryngology examination with filter X-ray of the trachea were consistent with mild laryngitis (“pencil-tip” stenosis). Funduscopic examination demonstrated mild-to-moderate optic disc edema, with mild attenuation of the retinal arteries, considered to be an early stage of papilledema or grade I hypertensive retinopathy, despite relatively satisfactory blood pressure control at the time. There were no physical complaints consistent with intracranial hypertension or neurological abnormalities. Brain computed tomography (CT) scan was normal.

Balloon percutaneous transluminal angioplasty (PTA) successfully dilated the SVC diameter to 7 mm, which was followed by a transient decrease in left facial edema. PTA was repeated periodically with each recurrence of the edema, but the results were less impressive, and, gradually, severe left facial, peri-orbital, and upper chest edema developed, with grossly dilated tortuous venous collaterals. The patient remained asymptomatic.

Repeated funduscopic examinations revealed progressive bilateral papilledema, more pronounced on the right side, and venous congestion without hemorrhage. No changes in visual acuity or in findings on repeated neurological examinations and brain CT scans were observed. However, enlarged blind spots and bilateral nasal defects appeared on the first visual field examination, performed approximately 9 months after the appearance of blurred optic discs.

Three months later, and almost 1 year from the appearance of the blurred discs, the patient presented with sudden blindness in her right eye. Examination revealed no light perception in the right eye, in addition to right optic atrophy and the long-standing papilledema on the left. Brain CT revealed no new findings. Lumbar puncture was performed, and cerebrospinal fluid (CSF) pressure measured more than 500 mm H2O, with normal CSF content. A lumbo-peritoneal shunt was inserted, with rapid improvement of the funduscopic findings in the left eye but no change in the vision of the right eye. Elevated intraocular pressure (up to 34 mmHg) was diagnosed in the left eye, and therapy was started. The right eye pressure was within normal limits.

Within 24 h of shunt insertion, the patient began to complain of severe headaches, which required frequent narcotics administration. Brain CT showed “slit-like” ventricles and diffuse brain edema. As acetazolamide is not recommended for intracranial hypertension in patients with end-stage renal failure, treatment with dexamethasone was started. The headaches gradually and partially resolved, but upper back pain appeared.

One month later, after 2 days of weakness and resurging headaches, the patient presented with generalized tonic–clonic seizures and decerebrate posturing. Magnetic resonance (MR) imaging (MRI) and MR venography (MRV) revealed bilateral parieto-occipital venous brain infarction (Fig. 1a) due to superior saggital venous thrombosis (Fig. 1b). Anomalous venous drainage of the left arm fistula into the left internal jugular vein was noted, in addition to drainage of the posterior intracranial venous collateral into the right external jugular vein, which, itself, drained into the SVC via multiple small and tortuous collaterals (Fig. 2). There was no significant SVC stenosis.

Fig. 1
figure 1

Brain MRI. a Diffusion-weighted MR axial image. Note the bilateral extensive high signals in the parieto-occipital subcortical regions. The location is typical for venous infarcts. b Axial T2-weighted MR image. Note the hyperintense signal in the sagittal sinus, compatible with thrombosis (arrow)

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Fig. 2
figure 2

MR venogram. Note the occlusion in the right subclavian and brachiocephalic veins and the numerous tortuous collateral veins in the neck and scalp, draining into the jugular vessels (thin arrows). The internal jugular vein is distended secondary to the increased retrograde flow (thick arrow)

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The anomalous retrograde venous blood flow seemed to be driven by the high flow in the vascular access in the left arm. Therefore, closure of the fistula was mandatory to relieve the intracranial pressure. Meanwhile, until a new vascular access was built in the lower limbs, partial surgical stenosis was induced. One day after partial fistula closure, the patient’s neurological status began to improve, and we were able to wean her from the ventilator. Full gross motor function returned, but the patient remained in delirium, with almost no signs of understanding her close environment. However, creation of a temporary access in the lower limbs failed, so continued use of the still-functioning left arm fistula was necessary for hemodialysis. During our planning of a graft to create a new vascular access in the lower limb, the patient experienced a repeated, prolonged convulsion, followed by severe cerebral damage and brain death.

Discussion

Sudden visual loss in the context of optic disc edema in patients with severe chronic renal failure might be caused by several conditions: uncontrolled hypertension with hypertensive retinopathy with or without encephalopathy; advanced uremia with optic neuropathy (similar to uremic peripheral neuropathy or encephalopathy), a condition rarely encountered in patients with accurate nephrological follow-up; anterior ischemic optic neuropathy (AION), mostly described in reduced perfusion states (such as relative hypovolemia and hypotension at the end of hemodialysis sessions or the morning after in patients on night intermittent peritoneal dialysis); and finally, long-standing papilledema secondary to intracranial hypertension [8]. In children, the most common culprit is AION [9–11]. Our patient’s blood pressure control (which was satisfactory) and efficient hemodialysis ruled out a diagnosis of hypertensive and uremic retinopathy. Also, the finding of protracted bilateral papilledema was incompatible with the characteristic finding of unilateral swollen disc in AION.

The long-standing optic disc swelling in our patient eventually evolved into full-blown papilledema with severely increased intracranial pressure (>550 mm H2O). Findings on CSF analysis were within normal range, and brain imaging did not reveal a mass lesion or ventricular enlargement, clearly establishing the diagnosis of intracranial hypertension (pseudotumor cerebri). The initial absence of visual complaints or headache, reported in 80–90% of patients with pseudotumor cerebri, combined with systemic hypertension (albeit not severe enough for high-grade retinopathy), contributed to the delay in measuring CSF pressure and the late diagnosis.

The incidence of intracranial hypertension in the pediatric population is 0.4–2.2 cases per 100,000, or ten-times lower than in adults [12]. The relationship of intracranial hypertension to renal compromise has been attributed to various factors: uremia or dialysis disequilibrium, iron-deficiency anemia, hypo-adrenalism, calcium and water metabolism abnormalities, hypervitaminosis A, and various drugs used in the treatment of chronic renal failure and after renal transplantation (GH, cyclosporine, corticosteroids, nitrofurantoin, minocycline) [13–17]. In the present patient, uremia, high blood pressure, and severe anemia were ruled out. However, GH therapy had been administered for 8 years. Although GH therapy is rarely associated with intracranial hypertension in patients with renal failure [18], and then, mainly within the first 13 weeks of therapy [19], later onset has been reported in some cases. In addition, the severe hyperparathyroidism and the high-dose calcitriol pulse therapy could have produced microscopic arachnoid villi calcification which impaired CSF reabsorption [20].

Nevertheless, the imaging findings of an anomalous retrograde venous flow draining the high-output arteriovenous fistula in the left arm into the ipsilateral internal jugular vein, together with the increased intraocular pressure in the left eye (where venous drainage was impaired), pointed to impaired cerebral venous flow as the probable cause. This assumption was supported by the later development of brain edema with the introduction of a lumbo-peritoneal shunt, in addition to sagittal vein thrombosis with venous cerebral infarction.

Several reports in the literature link increased intracranial hypertension with abnormalities of cerebral venous drainage, mainly SVC obstruction or serious stenosis (SVC syndrome). Most of these cases, however, occurred in the setting of cardiothoracic surgery (acquired hydrocephalus after Mustard operation, switch operation for transposition of great arteries) or extracorporeal membrane oxygenation or intensive care with central venous catheterization [21, 22]. The mechanism, described in early studies in dog models [23], involves the decreased absorption of the cerebral spinal fluid at the level of the arachnoid granulations. Today, cerebral venous outflow obstruction is considered the general pathogenetic mechanism underlying intracranial hypertension [24].

There are only a few reports of intracranial hypertension due to impaired cerebral drainage in patients with renal failure [25–30]. These cases are summarized in Table 1 and involve only adult hemodialysis patients after multiple vascular accesses with “worn out” central veins. The single pediatric case of intracranial hypertension in a patient on chronic hemodialysis was described by Mourani et al. [30], but they provided no vascular details.

Table 1 Review of the literature: neurological and ophthalmological complications of hemodialysis (HD) access
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SVC syndrome in patients on hemodialysis may be characterized by progressive edema of the face, neck, scalp and upper chest, as well as the arms, owing to the increased flow through internal and lateral thoracic veins, vertebral veins, or azygos, hemi-azygos or innominate veins. In hemodialysis patients with functioning upper-limb access, more specific signs include ipsilateral vascular access malfunction: elevated venous pressure during hemodialysis sessions, prolonged bleeding from puncture sites, and repeated thromboses [31, 32]. Dilatation of alternative drainage veins might produce more remote signs and symptoms, including esophageal varices and dysarthria [33, 34]. In rare situations, when both the innominate and azygos veins are partially or completely occluded bilaterally, retrograde flow into the internal jugular vein, dural sinuses, and the contralateral collaterals develops, adversely affecting cerebral venous drainage. If there is also a high-flow vascular access in an arm, intracranial venous overload ensues.

The most serious complication of high intracranial pressure is visual loss due to optic atrophy, reported in 30–40% of cases. Patients with chronic renal failure seem to be especially susceptible [14]. Intracranial hypertension is usually treated with repeated CSF drainage and administration of acetazolamide and corticosteroids. If these means prove inefficient, lumbo-peritoneal or ventriculo-peritoneal shunts and even optic nerve sheath fenestration may be used for decompression and vision preservation [14, 16, 17].

In the setting of intracranial hypertension secondary to cerebral venous overload due to vascular stenoses and impaired drainage, the main course of action is immediate decongestion of the cerebral venous system by closure of the active vascular access. An alternative vascular access must be secured for continuing renal replacement therapy. Other options include repeated percutaneous transluminal balloon angioplasty with or without stent insertion, venous reconstruction, including a polytetrafluoroethylene axillary to the saphenous graft bypass [35], an atrial graft bypass [36], a switch to a lower-limb vascular access, or peritoneal dialysis.

Before creating a new vascular access, the clinician must clearly identify the existing venous circulation. This may be done by spinal CT, venography, MRI, MRV, MR angiography, and color Doppler ultrasonography. The latter is especially useful in demonstrating the abnormal patterns of cerebral circulation and the consequences of closure of a high-flow access [37].

Conclusions

Patients receiving prolonged hemodialysis treatment are prone to extensive vascular abnormalities. The evaluation of increased intracranial pressure is required in those with an active vascular access and central venous stenosis or obstruction, as evidenced clinically by head, face, neck, chest or upper limb edema, intermittent headache or visual complaints (active enquiry has to be pursued), unexplained dysarthria, dysphagia, hoarseness, orthopnea, or back or chest pain, especially in the context of repeated vascular interventions (accesses, surgery, and central catheter insertion). Complete ocular examination, funduscopic examination, and visual field assessment might reveal optic disc swelling and high intraocular pressure—both significant parameters of early intracranial hypertension. CSF pressure determination is obviously imperative in hemodialysis patients with ophthalmological abnormalities. Brain MRI and MRV are indicated for evaluation of the abnormal intracranial circulation and planning of the appropriate intervention to prevent visual loss and a catastrophic neurological outcome.