Uremic Encephalopathy: MR Imaging Findings and Clinical Correlation

Discussion

UE is a neurologic complication associated with ARF or chronic renal failure. It is likely caused by the effects of neurotoxic compounds. Accumulation of uremic toxins such as guanidine compounds (eg, creatinine and guanidine) might stimulate the neurotoxic effect of excitatory N-methyl-D-aspartate receptors, and concomitant inhibition of inhibitory γ-aminobutyric acid receptors may play an important role in the etiology of UE.⁹ It may be an interruption of polysynaptic pathways and alterations in excitatory-inhibitory amino acid balance. The manifestations of this brain disorder include various neurologic symptoms such as movement disorders (tremor, asterixis, myoclonus), cognitive disorders, and alteration in mental status.^10,11

UE presents 3 patterns of imaging findings: basal ganglia involvement,^12⇓–14 cortical or subcortical involvement,^15,16 and white matter involvement.^17,18 Basal ganglia involvement is more common in Asian patients with DM. The LFS in patients with UE often affects Asians (from Taiwan,^12,13 Korea,^13,14,18 Japan¹⁹). DM may make the basal ganglia more vulnerable to uremic toxins because of endothelial dysfunction in cerebral vessels (vascular autoregulatory dysfunction²⁰), and uremic toxin inhibits mitochondrial function with destruction of the pallidum and putamen.²¹ Cortical involvement is a category of posterior reversible leukoencephalopathy syndrome,²² and DM does not have a great effect on the involvement.¹⁸ Reversible intracerebral disease entities mediated by vascular autoregulatory dysfunction can be classified into 2 distinct groups: hypertensive encephalopathy and UE.²² However, posterior reversible encephalopathy syndrome is also seen in the uremic conditions in which endothelial toxins are thought to play a role.¹⁶ Posterior reversible encephalopathy syndrome is a clinical-radiologic syndrome characterized by headache, confusion, seizures, and visual disturbance and is thought to be secondary to hypertension. It classically occurs in the cortical or subcortical regions of the dominant parieto-occipital lobes, holohemispheric watershed zones, superior frontal sulcal area, and, rarely, the brain stem or basal ganglia.^16,23,24 MR imaging typically demonstrates vasogenic edema in the subcortical white matter and cortex. Cytotoxic edema has been described in a relatively lower percentage of patients with posterior reversible encephalopathy syndrome.²⁵

Central-variant posterior reversible encephalopathy syndrome had been described as brain stem or basal ganglia involvement that spares the cerebral cortex and subcortical white matter.²⁶ Imaging findings of central variant posterior reversible encephalopathy syndrome include symmetric or asymmetric vasogenic edema (the pons and basal ganglia [caudate nucleus, globus pallidus, and not resulting in the LFS]; and, rarely, the thalamus, posterior limb of the internal capsule, cerebellum, periventricular white matter) without any foci of reduced diffusivity and multiple microhemorrhages in the affected regions on susceptibility-weighted images.²⁶ These imaging findings are substantially different from the imaging findings of UE. White matter involvement is the rarest form and occurs in the supratentorial white matter regions. This form might be considered a urea cycle disorder rather than UE.

The LFS has been described on T2WI/FLAIR images as a hyperintense rim delineating the lateral (external capsule) and medial (internal capsule, internal and external medullary laminae) boundaries of both putamina, resembling a fork (Fig 1B).¹ A literature review¹ reported that the LFS was found in only 1 of 21 patients with UE admitted during a 10-year period in a retrospective single-institution study, without note of the absence or presence of DM. However, data from the same literature review showed that 10 of 11 patients with UE who had the LFS had diabetes, and 1 patient with diabetic ketoacidosis had the LFS, implicating diabetes in the production of these characteristic lentiform lesions. In this study, 7 of 9 patients with UE who had the LFS during a 10-year period had long-term DM. The results may indicate a higher prevalence of the LFS in Asian patients with DM and UE.

Metabolic acidosis associated with disruption of the blood-brain barrier is an essential element in the generation of the LFS,^1,2 and this sign may be attributable to differences in metabolic vulnerability between neurons of the basal ganglia and the astrocytes of surrounding white matter. Although UE is associated with metabolic acidosis, in this study, 1 of 5 patients with the LFS had mild metabolic acidosis, and the other 4 patients had normal pH levels on arterial blood gas. These findings are different from the results of a literature review that showed that metabolic acidosis is the basis of the LFS, and the absence of LFS might be reflective of a normal pH.¹ We propose that the LFS can be seen in UE regardless of the presence of metabolic acidosis, though coexistent metabolic acidosis may exacerbate the damage of neurons in the basal ganglia.

In this study, T2WI/FLAIR images showed uniform imaging findings. Diffuse vasogenic edema in the bilateral basal ganglia and/or cortical lesions represents increased interstitial fluid from a disruption of autoregulation. These results correspond well with those of the earlier studies.^13,14 There was no significant difference between groups with diffuse mildly increased SI on DWI without restricted diffusion and others with normal SI on DWI in basal ganglia lesions.

Three of 9 patients who underwent DWI showed cytotoxic edema within the vasogenic edema of the basal ganglia, and all 3 lesions had cytotoxic edema in the unilateral or bilateral globus pallidus. Thus, the globus pallidus may be more vulnerable to cytotoxic damage than the putamen in UE. The globus pallidus is thought to be a vulnerable area of toxic/metabolic injury because of its high energy requirements and resultant sensitivity to mitochondrial and nuclear dysfunction.^21,27 Toxic/metabolic encephalopathy, including carbon monoxide, cyanide, cocaine, opiate, and manganese intoxication, and Wilson disease involve selective vulnerability of pallidal neurons.^{28⇓⇓–31} However, the vulnerability of the globus pallidus in UE has not been established, though cytotoxic edema in the globus pallidus has been described in UE.^13,14 Several pathologic studies reported cytotoxic edema in posterior reversible encephalopathy syndrome associated with fibrinoid necrosis and microinfarction³² and suggested a causal relationship between cytotoxic edema and larger areas of vasogenic edema.³³ However, in this study, there was no significant difference in the extent of vasogenic edema between groups with cytotoxic edema and other groups with vasogenic edema in basal ganglia lesions.

Cortical or subcortical lesions of UE are predominantly found in the parieto-occipital lobes.¹⁶ Cortical lesion in patients with UE may share pathophysiologic and imaging features with posterior reversible encephalopathy syndrome. Combined clinical features (the presence of neurologic impairment, renal dysfunction, renal failure, DM, metabolic acidosis, systemic hypertension, eclampsia, pre-eclampsia, vascular disease, autoimmune disease, or cancer chemotherapy) and imaging features (the presence of bilateral basal ganglia involvement with LFS, vasogenic/cytotoxic edema in affected regions, or microhemorrhage) should be considered in the differential diagnosis of UE and posterior reversible encephalopathy syndrome.

UE in renal failure is reversibly associated with hemodialysis or peritoneal dialysis, which removes neurotoxic compounds.³⁴ In this study, all patients showed improvement of their neurologic symptoms, normalization of serum Cr levels, decreased serum blood urea nitrogen levels by more than 60%, and complete resolution of imaging abnormalities on available follow-up MR imaging after intensified hemodialysis.

There are some limitations to this study. First, the sample size was small. Follow-up MR imaging was not performed in the patients who had restricted diffusion (cytotoxic edema) in their basal ganglia lesions. We cannot comment on the reversibility of these lesions. The sensitivity/specificity of the LFS for UE was not determined because of selection bias in this study. Finally, this study has not reliably demonstrated that the more severe the UE, the more likely it is to demonstrate the LFS on MR imaging, also due to selection bias.