Neurologic Complications of Organ Transplantation 

Updated: Apr 09, 2019
Author: Jasvinder Chawla, MD, MBA; Chief Editor: Stephen A Berman, MD, PhD, MBA 

Overview

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 2009, more than 20,000 hematopoietic stem cell transplantations and 27,000 solid organ transplantations were performed in the United States alone.[1] . Complex multiorgan failure may require simultaneous transplantation of several organs. A combined multiorgan transplantation approach may offer a lower rate of allograft rejection and lower immunosuppression needs.[2]

The posttransplantation clinical course is generally complicated by dysfunction of various organ systems, and early or delayed neurologic complications may develop in 30–60% of patients.[3, 4, 5, 6, 2, 7, 8, 9] 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, pluripotent stem cell 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 the 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.[10, 11] 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.

Epidemiology

Frequency

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

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 1–3% of transplant patients, with a reported mortality rate of 75–90%.[12]

 

Presentation

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, the declining function of a 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. The prevalence of stroke is reported to be around 8% with age >40 years, diabetic nephropathy as the underlying cause of end-stage kidney disease, and peripheral vascular disease being the strongest predictors.[13] Rarely, spinal cord ischemia may develop in patients in whom the iliac artery, which would have previously supplied the 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.[14, 15] Pretransplant bridging with artificial hearts and ventricular assist devices is associated with cardiac embolism and requires anticoagulation. Post-cardiac transplant neurologic complications can involve both peripheral and central nervous systems. The most common early complication is ischemic stroke. Other serious complications include hemorrhagic stroke, encephalopathy, and critical illness neuropathy. In children, seizures are the most common neurologic complication.[15]

  • 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 may be combined with heart transplantation. Lung transplantation is associated with increased risk of stroke, anoxic encephalopathy, and injury to the phrenic and recurrent laryngeal nerves.[16, 17, 18, 19]

  • 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.[20] . The spectrum of neurologic complications for pancreas and small bowel transplant recipients is similar to other organ transplants.[21]

  • 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.[22] . In addition, there are specific problems associated with liver transplantation including emerging brain edema requiring acute liver transplantation.[23]

  • 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. Intestinal transplantation requires relatively large doses or immunosuppressive medications, but newer tolerogenic protocols reduce the need for long-term heavy immunosuppression, so immunosuppressive drug neurotoxicity and opportunistic infections are becoming less common. Frequent neurologic complications include encephalopathy, neuromuscular complications, and seizures.[24] Patients with underlying hypercoagulable conditions may require long-term anticoagulation.[25] . Intestinal transplantation entails a high incidence of neurologic complications with a wide clinicalspectrum, and occurs more frequently than in other solid organ transplantations.[26]

  • Hematopoietic stem cell transplantation (HSCT)

    • HSCT is the transplantation of bone marrow and peripheral blood stem cells.[27] .

    • For patients receiving bone marrow transplantation, the survival rate of those who died from complications related to CNS abnormalities appears to be shorter compared to those who died from non-neurological complications. In addition, the incidence of neurologic complications appears to correlate with the degree of human leukocyte antigen (HLA) disparity as well as the risk status of the underlying disease.[28]

    • 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 neurologic complications, including peripheral and central nervous system complications.[29] Neuromuscular manifestations of chronic GVHD include inflammatory myopathy, neuropathy, and myasthenia. Less commonly, the CNS is affected by vasculitis, encephalitis, or CNS demyelination.

    • Immune-mediated demyelinating neurologic disorders involving central or peripheral nervous system (including ADEM, neuropathy) may occur after HSCT, typically at 2–12 months after transplantation and may coincide with systemic GVHD.[30, 31]

    • 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

See the list below:

  • 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. Calcineurin inhibitors may rarely precipitate reversible calcineurin inhibitor pain syndrome (CIPS), which usually improves after medications are changed.

  • 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 (calcineurin inhibitors, mycophenolate).

Causes

See the list below:

  • 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 1-3%

      • 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 Cryptococcus

      • Fungal sinusitis (ie, rhinocerebral zygomycosis) mortality rate up to 50%

      • Progressive multifocal leukoencephalopathy infrequent but carries up to 95% mortality rate

      • Endemic infections, including coccidioidomycosis and histoplasmosis, vary by geographic region[32]

      • Donor-related infection (via allograft) extremely rare, recently reported with rabies[33] , 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.[34, 35]

    • Posttransplant lymphoproliferative disorder

      • Commonly involves CNS (brain is primary site in up to 26% of patients)

      • Frequently associated with EBV infection, increased risk in younger and EBV-naive patients[35]

      • 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, oligodendroglioma[34]

  • De novo immune-mediated neurologic disorders: Occur after solid organ transplantation or HCST; may be difficult to distinguish from GVHD after HCST and may also coincide with GVHD[30, 31]

    • Immune-mediated neuropathies, including varaints of AIDP and CIDP

    • Acute demyelinating encephalomyelitis (ADEM)

  • Neuromuscular disorders

    • Perioperative neuromuscular complications include focal neuropathies and plexopathies and critical illness myopathy/polyneuropathy.[36, 37, 38] 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.[39]

    • 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.

    • Treatment of opportunistic bacterial infections may lead to toxic neuropathies (eg, linezolid).

    • Drug interactions may lead to statin-related myopathy.

    • GVHD may also be associated with neuromuscular complications including myasthenia, inflammatory myopathy, and neuropathy.[29]

  • 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.[17]

  • 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

    • Hyperammonemia - Hepatic glutamine synthetase deficiency, urea cycle abnormalities[40]

    • 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 image below). 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).

      Neurotoxicity of calcineurin inhibitors manifests Neurotoxicity of calcineurin inhibitors manifests on MRI with predominantly posterior hyperintensities on T2-weighted and FLAIR imaging sequences (FLAIR; TE 175.0, TR 9002).
    • 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[29]

      • 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

 

DDx

 

Workup

Laboratory Studies

See the list below:

  • Cerebrospinal fluid (CSF) studies: CSF analysis is essential in investigations of neurologic complications and possible opportunistic CNS infections in transplant recipients who are immunosuppressed.

    • Cell count and differential, protein, glucose

    • Microbiology - Gram stain, Ziehl-Nielsen acid-fast stain, India ink, and bacterial, viral, fungal, and mycobacterial cultures

    • Molecular studies - Polymerase chain reaction (PCR) for herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), EBV, human herpesvirus 6 (HHV-6), hepatitis E (HEV), measles virus, BK/JC virus, West Nile virus (WNV), and mycobacteria; PCR for EBV in patients with suspected PTLD

    • Immunology studies - Cryptococcal antigen, toxoplasma titers, syphilis tests (ie, microhemagglutination treponemal test [MHA-TP], fluorescent treponemal antibody absorbed test [FTA-ABS], venereal disease research laboratory [VDRL]), viral antibody titers (ie, HSV, VZV, HHV-6, EBV, CMV, WNV), histoplasma and mucor titers, and histoplasma and aspergillus antigens

    • Pathology - CSF cytology and flow cytometry, which are helpful in evaluation of possible PTLD

  • Other tests: Neurologic complications of transplantation mostly stem from underlying disorders that led to transplant, transplant procedures, and immunosuppression, and a variety of laboratory tests are helpful in establishing the cause of these complications.

    • Complete blood cell count and differential

    • Electrolytes, blood urea nitrogen, creatinine, magnesium, calcium and glucose, liver function tests, ammonia level, and thyroid-stimulating hormone (TSH) helpful in investigations of altered consciousness

    • Vitamins B-1, B-6, B-12, E, folic acid, homocysteine, and metyhlmalonic acid because many transplant recipients develop nutritional deficiencies

    • Urinalysis, urine cryptococcal antigen, and urine, blood, and sputum cultures because systemic infection may cause septic encephalopathy

    • Drug levels (note that neurotoxicity may occur even within therapeutic ranges of drug levels)

      • Immunosuppressive medications (eg, tacrolimus, cyclosporine)

      • Other medications (eg, phenytoin, valproate)

    • Creatine kinase (CK) is helpful in evaluation of toxic or inflammatory myopathy (may be within the reference range in critical illness myopathy after 2 wk)

Imaging Studies

See the list below:

  • Neuroimaging studies have a significant role in evaluation of neurologic posttransplant complications because they can provide important evidence on focal or diffuse nervous system injury.

  • CT scanning of the head is helpful when MRI is not immediately available, and it is sensitive for detection of intracranial hemorrhage. Cranial CT scanning may also confirm whether proceeding with lumbar puncture is safe. CT scanning of the sinuses can be used to evaluate opportunistic fungal sinus infections that may extend to the CNS.

  • Cranial MRI with and without gadolinium contrast is an essential diagnostic tool in the evaluation of transplant recipients with impaired consciousness or with focal findings. Cranial MRI findings may determine further diagnostic steps and possible therapeutic interventions. Diffusion-weighted imaging (DWI) and fluid-attenuated inversion-recovery (FLAIR) sequence images should be included in a standard protocol.

  • Magnetic resonance venography (MRV) is helpful in evaluation of possible cerebral venous sinus thrombosis.

  • MRI of the spine with and without contrast is helpful in the evaluation of epidural abscesses and other causes of myelopathy and radiculopathy.

Other Tests

See the list below:

  • EEG is indispensable in the evaluation of possible seizures and impairment of consciousness. It is necessary for establishing the diagnosis of nonconvulsive status epilepticus, and findings are crucial for differentiating metabolic encephalopathy from complex partial seizures. Certain features of EEG, including generalized slowing, are suggestive of metabolic encephalopathy, and triphasic waves are highly suggestive of uremic and hepatic encephalopathy. Prolonged continuous monitoring may be needed in patients with refractory seizures to titrate therapy.

  • Nerve conduction and electromyography studies (NCS/EMG) are very helpful in evaluation of focal weakness and possible perioperative neuropathies, critical illness myopathy/polyneuropathy, and other neuromuscular disorders. Studies in ICU setting may be technically limited. In patients with indwelling catheters, electrical safety risks of proximal nerve stimulation should be assessed. Needle electromyography may be limited in patients with coagulopathy. Direct muscle needle stimulation may be helpful to demonstrate inexcitability of muscle in critical illness myopathy.

  • Echocardiography (transthoracic or transesophageal) is used to determine the presence of intracardiac clots and nonbacterial thrombotic or infective endocarditis.

Procedures

See the list below:

  • Lumbar puncture may be indicated if it can be performed safely. It is indispensable in evaluation of possible opportunistic CNS infections.

  • Nerve and muscle biopsy is rarely used in transplant patients. It is helpful to document lymphoproliferative disorders involving nerve or muscle. Muscle biopsy (needle or open) may be helpful to document critical illness myopathy.{Imagenum2:2122992

 

Treatment

Medical Care

Once the diagnosis is made, medical treatment of neurologic complications in transplant recipients is not significantly different from that in nontransplant patients. Nevertheless, complex drug interactions that may potentially compromise immunosuppression and allograft function must be considered.

  • Encephalopathy: Impairments of consciousness of variable etiology and severity, from mild confusion to coma, are not uncommon in transplant recipients. Establishing the cause determines further treatment, and delirious patients may also need symptomatic treatment (neuroleptics). In patients with toxic-metabolic encephalopathies, treatment is directed towards correcting the underlying cause while providing medical support (eg, respiratory support, parenteral feeding). In patients with hyponatremia, gradual correction is recommended.

  • Seizure

    • The underlying etiology of seizures and overall medical condition (including type of allograft and comorbidities) determine which antiepileptic drugs (AEDs) are used for treatment. Symptomatic seizures resulting from transient toxic and metabolic disturbances are treated by correcting the metabolic disturbance.

    • The most commonly used AED in transplant recipients is phenytoin because it is effective and simple to administer. Benzodiazepines (eg, lorazepam, diazepam) are useful in the acute management of seizures, whereas propofol is a third-line agent used for treatment of refractory status epilepticus. Phenobarbital is rarely used because of activation of liver enzymes, sedation, and long half-life, but it may be helpful in individual patients. Other medications used for treatment of refractory status epilepticus include midazolam and pentobarbital.

    • Levetiracetam should be considered for acute and maintenance treatment of seizures given the availability of

    • Valproic acid may be helpful in patients allergic to phenytoin or if phenytoin cannot be used because of drug interactions. Its use is avoided in children younger than 2 years and in liver transplant recipients because of potential hepatotoxicity. Use of carbamazepine and oxcarbazepine is limited by the lack of

    • Newer AEDs are mostly used as adjunctive agents, and the lack of significant drug interactions of topiramate, pregabalin and gabapentin makes them very attractive in transplant patients.

  • CNS infections

    • CNS infections carry high risk of morbidity and mortality. Because presenting signs and symptoms may be quite subtle in transplant recipients who are immunosuppressed, CNS infection should almost always be considered in the differential diagnosis. Depending on the clinical setting, therapy may be initiated with broad coverage (ie, antibiotic, antifungal, antiviral) or may be more focused. Delaying treatment may have catastrophic consequences.

    • Reversal of immunosuppression in the setting of effective antimicrobial therapy may precipitate immune reconstitution syndrome (IRS), which may manifest with neurologic complications (encephalomyelitis).[41]

  • Stroke and intracranial hemorrhage

    • The treatment of ischemic stroke in transplant recipients depends on the etiology and type of stroke (eg, cardioembolic, thrombotic, CNS infection, hypercoagulable state) as in nontransplant patients. Long-term control of cerebrovascular risk factors (eg, cholesterol, glucose control, hypertension, tobacco use) is needed as in nontransplant patients, particularly as improved protocols enable long-term survival. Some immunosuppressive medications (ie, sirolimus, cyclosporin) may worsen or trigger hyperlipidemia and hypertension.

    • Intracranial hemorrhage may be difficult to treat in transplant recipients, particularly if it is associated with coagulopathy, thrombocytopenia, or CNS infection.

    • Replacement of platelets and clotting factors (fresh frozen plasma) is needed in patients with thrombocytopenia and coagulopathy.

  • Neuromuscular disorders: Treatment of neuromuscular complications of transplantation is identical to that in nontransplant patients. Most common neuromuscular disorders in transplant recipients are perioperative neuropathies and critical illness myopathy/polyneuropathy (CIM/CIP). Treatment of patients with perioperative neuropathies and CIM/CIP is supportive with early initiation of physical therapy. Cautious use of paralytic agents and steroids in intensive care settings may decrease the occurrence of CIM. Patients with refractory myasthenia associated with chronic GVHD may benefit from rituximab.

Surgical Care

See the list below:

  • Surgical removal of a cerebral hematoma in the acute stage, either by evacuation or aspiration, may be lifesaving.

  • Brain biopsy obtained by open or stereotactic technique is helpful in the evaluation of cranial masses of unknown origin, particularly if PTLD or brain tumors are suspected.

  • The decision to proceed with aspiration or open removal of a brain (or spinal cord) abscess is guided by the location, clinical course, and the degree of mass effect exerted by the abscess on the surrounding tissue. Stereotactic aspiration can be performed with deep abscesses.

  • Decompressive surgery is an emergency treatment of rapidly evolving hydrocephalus that is not responding to medical measures (ie, hyperventilation, mannitol).

  • Intraventricular placement of an Ommaya reservoir permits intrathecal treatment of fungal CNS infection.

Consultations

A multidisciplinary approach is essential to the effective care of a transplant recipient. The transplant team has a central role in determining the level of immunosuppression. Various consultants play active roles in the care of these patients.

  • A neurologist is usually a consultant in the management of transplant patients, but may also admit the patient to neurology service.

  • Transplant team members have a central role in the treatment of transplant recipients. They coordinate with other teams and determine the required level of immunosuppression.

  • A critical care medicine specialist is particularly important in the early postoperative course.

  • An infectious disease specialist is invaluable in helping to evaluate possible opportunistic systemic and CNS infections.

  • Consulting a physical therapist is important because early initiation of physical therapy may accelerate recovery of transplant recipients.

  • Other medical and surgical specialists (including nephrologists, pulmonologists, cardiologists, neurosurgeons, and others) are also actively involved in the care of transplant recipients, depending on the type of allograft, comorbidities, and ongoing medical problems.

Diet

Following transplantation, various dietary products may interfere with pharmacokinetics of immunosuppressive and other medications (eg, grapefruit juice).

  • Certain foods may increase risk of infection such as raw milk, soft cheeses, and hot dogs (Listeria monocytogenes).

  • Sodium restriction (2 g/d) may be helpful in management of cyclosporine-related hypertension.

  • Rapamycin and, to a lesser extent, cyclosporine are associated with hypercholesterolemia. Conversion from cyclosporine to tacrolimus may be helpful.

  • Use of statins in combination with cyclosporine may lead to rhabdomyolysis.

Activity

No specific activity restrictions are necessary for patients with neurologic complications of transplantation.

 

Medication

Medication Summary

Principles of medical therapy of neurologic complications in transplant patients are not altered by their transplant status. Nevertheless, additional attention must be paid to complex drug interactions and possible neurotoxicity so that the immunosuppression regimen and allograft function are not compromised.

Antibiotics

Class Summary

Bacterial CNS infections are relatively uncommon in transplant recipients and are usually caused by opportunistic pathogens rare in immunocompetent individuals.

Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin)

Bactericidal activity against susceptible organisms.

Gentamicin (Garamycin, I-Gent, Jenamicin)

Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes.

Not the DOC. Consider if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms.

Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution. May be administered IV/IM.

Amoxicillin (Amoxil)

Derivative of ampicillin and has similar antibacterial spectrum, namely certain gram-positive and gram-negative organisms. Superior bioavailability and stability to gastric acid and has broader spectrum of activity than penicillin. Somewhat less active than that of penicillin against Streptococcus pneumococcus. Penicillin-resistant strains also resistant to amoxicillin, but higher doses may be effective. More effective against gram-negative organisms (eg, N meningitidis, H influenzae) than penicillin. Interferes with synthesis of cell wall mucopeptides during active multiplication resulting in bactericidal activity against susceptible bacteria.

Antifungals

Class Summary

Fungal CNS infections are frequently fatal in transplant recipients, and early diagnosis and initiation of treatment are of uttermost importance.

Amphotericin (Amphocin, Fungizone)

Polyene antibiotic produced by a strain of Streptomyces nodosus. Can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death.

Liposomal preparation is more expensive but is associated with less nephrotoxicity.

Voriconazole (VFEND)

Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal cytochrome P450-mediated 14-alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. Also may be used in the treatment of coccidiosis and blastomycosis.

Antiviral agents

Class Summary

Viral CNS infections in immunosuppressed transplant recipients are caused by a variety of pathogens, and early treatment is essential.

Acyclovir (Zovirax)

Has affinity for viral thymidine kinase and once phosphorylated causes DNA chain termination when acted on by DNA polymerase.

Has demonstrated inhibitory activity against both HSV-1 and HSV-2. Selectively incorporated into infected cells.

Ganciclovir (Cytovene, Vitrasert)

Used in the treatment of viral infections with limited response to acyclovir, particularly with CMV infections.

Synthetic guanine derivative active against CMV. An acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of preferential phosphorylation of ganciclovir in virus-infected cells.

Immunomodulatory agents

Class Summary

Agents with targeted immunotherapy are emerging treatment options that may find wider use in the near future.

Rituximab (Rituxan)

Rituximab has been used in the treatment of PTLD and refractory myasthenia in transplant recipients and in the treatment of paraproteinemic neuropathies in nontransplant patients.

Antibody genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Antibody is an IgG1 kappa immunoglobulin containing murine light and heavy chain variable region sequences and human constant region sequences.

Anticonvulsant

Class Summary

Seizures in transplant recipients can be attributable to transient metabolic disturbances, drug neurotoxicity, focal CNS lesions, to the activation of a low seizure threshold, or to the exacerbation of a preexisting seizure disorder.

Long-term treatment with antiepileptic drugs (AEDs) may significantly complicate maintenance of immunosuppression because some AEDs (particularly phenytoin) may interfere with metabolism of cyclosporine and tacrolimus. Newer AEDs including topiramate, levetiracetam, and gabapentin seem to have a better adverse effect profile and may be better tolerated by transplant recipients.

Phenytoin (Dilantin)

First-line agent in the treatment of seizures and status epilepticus.

In transplant recipients, phenytoin may interfere with tacrolimus and cyclosporine metabolism.

Individualize dose. Administer larger dose before retiring if dose cannot be divided equally.

Fosphenytoin (Cerebyx)

Phenytoin derivative with better adverse effect profile.

Diphosphate ester salt of phenytoin, which acts as water-soluble prodrug of phenytoin. Following administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde, and phenytoin. Phenytoin in turn stabilizes neuronal membranes and decreases seizure activity. To avoid need to perform molecular weight–based adjustments when converting between fosphenytoin and phenytoin sodium doses, express dose as phenytoin sodium equivalents (PE). Although can be administered IV and IM, IV route is route of choice and should be used in emergency situations.

Concomitant administration of an IV benzodiazepine is usually necessary to control status epilepticus. The antiepileptic effect of phenytoin, whether administered as fosphenytoin or parenteral phenytoin, is not immediate.

Midazolam (Versed)

Short-acting benzodiazepine used for sedation and treatment of refractory status epilepticus.

Because midazolam is water soluble, reaching peak EEG effects takes approximately 3 times longer than diazepam. Thus, the clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose.

Lorazepam (Ativan)

First-line medication for immediate treatment of seizures and status epilepticus.

By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation. Important to monitor patient's blood pressure after administering dose. Adjust as necessary.

Propofol (Diprivan)

Used in treatment of refractory status epilepticus.

Phenolic compound unrelated to other types of anticonvulsants. Has general anesthetic properties when administered IV.

Levetiracetam (Keppra)

Used as adjunct therapy for partial seizures and myoclonic seizures. Also indicated for primary generalized tonic-clonic seizures. Mechanism of action is unknown. Useful in transplant patients as it has minimal drug-drug interactions.

Topiramate (Topamax)

Used as add-on therapy for partial seizures.

May be used in patients with hepatic impairment, but use is limited by lack of IV preparation.

Sulfamate-substituted monosaccharide with broad spectrum of antiepileptic activity that may have a state-dependent sodium channel blocking action. Potentiates the inhibitory activity of GABA. May block glutamate activity. Not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy. On occasions, addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome.

Valproic acid (Depacon, Depakene, Depakote)

Because of potential hepatotoxicity, this drug is avoided in liver transplant recipients.

Chemically unrelated to other drugs that treat seizure disorders. Although the mechanism of action is not established, activity may be related to increased brain levels of GABA or enhanced GABA action. Valproate may also potentiate postsynaptic GABA responses, affect potassium channels, or have a direct membrane-stabilizing effect. For conversion to monotherapy, concomitant AED dosage can ordinarily be reduced by approximately 25% q2wk. This reduction may start at initiation of therapy or be delayed by 1-2 wk if concern exists that seizures may occur with a reduction. Monitor patients closely during this period for increased seizure frequency.

As adjunctive therapy, divalproex sodium may be added to the patient's regimen at 10-15 mg/kg/d. May increase by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses < 60 mg/kg/d.

 

Follow-up

Prognosis

Most transplant recipients with neurologic complications recover successfully, and the outcome is determined by the function of the allograft. Nevertheless, patients with anoxic encephalopathies, brain hemorrhage, and CNS infections frequently have very poor outcomes.

  • Fungal CNS infections have a high mortality rate in immunosuppressed transplant recipients (75%) and may be very difficult to treat. Timely diagnosis may improve outcome. Similarly, rare patients with progressive multifocal leukoencephalopathy (PML) also have very high mortality rates (>90%).

  • Patients with CIM/CIP may face prolonged recovery, but the outcome is determined by underlying medical condition and allograft status.

Patient Education

For excellent patient education resources, visit eMedicineHealth's Brain and Nervous System Center. Also, see eMedicineHealth's patient education articles Heart and Lung Transplant, Kidney Transplant, Liver Transplant, and Brain Infection.