Central venous disease (CVD) is a serious complication in patients undergoing hemodialysis. It is defined as >50% lesion (stenosis or occlusion) in one of the following central veins of the chest: inferior and superior vena cava, brachiocephalic vein (BCV), subclavian vein (SCV), or internal jugular vein (IJV) [1]. Its clinical presentation varies depending on the site of the injury, being more serious the closer it is to the right atrium. It typically manifests with ipsilateral upper limb and facial edema, although it can occur asymptomatically [2]. Neurological manifestations secondary to CVD are rare [3,4]. We describe a patient who presented neurological manifestations secondary to central venous reflux due to throm botic occlusion of the left BCV. We also performed a systematic review of the literature.

A 51-year-old female presented with a 3-month duration of throbbing headache, of moderate to severe intensity, located in the frontal and retroocular region, without nausea or vomiting. It got worse during dialysis sessions and interfered with her activities of daily living. She also complained of paresthesia, weakness, and abnormal posture of her right hand during headache episodes. Motor symptoms completely resolved after each dialysis session, although the headaches persisted for several hours. No neurological deficit was evidenced on physical examination. Her past medical history includes arterial hypertension and chronic renal failure secondary to focal segmental glomerulosclerosis. Six years ago, she had a deceased donor kidney transplant. Due to the rejection of the transplant, she required hemodialysis through a central venous catheter (CVC) in the right IJV for 7 months. Then, an arteriovenous fistula (AVF) was performed in her left upper limb, and she undergoes hemodialysis through this access until now.

Brain tomography and magnetic resonance imaging did not show acute lesions or signs of intracranial hypertension (optic nerve sheath hydrops, reduced pituitary height, optic disc protrusion, or optic nerve edema). The fundus examination was normal. Magnetic resonance angiography showed high signal intensities of the sigmoid sinus, transverse sinus, and inferior petrosal sinus on the left side due to venous reflux (Fig. 1A–D). Digital subtraction angiography (DSA) ruled out intracranial AVF and identified an incomplete thrombosis (75%) of the left BCV (Fig. 1E). Delayed venous phase images of DSA showed reverse venous flow in the IJV, sigmoid sinus, and transverse sinus on the left side (Fig. 1F). The patient was not eligible for endovascular treatment due to the difficulty of making a new venous access. The decision was to start anticoagulation with complete resolution of symptoms after 3 months of follow-up.

We described a hemodialysis patient who developed neurological symptoms due to thrombotic occlusion of the left BCV. The estimated incidence of CVD in patients undergoing hemodialysis ranges from 16% to 50%. However, the presence of neurological symptoms is rare and nonspecific [5,6]. In Table 1 [1-20], we summarize the cases of neurological manifestations secondary to CVD reported so far. There is no sex prevalence with a mean age of 55.4 years (standard deviation [SD] ±14.1). Cardiovascular risk factors were identified in 14 out of 23 patients, with arterial hypertension being the most frequent factor (50%), and the average time of hemodialysis was 7.1 years (SD ±3.4).

The etiology of CVD is multifactorial. However, CVC placement has been associated with an increased risk of CVD, even after its removal. SCV access has up to 4 times the risk compared to IJV for the development of this pathology [2]. As well as our patient, CVC placement was described in 6 out of 23 of the reported cases.

In patients without a history of endoluminal devices, hemodynamic abnormalities could explain the development of CVD. Turbulent blood flow due to the presence of AVF would damage the vessel wall, stimulate the development of neointimal hyperplasia, and cause stenosis. Shunts located on the left side are associated with an increased risk of stenosis or thrombosis due to anatomical causes (left BCV is located between the sternum and pulsating aorta, which contributes to stenosis) [5,6].

Among the reported cases, 14 patients (60.9%) had an AVF, 7 (30.4%) had an arteriovenous graft, and in 2 cases (8.7%) the type of shunt was not specified. The mean time from AVF creation to symptoms onset was 4.5 years (SD ±4.2), and in 65.2% of patients (15/23), including the present case, the shunt was located in the left upper limb.

Previous studies have found associations between venous reflux and neurological manifestations. Retrograde flow caused by CVD (especially BCV) could cause alteration of the cerebral venous drainage, affect the circulation of the cerebrospinal fluid, and develop intracranial hypertension [6,7]. Headache attacks in our patient could be explained by this mechanism. On the other hand, intracranial venous congestion decreases cerebral perfusion pressure, which leads to a reduced supply of brain nutrients and potentially causes a hypoxia-like condition and affects neuronal function [8,9]. This is some of the currently available evidence about the pathophysiology of central venous reflux as a cause of neurological signs and symptoms. Among the patients described, occlusion/thrombosis prevailed over stenosis as a more frequent central lesion, and in the majority of them (87%) there was BCV involvement. The most frequent symptoms and signs were: headache (60.9%), motor deficits (21.7%), cranial nerve involvement (17.4%), and sensory symptoms (4.3%).

Change of flow direction could also lead to increased cerebral venous pressure, causing ischemia (due to altered cerebral perfusion pressure) or bleeding [1,8,10]. A brain lesion was present in 30.1% of reported cases at symptoms onset, which included 3 cerebral infarctions and 3 intraparenchymal hemorrhages. We did not identify brain lesions in our case.

The diagnosis of CVD is based on clinical and imaging findings. A high index of suspicion is necessary for this pathology, where DSA is the gold standard for the diagnosis of this disease due to its greater sensitivity compared to other imaging methods [10].

Symptoms can be reversible if CVD is treated early. Treatment options include percutaneous transluminal angioplasty (PTA), stenting, and surgery. PTA with a dilatation balloon is the current mainstay of treatment and should be performed only if there is a clinical indication (arm or face swelling) [4]. Balloon dilation for a narrow lesion found incidentally without symptoms accelerates the growth of the lesion. All the current treatment options will lead to recurrent stenosis or occlusion requiring multiple repeat interventions to maintain patency, but the risk of vessel rupture may increase [2].

Other options may be decongestion of the cerebral venous system by closing the active vascular access, but an alternative vascular access should be insured to continue renal replacement therapy [6,11]. Ligation/occlusion was performed in half of the reported patients, and less frequently (39.1%) when they underwent PTA. Twenty patients had good outcomes with a disappearance or clear improvement of symptoms after treatment.

Due to the location and type of lesion, our patient was not eligible for endovascular treatment. AVF ligation was not possible because the patient did not have another adequate venous access for a new AVF placement. Our patient represents the first reported case of neurologic manifestations secondary to CVD with complete resolution of symptoms after oral anticoagulants therapy. We have no evidence about medical therapy for secondary prevention for CVD. Further randomized controlled trials of currently available treatment options with long-term follow-up are essential in the future to develop adequate treatment algorithms.

Central venous reflux due to CVD is a serious complication in patients undergoing hemodialysis. Neurological manifestations are infrequent; therefore, this entity requires a high index of suspicion in those patients under hemodialysis who present neurological symptoms. Moreover, anticoagulation could be considered as an alternative treatment in special cases.