Neurologic complications occur frequently in the setting of kidney disease and transplantation, with an incidence reported at 10% to 21% in the posttransplant setting. Neurologic complications may arise immediately after transplantation or can occur months to years after transplant. Renal disease can also lead to neurologic conditions, some of which can be improved or resolved by kidney transplantation. In this chapter, we will first discuss the neurologic complications of chronic kidney disease in terms of central and peripheral neurologic complications. We will also discuss the neurologic complications of renal transplantation by the timing of the onset of symptoms and by clinical localization. Encephalopathy and seizures can occur due to a variety of etiologies, and are some of the more common symptoms of the neurologic complications detailed in this chapter. Tables 33.1 and 33.2 list the most common etiologies of encephalopathy and seizures, respectively, in kidney disease and transplantation by the timing of onset.
| Differential Diagnosis of Encephalopathy | |||
|---|---|---|---|
| Pretransplant | Acute | Subacute | Chronic |
| Uremic encephalopathy | Allograft dysfunction | Allograft dysfunction | Allograft dysfunction |
| Electrolyte disturbance | Neurotoxicity from immunosuppressants | Neurotoxicity from immunosuppressants | Neurotoxicity from immunosuppressants |
| Dialysis disequilibrium syndrome | PRES | PRES | PTLD |
| Wernicke encephalopathy | Donor-derived opportunistic infections | Opportunistic infections | Opportunistic infections |
| Dialysis dementia | Residual effect of anesthesia | Cognitive decline | |
| Subdural hematoma | Cerebrovascular complications | ||
| Metabolic derangements | Metabolic derangements | ||
| Differential Diagnosis of Seizures | |||
|---|---|---|---|
| Pretransplant | Acute | Subacute | Chronic |
| CNI side effect | CNI side effect | CNI side effect | CNI side effect |
| PRES | PRES | PRES | Metastatic cancer |
| Uremia | Opportunistic infection | Opportunistic infection | |
| Electrolyte disturbance | Electrolyte disturbance | ||
| Hemorrhagic or ischemic stroke | |||
| Dialysis disequilibrium syndrome | |||
Neurologic Complications of Chronic Kidney Disease
Chronic kidney disease (CKD) affects 12% of adults in the US. Renal failure and its management with hemodialysis are associated with both central and peripheral nervous system complications.
Central Nervous System
When renal failure results in insufficient clearance of nitrogen waste products, buildup of these products can result in uremia. Patients will present with an elevated blood urea nitrogen (BUN) level; however, the absolute value of the BUN or BUN to creatinine ratio does not always correlate to the clinical presentation. Acute kidney failure can often result in more dramatic neurologic clinical presentations than chronic kidney failure. The majority of the neurologic manifestations of uremia affect the central nervous system, but uremic polyneuropathy and uremic myopathy can also be seen (as below). In addition to uremia, patients with CKD may exhibit neurovascular disease, including subdural hematomas.
Dialysis presents a unique challenge in that it can improve or stabilize many central nervous system sequelae of CKD, but it can also lead to new neurologic symptoms and syndromes. Dialysis disequilibrium syndrome, hemodialysis-related headaches, dialysis dementia, and sleep disorders may be seen after initiation of renal replacement therapy.
Uremic Encephalopathy
Uremic encephalopathy exists on a spectrum and can range from fatigue and confusion to coma. Initial presenting symptoms may be subtle, consisting of fatigue, apathy, clumsiness, and poor concentration. Symptoms can progress to emotional lability, sluggishness, irritability, and impaired abstract thinking; later symptoms include delirium with visual hallucinations, disorientation, and agitation, before progressing to coma and death. Uremia was usually fatal before the advent of renal replacement therapy. Chronic uremia may cause progressive subtle cognitive changes, including psychomotor slowing personality changes, forgetfulness, and symptoms similar to attention deficit disorder. Patients with acute kidney injury or acutely decompensated chronic kidney disease are more susceptible to severe uremic symptoms due to the rapid rise in BUN. ,
Neuroimaging is typically not necessary to make a diagnosis of uremic encephalopathy in patients with CKD who have altered mental status in the setting of elevated BUN or BUN to creatinine ratio or in dialysis patients who have missed dialysis; however, imaging may help exclude other causes of encephalopathy. Patients with chronic uremic encephalopathy may develop reversible magnetic resonance imaging (MRI) changes (low signal intensity on T1 imaging and high signal intensity on T2 imaging) in the basal ganglia, periventricular white matter, and internal capsule, which resolve with dialysis. Electroencephalogram (EEG) may show diffuse slowing, generalized periodic discharges with triphasic morphology, frontal intermittent rhythmic theta, or paroxysmal bilateral diffuse high-voltage theta. , EEG may become slower with higher creatinine values, with a correlation between the percentage of frequencies below 7 Hz and increase in serum creatinine. EEG during sleep may show increased vertex waves, a lack of spindles in stage 2 sleep, and prolonged high-voltage, slow bursts on awakening.
The pathology of uremic encephalopathy has been debated, but leading theories include the accumulation of uremic neurotoxins, inflammatory response in the acute setting leading to breakdown of the blood-brain barrier, hormonal disturbances, alterations in intermediary metabolism, and alterations in relative neurotransmitter concentrations. , There is no single metabolite that has been identified as the cause of uremia.
Movement Disorders Associated With Uremia
Uremia may present with involuntary movements, including asterixis (sudden loss of tone causing flapping movements), myoclonus (sudden brief muscle jerking, which can be seen in a single limb or generalized), and coarse postural and kinetic tremor ; these abnormal movements are sometimes seen with fasciculations and are referred to as the twitch-convulsive syndrome. EEG is sometimes performed to differentiate involuntary movements, which are typically asynchronous but may become rhythmic at times, from seizures. Chorea or parkinsonism occur less frequently, but can be associated with radiologic changes in the basal ganglia.
Seizures
Patients with renal failure may present with seizures in the setting of uremia alone or secondary to other structural or metabolic complications. Up to one-third of patients with uremic encephalopathy develop seizures, which may be focal or generalized, convulsive or nonconvulsive. , Convulsive or nonconvulsive status epilepticus is common. Treatment with antibiotics, such as beta-lactam penicillins, cephalosporins, carbapenems, and quinolones, can cause neurotoxicity leading to convulsive or nonconvulsive status epilepticus. Fluctuations in blood pressure can cause patients with CKD to develop posterior reversible encephalopathy syndrome (PRES), which is associated with seizures in 60% to 75% of patients.
Patients with CKD who require antiepileptic drugs (AEDs) for seizure management may require renal dosing of their medications. Renally cleared AEDs, such as levetiracetam, topiramate, or gabapentin, require supplemental dosing after dialysis sessions, and may require lower doses in patients who do not require dialysis. Highly protein-bound AEDs, such as phenytoin, valproic acid, and carbamazepine, are less susceptible to dialysis and are generally preferred in these patients, although dosing adjustments may still be necessary for renally excreted metabolites.
Pharmacologic Neurotoxicity
Patients with CKD are at increased risk of side effects and toxicity from medications. Cefepime, in particular, can cause encephalopathy ( Fig. 33.1 ) and myoclonus, and less commonly seizures including nonconvulsive status epilepticus. Cefepime and other medications must be renally adjusted to avoid neurotoxicity.
Cerebrovascular Disease
Chronic kidney disease predisposes patients to both hemorrhagic and ischemic stroke and progressive microvascular disease, and CKD patients requiring dialysis have an even higher risk of stroke. Impaired regulation of cerebral blood flow is seen in patients with CKD and may contribute to elevated risk of stroke and white matter injury. Outcomes in patients with CKD who are hospitalized with acute ischemic or hemorrhagic stroke are worse than in patients without renal disease.
Atherosclerosis and thromboembolic disease are the most common causes of ischemic strokes in patients with CKD, although hypotensive episodes during dialysis may also cause watershed infarcts. Patients with CKD have advanced carotid atherosclerosis compared with patients without renal disease, and a component of atherosclerotic disease may be due to uremia itself. Anemia, which is a common sequela of CKD, is an independent risk factor for stroke ; the combination of CKD and anemia produces a marked increase in stroke risk.
The most likely etiology of hemorrhagic stroke in patients with CKD is hypertension, and the most likely locations for hypertensive hemorrhages are the basal ganglia, cerebellum, and brainstem. Cerebral microhemorrhages are observed on brain imaging of patients with CKD, and the extent of microhemorrhages inversely correlates with glomerular filtration rate (GFR). Uremia can lead to platelet dysfunction, which, along with anticoagulation used during hemodialysis, can contribute to risk of hemorrhagic stroke. There is also an association between CKD and retinal artery disease, with microvascular changes that are independent of diabetes history.
Subdural Hematomas
Patients undergoing both hemodialysis and peritoneal dialysis are at increased risk of developing subdural hematomas, which most commonly occur after trauma. This increased risk may be due to uremia-related coagulation disturbances or platelet dysfunction, use of anticoagulants during dialysis, and use of rapid filtration and hypertonic dialysate. Patients who sustain subdural hematomas or are thought to be at especially high risk may benefit from heparin-free dialysis and fall prevention education. Symptoms may be focal, such as hemiparesis, or may consist of more generalized symptoms such as encephalopathy and ataxia.
Dialysis Disequilibrium Syndrome
Dialysis disequilibrium syndrome describes a pattern of symptoms including headache, irritability, restlessness, blurred vision, nausea, muscle cramps, myoclonus, encephalopathy, and seizures, which develops toward the end of the dialysis session and typically resolves over hours. Symptoms may include focal deficits, creating a stroke-like presentation, and can last for days in severe presentations. The risk of developing dialysis disequilibrium syndrome is highest with initiation of dialysis or in the setting of missing dialysis sessions. Dialysis disequilibrium syndrome has become uncommon with preventive measures, including adding osmotically active solutes to dialysate, and should be treated as a diagnosis of exclusion, particularly when presenting with symptoms that are prolonged or focal.
Several theories as to the etiology of dialysis disequilibrium syndrome have been posited. The reverse urea hypothesis suggests that slower cerebral urea clearance causes osmotic shifts in the brain leading to cerebral edema. The idiogenic osmole hypothesis offers the idea that newly formed osmoles within the brain create an osmotic gradient between the brain and the periphery. Another theory proposes edema is caused by increased production of organic acids, causing cortical intracellular acidosis.
Hemodialysis-Related Headache
The International Headache Society defines hemodialysis-related headaches as headaches that develop during at least half of hemodialysis sessions, occur at least three times, and resolve within 72 hours of dialysis. These headaches are thought to be the result of water and electrolyte shifts during dialysis, but hypoxemia occurring at the beginning of sessions, changes in serotonin levels, hyponatremia, urea disturbances, or a mild dialysis disequilibrium syndrome have also been proposed as etiologies. Hemodialysis-related headaches typically resolve with kidney transplantation.
Dialysis Dementia
Dialysis dementia is a subacute neurodegenerative condition consisting of apathy, personality changes, dysarthria, dysphagia, ataxia, myoclonus, seizures, and dementia, progressing to immobilization and mutism followed by death within 6 months. This condition was more common before 1980, when patients were dialyzed with an aluminum-containing dialysate used to bind dietary phosphate. Dialysis dementia has become less common with the use of aluminum-free phosphate binders and low concentration of aluminum in modern dialysate; however, dementia in dialysis patients, particularly vascular dementia, still occurs at rates higher than age-matched healthy controls. Cognitive impairment can be seen in 50% to 87% of dialysis patients. Transplantation may improve memory and processing speeds, but not attention and executive functioning.
Sleep Disorders
About 80% of patients on dialysis report sleep complaints, and the most common sleep disorders include insomnia, excessive daytime sleepiness, obstructive sleep apnea (OSA), and restless legs syndrome (RLS). Nightmares, sleepwalking, rapid eye movement (REM) behavior disorder, and narcolepsy have also been reported.
Patients with CKD lack the evening melatonin surge that controls the circadian sleep-wake cycle. Melatonin supplementation, along with good sleep hygiene and sleep-focused cognitive behavioral therapy, may be helpful for patients with insomnia. Acidemia increases ventilatory effort in patients with CKD and may contribute to OSA. Dialysis patients may be predisposed to RLS and periodic limb movements due to cerebral iron deficiency, accumulation of uremic toxins, central dopamine deficiency, or uremic polyneuropathy. Cool dialysate, early morning dialysis sessions, short daily hemodialysis, dopaminergic medications (levodopa, ropinirole, pramipexole, and rotigotine), and gabapentinoids (gabapentin or pregabalin) can improve RLS symptoms, and transplantation can cause lasting relief.
Wernicke’s Encephalopathy
Patients on hemodialysis or peritoneal dialysis are at risk of developing thiamine deficiency leading to Wernicke’s encephalopathy because of a combination of reduced oral intake and increased loss of thiamine. Thiamine deficiency is most likely to develop in patients on chronic dialysis, but can also occur at the initiation of dialysis. Patients typically present with ataxia, ophthalmoplegia, and altered mental status or memory loss. Presentation can be atypical in patients on chronic dialysis, and Wernicke’s encephalopathy may be underdiagnosed in this patient population.
Peripheral Nervous System
Peripheral nervous system complications of CKD include polyneuropathy, mononeuropathies, and uremic myopathy. Mononeuropathies, especially median neuropathy, are common in patients with CKD, and may result from uremia.
Polyneuropathy
Polyneuropathy occurs in 60% to 100% of patients with end-stage renal disease. Neuropathy can stem from uremia alone, but it can also be attributed to diseases that cause renal failure, such as diabetes mellitus and vasculitis.
Uremic polyneuropathy can be painless or present with numbness, tingling, burning, or other abnormal sensations in the distal extremities. There is a male predominance, and the course is variable. On examination, patients typically have loss of pinprick, temperature, proprioception, and vibration sensation in the distal extremities, with lower extremities being affected before upper extremities, followed by loss of Achilles reflexes. Later, weakness and muscle wasting of the lower before upper extremities occurs, and autonomic involvement has been reported. Uremic polyneuropathy is classically a length-dependent, distal, axonal, sensorimotor, large-fiber neuropathy, but cases of pure motor and pure sensory neuropathy have also been reported. Treatment includes erythropoietin, biotin, pyridoxine, cobalamine, and thiamine. Uremic neuropathy may stabilize or improve with initiation of dialysis and typically resolves with transplantation, but a few patients have reported worsening of their neuropathy with initiation of dialysis.
Mononeuropathies
Isolated mononeuropathies can be an effect of uremia or may be due to increased susceptibility of patients with CKD to compression or ischemia of peripheral nerves. The most common nerves affected are the ulnar, median, and femoral nerves; optic, facial, trigeminal, and vestibulocochlear nerves may also be affected.
Carpal tunnel syndrome is a compressive neuropathy affecting the median nerve at the wrist. Symptoms include numbness, paresthesia, and pain in the thumb and first two or three fingers, followed by weakness and atrophy of the thenar muscles in severe cases. Carpal tunnel syndrome can be confirmed by nerve conduction studies, electromyography (EMG), and ultrasound. Patients undergoing hemodialysis are at increased risk of developing carpal tunnel syndrome, especially in the upper extremity ipsilateral to the arteriovenous fistula. The frequency of diagnosis of carpal tunnel syndrome increases with the duration of hemodialysis. Mechanisms include local deposition of amyloid, increased venous pressures distal to the fistula, direct uremic toxic effect, and nerve ischemia.
Ulnar neuropathy at the wrist due to uremic tumoral calcinosis in Guyon canal results in weakness of the intrinsic hand muscles and sensory loss in an ulnar nerve distribution.
The vestibulocochlear nerve can be affected by uremia, leading to hearing loss and deafness; these symptoms can reverse with dialysis or renal transplantation.
Ischemic optic neuropathy can result in sudden vision loss due to vascular compromise to the anterior or posterior portion of the optic nerve. In anterior ischemic optic neuropathy, funduscopic examination reveals pale optic discs with blurred margins and retinal hemorrhage. Posterior ischemic optic neuropathy, on the other hand, initially has a normal funduscopic examination, but pallor appears within 4 to 8 weeks.
Myopathy
Uremic myopathy consists of proximal limb weakness, muscle wasting, easy fatigability, limited exercise tolerance, and pain. Up to 50% of patients on hemodialysis have some functional alteration of skeletal muscle, and cardiomyopathy is sometimes present as well. Neurologic examination and serum creatine kinase are typically normal, but a myopathic pattern may be revealed on EMG. Uremic myopathy often worsens as renal failure progresses but improves with renal transplantation. Possible mechanisms include direct toxic effect from uremic toxins, altered vitamin D metabolism, carnitine deficiency, lactic acidosis, insulin resistance, ischemia, and malnutrition.
Neurologic Complications After Kidney Transplantation
Acute Neurologic Complications (Less Than 1 Month)
Neurologic symptoms may present quickly posttransplantation or may develop months or years later. In this section, we will explore the central and peripheral nervous system complications that arise within the first month of transplantation.
Central Nervous System
Perioperative Vascular Insults
Patients with CKD are at high risk of cerebrovascular disease, and this risk is still present posttransplantation. The perioperative state is a high-risk period due to volume and blood pressure shifts intraoperatively, but the mean timing of strokes is 49 months posttransplantation. Major surgery in the last 14 days is a relative contraindication to thrombolytic administration for acute stroke, but thrombolysis should be considered if strokes occur outside of this time period. Acute large vessel occlusions should be considered for mechanical thrombectomy if patients present within the treatment window.
Spinal cord infarctions are possible during renal transplant surgery. Normally, the caudal spinal cord is supplied by the intercostal arteries; however, a normal variant may occur with branches of the internal iliac arteries supplying the caudal spinal cord. When the iliac artery is manipulated in the setting of this variant, spinal cord ischemia can occur, causing conus medullaris syndrome, a constellation of lower extremity pain and sensory loss, sphincter disturbance, and mixed upper and lower motor neuron signs. Caudal spinal cord ischemia is irreversible and is therefore not a neurosurgical emergency.
Postsurgical Encephalopathy
Patients with early graft failure may have more difficulty clearing anesthetics or paralytics and may present with encephalopathy or paralysis in the postoperative period due to medication effect. Perioperative stroke should be ruled out with head imaging, especially if patients have focal neurologic deficits.
Uremic and Metabolic Encephalopathy
Patients who undergo kidney transplantation are at high risk of metabolic derangements. Allograft dysfunction may cause recurrence of uremia, with patients developing encephalopathy, seizures, myoclonus, and asterixis. Separate from uremia, rejection encephalopathy is seen in transplant patients with allograft dysfunction and is thought to be due to cytokine release. Hyponatremia and hypocalcemia may also develop and present with encephalopathy. Polypharmacy and hospital delirium may also play a role in altered mental status in the immediate postoperative phase.
Side Effects of Immunosuppressant Medications
Immunosuppressant medications are used as antirejection agents after transplantation. Side effects of calcineurin inhibitors (CNI), such as tacrolimus and cyclosporine, include tremor, hyperreflexia, insomnia, headache, and mood disturbances; less commonly, akinetic mutism, hearing loss, optic neuropathy, pseudotumor cerebri, tumefactive demyelination, leukoencephalopathy, and seizures can occur. CNI can also lead to hippocampal sclerosis and development of refractory epilepsy. CNI, through an unknown pathophysiology, can cause a chronic pain syndrome referred to as CNI-induced pain syndrome, or CIPS. Medication side effects and toxicity can occur at any time and at any drug level, including within the therapeutic range. If side effects are addressed by dose adjustment or discontinuation, immunosuppressants may be changed or restarted at a lower dose once symptoms improve.
Seizures
Seizures occur in 5% to 10% of transplant recipients, most often in the immediate posttransplant period. CNI side effect or toxicity is the most common cause of seizures, and CNI levels may be normal or elevated at time of seizure. Hypomagnesemia due to cyclosporine-induced renal wasting can cause seizures, and other metabolic abnormalities such as hyponatremia, hypocalcemia, and hypoglycemia should also be included in the differential of a posttransplant patient who develops new onset seizures. Seizures can be seen as part of PRES or can occur as a symptom of a central nervous system (CNS) infection or stroke.
The aim of treating seizures in posttransplant patients is seizure control without significant side effects or medication interactions. Patients who present in status epilepticus, with seizures lasting longer than 5 minutes or multiple seizures without return to baseline, should be treated with intravenous lorazepam followed by intravenous fosphenytoin, although intravenous valproate and levetiracetam are also supported by guidelines. Patients who develop recurrent seizures or who have a single seizure with an epileptogenic focus on brain imaging or EEG should be started on an AED. Seizures are typically provoked, and therefore only short-term treatment (1–3 months) is generally needed. Phenytoin, phenobarbital, and carbamazepine induce cytochrome P450 enzymes and interact with CNI and corticosteroids, so they are not typically recommended for transplant patients, except for treatment of status epilepticus. Newer agents such as levetiracetam and lacosamide are preferred, because they can be loaded intravenously, have few medication interactions, and are not highly protein bound. Gabapentin and pregabalin are safe for use as adjunctive therapy in transplant patients with focal-onset seizures, but cannot be given intravenously, are not approved for use in generalized seizures, and are not highly effective first-line agents.
Posterior Reversible Encephalopathy Syndrome
PRES is commonly associated with CNI use and occurs most often in the first 3 months posttransplantation, but may present at any point. Risk factors include hypertension, large blood pressure fluctuations, CNI administration, vascular endothelial growth factor (VEGF) inhibitors such as bevacizumab, sepsis, and renal failure, so both patients with CKD and patients who have received a kidney transplant are at risk. In patients who are treated with CNI, most cases of PRES occur within 2 weeks of medication initiation or dose increase, but 20% of cases present months to years after starting the offending agent. Patients treated with CNI who develop PRES can have onset of symptoms at relatively low blood pressures, so PRES should not be ruled out because of normotension on presentation.
Patients with PRES typically present with hours to days of altered mental status, seizures, headache, and vision changes. Imaging reveals patchy or confluent cortical and subcortical vasogenic edema, most commonly in the bilateral occipital lobes extending anteriorly to the parietal lobes in a gyriform pattern, but sometimes involving the frontal and temporal lobes as well ( Fig. 33.2 ). PRES has been reported in the spinal cord and in the brainstem and cerebellum, which can cause reversible obstructive hydrocephalus. Etiology is thought to be secondary to autoregulatory failure, direct effect of cytokines, or compromised endothelial integrity, causing capillary leakage into the parenchyma.
