Clinically, the diagnosis of uremic encephalopathy is suspected in patients with advanced CKD who present with a constellation of neurologic clinical signs and symptoms, as described earlier. The diagnosis can be confirmed with the resolution of signs and symptoms after a series of dialysis. Electroencephalographic findings in uremic encephalopathy are nonspecific. Typical findings are generalized slowing with an excess of delta and theta waves and sometimes bilateral spike-wave complexes.¹⁹ EEG is rarely needed for diagnosing uremic encephalopathy.

Similarly, brain images are rarely performed for patients with uremic encephalopathy. In one study, a diffusion-weighted magnetic resonance imaging (MRI) was performed prior to the initiation of hemodialysis in eight ESRD patients. The average blood urea nitrogen (BUN) level was 161 mg per deciliter. None of these patients had prior neurologic disorders. MRI revealed diffuse interstitial brain edema with a increased apparent diffusion coefficient.²⁰ However, reversible diffuse cytotoxic brain edema was reported in a patient with left facial palsy, aphasia and confusion, and a BUN level of 220 mg per deciliter.²¹ It appears that uremic encephalopathy is associated with brain edema, which may advance from interstitial form to cytotoxic form if left untreated.

In patients on maintenance dialysis, the diagnosis of uremic encephalopathy can be difficult. The neurologic symptoms and signs are similar between uremic encephalopathy and other brain pathologies such as strokes, hepatic encephalopathy, hypertensive encephalopathy, Wernicke encephalopathy, and others (Table 78.2). Other differential diagnoses include electrolyte and endocrine abnormalities, drug and food effects, dementia, and depression (Table 78.2). In ESRD patients, an altered mental status may occur due to electrolyte and endocrine abnormalities such as hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, and hypoglycemia. The drugs listed in Table 78.2 are commonly associated with neurotoxicity in patients with ESRD. They cause confusion or seizure probably due to changes in drug metabolism or clearance of the drugs, or their potentially toxic metabolites. Starfruit (Fig. 78.1), a popular fruit in Southeast Asia and Central and South America, can cause neurologic symptoms in patients with advanced CKD within hours. Symptoms include hiccups, vomiting, confusion, seizure, and even death.²² In one series from Taiwan, the mortality was as high as 40%.²³

If BUN and serum creatinine (Cr) levels are elevated, uremic encephalopathy due to inadequate dialysis can be diagnosed without difficulties. Frequently, BUN and serum Cr levels may not be elevated due to malnutrition and sarcopenia, which are frequently associated with inadequate dialysis. A careful evaluation of dialysis records and physical and laboratory findings are needed to eliminate possibilities of other encephalopathies because the management could be quite different for each disease. For example, Wernicke encephalopathy (ophthalmoplegia, ataxia, and disturbance of consciousness) is due to the depletion of thiamine from dialysis removal of this water-soluble vitamin, and can be treated with supplementation of thiamine along with other water soluble vitamins.²⁴ If uremic encephalopathy is highly suspected, a therapeutic trial with renal replacement frequently ameliorates CNS symptoms and confirms the diagnosis.

Of note, there are a few case reports of posterior reversible encephalopathy syndrome (PRES) in patients with ESRD and neurologic symptoms.²⁵,²⁶,²⁷ These patients had bilateral
symmetric hypodense lesions in the territories of the posterior circulation, which were reversible after hypertension was controlled. Almost all of them presented with uncontrolled hypertension (frequently > 200 mm Hg systolically). The brain edema is due to the leakage of fluid from hypertension-damaged blood vessels, so called “vasogenic edema.” The edema occurs preferentially in the posterior of the brain, whereas brain edema associated with uremic encephalopathy is diffuse. Because the pathogenesis and treatment of these two diseases are different, it is critical to distinguish them as separate disease entities.

The diagnosis of DDS is mainly based on the onset of symptoms, the history of prolonged and untreated renal failure, markedly elevated BUN levels, and the association with hemodialysis. Unfortunately, up to now there are no clinical criteria for the diagnosis of DDS. As a result, DDS has become a wastebasket for any neurologic symptoms that occur after hemodialysis. Although DDS is rarely encountered in current nephrology practice, there have been several cases reported in recent literature, including two lethal cases.³³,³⁴,³⁵,³⁶,³⁷ These cases are summarized in Table 78.3. Most of them are young, with a predialysis BUN level in the range of 109 to 241 mg per deciliter and a decrease in the BUN level of 60 to 92 mg per deciliter. The blood flow rate and dialysis time in some cases are excessive. The onset of symptoms is closely related to hemodialysis. Most of them had documented brain edema with imaging studies. Two out of 5 patients died, and the others recovered without sequelae. From these case reports, it appears that a predialysis BUN level greater than 100 mg per deciliter with a decrease in BUN level greater than 60 mg per deciliter are reasonable criteria for the diagnosis of clinically significant DDS (i.e., altered mental status, seizure, and neurologic defects). The onset of symptoms occurs immediately after hemodialysis and brain edema, which are demonstrated by imaging studies that may further confirm the diagnosis. It should be mentioned that uremic patients with a head injury, subdural hematoma, stroke, malignant hypertension, and other conditions associated with brain edema are at a higher risk of DDS due to existing conditions that predispose them to cerebral edema.³⁶

Dialysis dementia is suspected in patients on maintenance dialysis who develop speech disorders, personality changes, and dementia. EEGs are diagnostic for dialysis dementia. The characteristic EEG changes are a mild slowing of the dominant rhythm with increased low voltage theta and bursts of anteriorly predominant high voltage delta. Occasionally, the paroxysmal activity may take the form of a 1.3 to 3.0 c per second spike and wave, mainly in the frontocentral region.³ Blood aluminum levels may not be elevated, but should be increased after the infusion of the chelating agent, deferoxamine (DFO).⁴¹ The concurrence of osteomalacia and microcytic anemia also prompts physicians to look for aluminum toxicity.

Cognitive impairment and dementia in CKD patients are frequently ignored. As a result, they tend to progress rapidly to an irreversible state. The prevalence of dementia in ESRD patients has been reported to be as high as 37%⁴⁴; however, in a cohort of 16,694 patients in the Dialysis Outcomes and Practice Patterns Study, dementia was documented in the medical records as a comorbid condition in 4% of the entire study population.⁵⁶ It is recommended that screening for cognitive impairment should start from the onset of ESRD. There are many screening tests available. The Mini-Mental State Exam (MMSE) is perhaps the most studied cognitive test for dementia. There are other tests such as Mini-Cog and the Kidney Disease Quality of Life test, which can be used annually to assess the progression of cognitive impairment.⁴,⁴⁸ The most critical part of the evaluation of dementia is the search for reversible causes of altered mental status, including electrolyte abnormalities, drug effects, infections, depression, uremia, hepatic or cardiac failure, and others (Table 78.2). The laboratory evaluation should include HIV serologies, vitamin B12 levels, and thyroid function tests.⁴

Brain imaging studies are valuable for diagnosing cognitive impairment and dementia in CKD patients, particularly for identifying vascular dementia. Two major MRI findings are related to cerebral small vessel disease: lacunar infarct and white matter lesions. Both of them are increased in patients with CKD.⁵¹,⁵²,⁵³ However, these findings are common in CKD patients; thus, the presence of these findings does not exclude other causes of cognitive impairment.