eMedicine Specialties > Neurology > Critical Care Neurology

Neurologic Complications of Organ Transplantation

Author: Sasa Zivkovic, MD, MSc, Assistant Professor, Department of Neurology, Division of Neuromuscular Diseases, University of Pittsburgh and VA Pittsburgh Healthcare System
Contributor Information and Disclosures

Updated: Jan 25, 2008

Introduction

Background

Organ transplantation has developed at an incredibly rapid pace since its introduction in the 1950s, and it has become a life-saving procedure for patients with end-stage organ failure. In 2006, more than 20,000 hematopoietic stem cell transplantations and 27,000 solid organ transplantations were performed in the United States alone.

The posttransplantation clinical course is frequently complicated by dysfunction of various organ systems, and early or delayed neurologic complications may develop in 30-60% of patients.^1,2 Because of the constantly changing protocols of transplantation and immunosuppression, the nature of neurologic complications has changed over time. Improved survival of patients undergoing transplant also shifts the focus of neurologic complications towards long-term complications. Nevertheless, diagnosis and management of perioperative complications of organ transplantation still plays a prominent role in determining the postoperative course of allograft recipients.

Organ transplantation may also improve neurologic function in various disorders with neurologic manifestations such as Wilson disease (liver transplantation), familial amyloidosis with neuropathy (liver transplantation), and diabetic neuropathy (pancreas transplantation).

Future developments in the field of organ transplantation, including newer immunosuppressive medications and xenograft and neural tissue transplantation, will further change the spectrum of neurologic and other complications in transplant recipients.

Pathophysiology

Neurologic complications are related to the surgical procedure of transplantation, posttransplant immunosuppression, opportunistic infection, or inherent disorders that led to transplantation.

Some neurologic complications of transplant surgery are inherent to all transplant types (eg, opportunistic CNS infections, immunosuppressant neurotoxicity, anoxic encephalopathy), while others are more common with certain types of allografts.

Posttransplant immunosuppression increases the risk of opportunistic infections, particularly after 1 month posttransplantation. While greater immunosuppression increases the risk of opportunistic infections and immunosuppressant neurotoxicity, it may be needed for treatment of allograft rejection. Exposure of patients undergoing transplant to endemic pathogens may result in increased frequency of certain infections.

The variety of conditions that led to organ failure requiring transplantation may also be associated with neurologic complications, including amyloid and diabetic neuropathy. Delayed allograft function may also precipitate various complications, including impairment of consciousness with hepatic and uremic encephalopathy.

Frequency

United States

Neurologic complications affect up to 30-60% of allograft recipients.

International

Neurologic complications of organ transplantation occur internationally with a similar frequency as in the United States.

Because the spectrum of CNS infectious pathogens depends on exposure, some endemic pathogens, mucormycosis, and parasitic diseases may be more common in tropical regions.

Mortality/Morbidity

Neurologic complications in patients undergoing transplant complicate posttransplant recovery, and opportunistic CNS infections may be very difficult to treat in patients who are immunosuppressed. Opportunistic CNS infections affect 5-10% of transplant patients, with a reported mortality rate of 75-90%.

Race

No racial predilection exists.

Sex

No significant association between sex and incidence exists.

Age

Neurologic complications of transplantation may develop in patients of any age.

Clinical

History

Consider the onset of symptoms in relation to pretransplant neurologic status, to transplantation procedure, and to the current status of the transplanted allograft because the spectrum of complications changes over time and is influenced by a multitude of factors.

Early after transplantation, the use of a higher dose of immunosuppressive medications predisposes patients to their neurotoxicity. The presence of pretransplant infection may be associated with hyperacute infections after surgery, while the incidence of newly acquired opportunistic infections in solid organ allograft recipients rises after 1 month posttransplantation.

Rejection episodes may require heavier immunosuppression, and this results in increased risk of drug neurotoxicity (eg, tacrolimus, cyclosporin, OKT3, steroids) and also in an increased risk of opportunistic infections. At the same time, declining function of rejected allograft may also precipitate metabolic encephalopathy or other neurologic complications.

• Kidney transplantation: Kidney transplantation is usually performed in patients with diabetic and hypertensive nephropathy or glomerulonephritis. Kidney transplantation is associated with a low rate of neurologic complications, including femoral neuropathy, lumbosacral plexopathy, and ischemic stroke. Rarely, spinal cord ischemia may develop in patients in whom the iliac artery, which would have previously supplied spinal cord circulation, is used for allograft blood supply.
• Heart transplantation: Heart transplantation is used to treat patients with intractable cardiomyopathies and ischemic heart disease. The surgery of heart transplantation has similar complications as other open-heart procedures, including ischemic stroke, encephalopathy, and peripheral nerve injury. Pretransplant bridging with artificial hearts and ventricular assist devices is associated with cardiac embolism and requires anticoagulation.
• Lung transplantation: Lung transplantation is used in treatment of end-stage lung disease caused by various diseases, including cystic fibrosis, idiopathic pulmonary fibrosis, and alpha1-antitrypsin deficiency. The surgical procedure of lung transplantation is frequently combined with heart transplantation. Lung transplantation is associated with increased risk of stroke, anoxic encephalopathy, and injury to the phrenic and recurrent laryngeal nerves.
• Pancreas transplantation: Pancreas transplantation is performed in treatment of patients with advanced diabetes mellitus and extensive end-organ damage, including nephropathy, retinopathy, and neuropathy. If transplantation is successful, euglycemia is established and reversible end-organ damage may improve. Pancreas transplantation is frequently combined with kidney transplantation, particularly in patients with advanced diabetic nephropathy.
• Liver transplantation: Liver transplantation is used to treat liver failure caused by alcoholic or cryptogenic liver cirrhosis, viral and toxic hepatitis, metabolic liver diseases (eg, amyloidosis, Wilson disease), or other causes. Patients with hepatic failure may have prominent encephalopathy prior to transplantation, and this may continue after transplantation until adequate liver function is established. Patients undergoing liver transplantation may develop central pontine myelinolysis (CPM) perioperatively.
• Intestinal transplantation: Intestinal transplantation is used in the treatment of patients with intestinal failure who cannot be maintained on total parenteral nutrition. Prolonged intestinal failure with dependence on total parenteral nutrition may result in complex nutritional deficiencies. Many patients undergo combined liver-intestine transplantation for concurrent hepatic insufficiency. Newer tolerogenic protocols reduce the need for long-term heavy immunosuppression, so immunosuppressive drug neurotoxicity and opportunistic infections are becoming less common. Patients with underlying hypercoagulable conditions may require long-term anticoagulation. 
• Hematopoietic stem cell transplantation (HSCT)
  • HSCT is the transplantation of bone marrow and peripheral blood stem cells.
  • Autologous and allogeneic stem cells from bone marrow transplantation are used in the treatment of hematologic and solid organ malignancies and autoimmune and metabolic diseases. Neurologic complications are most common with allogeneic bone marrow transplantation, which usually requires long-term immunosuppression.
  • Idiopathic hyperammonemia is a rare, but frequently fatal, complication in patients undergoing bone marrow transplantation.
  • Chronic graft versus host disease (GVHD) may be associated with neuromuscular complications, including inflammatory myopathy, neuropathy, and myasthenia. Rarely, CNS is affected (vasculitis).
  • In patients with hematologic malignancies, pretransplant cranial irradiation and intrathecal chemotherapy may cause delayed leukoencephalopathy, even years after irradiation. Patients undergoing bone marrow transplantation are at risk from opportunistic CNS infections immediately after the transplantation procedure when pancytopenia is most prominent.

Physical

• Impairment of consciousness
  • Early postoperative period (first 30 d)
    • Metabolic disturbances (eg, electrolyte and glucose abnormalities, central pontine myelinolysis)
    • Anoxic encephalopathy
    • Immunosuppressive drug toxicity
    • Other drug toxicity
    • Opportunistic infection (bone marrow transplantation)
  • Subacute posttransplantation period (1-6 mo)
    • Opportunistic infection (solid organ allografts)
    • Metabolic disturbances (eg, electrolyte and glucose abnormalities)
    • Immunosuppressive drug toxicity
    • Other drug toxicity
  • Chronic posttransplantation period (>6 mo)
    • Opportunistic infection (solid organ allografts)
    • Metabolic disturbances (eg, electrolyte and glucose abnormalities)
    • Immunosuppressive drug toxicity
    • Other drug toxicity
• Psychiatric disturbances
  • Psychogenic reactions
  • Major depression (more common in liver allograft recipients transplanted for hepatitis C), anxiety disorders, adjustment disorders
  • Postoperative delirium (more common in liver transplant recipients with history of alcoholism)
• Cranial nerve palsies: Cranial nerve palsies in patients undergoing transplant may be related to brainstem lesions (eg, ischemic stroke, hemorrhage, tumor), basilar meningitis, invasive fungal sinusitis, or lymphomatous infiltration of cranial nerves. Tacrolimus neurotoxicity may cause reversible internuclear ophthalmoplegia.
• Vision difficulties: Various visual disturbances have been reported in allograft recipients, mostly as a result of tacrolimus and cyclosporin toxicity. Cortical blindness, complex visual disturbances, and hallucinations occur in the setting of reversible dose-related toxicity of calcineurin inhibitors but may occur with focal lesions and corresponding visual field deficits. Opsoclonus has been described with cyclosporin neurotoxicity. Retinal toxicity and optic neuropathies are observed with calcineurin inhibitors as well, while cardiac allograft recipients may infrequently develop anterior ischemic optic neuropathy.
• Motor weakness: Motor weakness in allograft recipients is associated with various causes of lower and upper motor neuron dysfunction.
  • Lower motor neuron dysfunction
    • Focal neuropathy
    • Critical illness myopathy/polyneuropathy
    • Neuromuscular junction disorder
    • Acute and chronic inflammatory demyelinating polyneuropathy (AIDP, CIDP)
  • Upper motor neuron dysfunction
    • Mass lesions (eg, stroke, intracranial hemorrhage, abscess)
    • Myelopathy
• Sensory symptoms (eg, numbness, paresthesias): Patients undergoing transplant may report numbness related to central or peripheral causes. Perioperatively, several types of entrapment neuropathies may develop. Patients with a history of diabetes mellitus may have diabetic neuropathy, and many transplant recipients have some degree of nutritional deficiency predisposing them to entrapment neuropathies. Focal CNS lesions (eg, stroke, hemorrhage, tumor) might also cause localized areas of numbness.
• Abnormal movements: Transplant recipients frequently develop tremor associated with use of calcineurin inhibitors (ie, cyclosporin, tacrolimus). Infrequently, tremor may be quite disabling, requiring adjustments of the immunosuppression regimen. In the context of hepatic or uremic encephalopathy, they may also develop asterixis. Patients undergoing cardiopulmonary bypass may develop postpump chorea. Chorea was also reported with cardiac allograft rejection and with pontine and extrapontine myelinolysis.
• Headache: Headache is not uncommon in transplant recipients, although it is rarely mentioned in most studies on neurologic complications of organ transplantation. Patients may develop worsening of preexisting migraines or more worrisome new onset of headache. Most commonly, these headaches are benign, but infrequently, headache may be one of the initial manifestations of opportunistic CNS infection. Therefore, new onset of headaches in transplant recipients warrants careful examination and consideration of neuroimaging and cerebrospinal fluid studies. More common causes of newly developed headaches include fungal sinusitis and immunosuppressant toxicity.

Causes

• Infection: Immunosuppression required to suppress allograft rejection increases the risk of systemic and CNS infection. In recipients of solid organ allografts, risk of infection increases 1 month after transplantation, while recipients of bone marrow transplants are at higher risk in the early posttransplant course while their bone marrow function is still not established.
  • CNS infection
    • Recent studies report prevalence of 1-2%
    • Mortality rate 75%
    • Commonly viral or fungal
    • Bacterial or protozoal causes less common
    • Incidence higher after 1 month posttransplantation with solid organ transplantation
    • May occur with dissemination of systemic infection or with direct extension of fungal sinusitis
    • Abscesses (1% of patients) usually fungal (ie, aspergillus) and frequently involve multiple organisms
    • Meningoencephalitis most commonly viral (ie, herpes viruses), also related to Listeria, Toxoplasma, or Cryptococcus³
    • Fungal sinusitis (ie, rhinocerebral zygomycosis) mortality rate up to 50%
    • Progressive multifocal leukoencephalopathy infrequent but carries up to 95% mortality rate
    • Endemic infections of coccidioidomycosis and histoplasmosis
    • Donor-related infection (via allograft) extremely rare, recently reported with rabies⁴ , lymphocytic choriomeningitis virus, and West Nile virus
  • Septic encephalopathy - Systemic infection without direct CNS involvement
• De novo CNS malignancy: Allograft recipients who are immunosuppressed have an increased incidence of de novo malignancies. Most common CNS neoplasms are lymphoma (posttransplant lymphoproliferative disorder [PTLD]), frequently associated with Epstein-Barr virus (EBV) infection and glioma.
  • Posttransplant lymphoproliferative disorder
    • Commonly involves CNS (brain is primary site in up to 26% of patients)
    • Frequently associated with EBV infection
    • May improve with decreased immunosuppression
    • Also treated with local radiotherapy, antiviral medications, and anti-CD20 monoclonal antibodies (rituximab)
  • Glioma
    • Ten times more common than in the nontransplant population
    • Glioblastoma, oligodendroglioma⁵
• Neuromuscular disorders
  • Perioperative neuromuscular complications include focal neuropathies and plexopathies and critical illness myopathy/polyneuropathy. Paradoxically, some patients with diabetic neuropathy may develop worsening of weakness after pancreas transplantation, but this appears to be related to myopathy (critical illness myopathy), rather than worsening of their underlying diabetic neuropathy.
  • Depending on the type of allograft, patients may develop perioperative focal neuropathies, including femoral neuropathy (kidney), phrenic neuropathy (heart, lung), brachial plexopathy (heart, lung, liver), lumbosacral plexopathy (kidney), and peroneal neuropathy (all types).
  • Patients with prolonged stay in intensive care units frequently develop critical illness myopathy or critical illness polyneuropathy that usually occur after use of bolus steroids and prolonged neuromuscular junction blockade.
  • GVHD may also be associated with neuromuscular complications including myasthenia, inflammatory myopathy, and neuropathy.
• Seizures: A variety of seizure types occur in transplant recipients, including both convulsive and nonconvulsive status epilepticus. Often, multiple potential causes are present, and determining a single cause may be difficult. Common potential causes include electrolyte and glucose abnormalities, anoxic encephalopathy, and drug neurotoxicity (ie, from immunosuppressive and other medications), while mass lesions (eg, stroke, hemorrhage, abscess, tumor) and CNS infections are less common. Long-term treatment is frequently not needed.⁶
• Metabolic disorders: Metabolic disturbances usually result in various degrees of impairments of consciousness, but focal symptoms may also occur.
  • Hepatic encephalopathy - Rejection of liver allograft
  • Uremic encephalopathy - Rejection of kidney allograft
  • Glucose abnormalities - Hypoglycemia, hyperglycemia (worsened by corticosteroids and tacrolimus)
  • Electrolyte abnormalities - Hypomagnesemia, hyponatremia
• Central pontine myelinolysis
  • More common after liver transplantation
  • Prevalence estimated at 1-4% on autopsy series of liver allograft recipients
  • Pseudobulbar palsy, quadriparesis, and stupor after rapid correction of hyponatremia
  • Increased T2 signal in central pons on MRI; serial studies may show improvement in some patients
  • Usually follows massive fluid shifts when not associated with correction of hyponatremia
  • Treatment supportive
• Immunosuppressant toxicity
  • Calcineurin inhibitors (eg, cyclosporine, tacrolimus): Calcineurin inhibitor toxicity is usually dose-related, but patients may also present with reference range serum drug levels, particularly in the early posttransplantation period. Monitoring the use of medications that may alter function of cytochrome CYP3A is important because it can drastically alter levels of tacrolimus and cyclosporine. Neuroimaging studies may demonstrate posterior leukoencephalopathy with T2-hyperintense signal on MRI (see Media file 1). Clinical manifestations include akinetic mutism, seizures, psychosis, encephalopathy, cortical blindness, opsoclonus, tremors, and headaches. Importantly, immunosuppressant toxicity frequently resolves after substitution of offending calcineurin inhibitor (eg, cyclosporine) with another immunosuppressant (sirolimus) or another calcineurin inhibitor (eg, tacrolimus).
  • OKT3: OKT3 is a monoclonal antibody targeted against CD3 adhesion molecule. Its use has been associated with aseptic meningitis, seizures, and rarely with akinetic mutism. Similar complications have been reported after use of antithymocyte globulin (ATG) antibodies.
  • Corticosteroids: The use of corticosteroids, particularly at higher doses, may lead to psychotic reactions (ie, steroid psychosis) or to mood alterations (eg, mania, depression). Patient may also develop steroid myopathy or, in the context of critical illness, may develop critical illness myopathy (or polyneuropathy). Higher risk of steroid psychosis has been reported for nontransplant patients with hypoalbuminemia. Rarely, long-term use of steroids may be associated with epidural lipomatosis and myelopathy.
  • Other: Other immunosuppressive medications are less commonly associated with neurologic complications. Mycophenolate is a new purine antagonist, and its use has been associated with few neurologic adverse effects. A small number of patients have reported headache. Azathioprine does not cause neurologic complications. It is potentially hepatotoxic. Sirolimus is a newer tacrolimus-like immunosuppressive medication, without calcineurin inhibition properties. Most common adverse effects are tremor and headache, and recently a case of sirolimus-associated posterior leukoencephalopathy was described.
• Toxicity of nonimmunosuppressive medications: Consider altered pharmacodynamics of various medications with renal and hepatic insufficiency and with complex drug-drug interactions. The following are only a few examples of adverse effects of nonimmunosuppressive medications in transplant patients:
  • Busulfan - Seizures (bone marrow transplant)
  • Imipenem - Seizures
  • Linezolid - Neuropathy, optic neuropathy, serotonin syndrome
  • Colchicine - Neuromyopathy
  • Serotonin reuptake inhibitors (SSRI) - Serotonin syndrome (may be precipitated with a change of dose, or combination of medications [eg, SSRI + tricyclics])
  • Acyclovir - Encephalopathy (with renal insufficiency)
  • Statins - Rhabdomyolysis (in combination with cyclosporine)
  • Thalidomide - Neuropathy (bone marrow transplantation)
  • Bortezomib - Neuropathy (bone marrow transplantation)
• Cerebrovascular disorders
  • Ischemic stroke
    • Hypercoagulable state
    • Vasoinvasive infection (eg, aspergillosis, mucormycosis)
    • Polycythemia (kidney transplantation)
    • Cardioembolic disorders (eg, intracardiac clot [heart transplant], bacterial and nonbacterial thrombotic endocarditis [bone marrow transplant])
    • Cerebral vasculitis secondary to infection, rarely associated with GVHD
    • Spinal cord ischemia associated with use of iliac arteries for allograft blood supply (kidney transplant)
  • Intracranial hemorrhage
    • Hemorrhagic conversion of ischemic stroke
    • Coagulopathy, thrombocytopenia
    • Systemic and CNS infection
    • Polycystic kidney disease (kidney transplantation)
  • Cerebral venous sinus thrombosis
    • Rarely described in transplant recipients
    • Dehydration, systemic or CNS infection
    • Hypercoagulable state

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