Central Nervous System Manifestations

Mild deficits on psychometric testing are the most common cerebral abnormalities in patients with Sjögren’s syndrome. In rare cases, the neuropsychological impairment is severe enough to cause dementia. Deficits are sometimes correlated with specific areas of brain hypoperfusion, demonstrable with techniques such as single photon emission computed tomography (SPECT), even in patients who have normal magnetic resonance imaging (MRI) brain scans and no other manifestations of central nervous system (CNS) disease.²

A wide variety of focal brain lesions can occur in patients with Sjögren’s syndrome. The findings can appear gradually or as suddenly as a stroke. Sjögren’s syndrome affects either gray or white matter, above or below the tentorium; thus, clinical manifestations are diverse and include hemiparesis or hemisensory loss, ataxia, eye movement abnormalities, and dysarthria.

At times, CNS disease in Sjögren’s syndrome follows a relapsing-remitting multifocal pattern, mimicking the course of multiple sclerosis. Nonetheless, surveys in multiple sclerosis clinics suggest that the incidence of sicca syndrome among patients with multiple sclerosis approximates that in the general population. Clues that a relapsing-remitting CNS illness might be associated with Sjögren’s syndrome include older age at onset; associated peripheral neuropathy; lesions on spinal MRI that span multiple spinal segments; atypical brain MRI appearance for multiple sclerosis, such as gray matter lesions or absence of lesions in the corpus callosum; and lack of cerebrospinal fluid (CSF) oligoclonal bands.

Sjögren’s syndrome is rarely associated with aseptic meningitis, which is sometimes recurrent. Pleocytosis, usually mild, can also be found in some patients with focal or multifocal CNS syndromes. CSF protein level is sometimes increased, and glucose level is usually normal. Oligoclonal bands are present in CSF in a minority of patients.

Myelopathy caused by intramedullary spinal cord lesions is among the most common of CNS abnormalities in Sjögren’s syndrome. The clinical varieties include acute, subacute, or chronic transverse myelopathies; lateralized spinal cord inflammation leads to hemicord syndromes, such as hemiplegia; motor syndromes resembling motor neuron disease or primary lateral sclerosis; and predominantly posterior cord abnormalities.

Spinal cord MRI is abnormal in approximately 75% of patients with clinical myelopathies, usually showing areas of hyperintensity on T2-weighted scans. On occasion, the cord appears swollen. In some cases, the lesions are enhanced with gadolinium. The MRI lesions usually extend over multiple spinal levels, in contrast to the localized appearance that is typical of the plaques of multiple sclerosis.

Peripheral Nervous System Manifestations

Symmetrical length-dependent neuropathy is the most common peripheral nervous system finding in patients with Sjögren’s syndrome and can be the presenting clinical finding. Manifestations include small- or mixed-fiber sensory axonal neuropathy or sensorimotor neuropathies. Motor neuropathies resembling Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy are infrequent. Clinical peripheral nervous system disease probably occurs in 10% to 20% of patients with primary Sjögren’s syndrome; a higher incidence of peripheral nerve abnormalities is noted among patients with Sjögren’s syndrome who are carefully screened with quantitative sensory and electrodiagnostic testing. Conversely, if patients with idiopathic axonal neuropathies are screened for Sjögren’s syndrome, a few meet definite diagnostic criteria for Sjögren’s syndrome, and more have isolated features of Sjögren’s syndrome, such as symptoms of sicca syndrome or a positive findings on lip biopsy.³ Most patients with peripheral neuropathy and sicca syndrome do not eventually develop other extraglandular manifestations of Sjögren’s syndrome.⁴

Nerve biopsy findings in patients with peripheral neuropathy and Sjögren’s syndrome are generally no more specific than those in other axonal neuropathies. Nonspecific epineurial inflammatory cells are often present, but there is rarely definite evidence of vasculitis.⁴

Sensory neuronopathy, apparently caused by inflammation in the dorsal root ganglia, is an uncommon but distinctive manifestation of Sjögren’s syndrome. The sensory findings can manifest acutely or indolently, often in a proximal, asymmetrical pattern. Dysfunction of large-fiber functions can cause loss of joint position sense and of tendon reflexes, pseudoathetosis and ataxia, and low-amplitude or unobtainable sensory nerve action potentials. Pain and temperature fiber dysfunction can cause sensory loss and neuropathic pain. The sensory neuronopathy often is the presenting manifestation of Sjögren’s syndrome in these patients; however, investigation shows typical diagnostic findings such as sicca syndrome symptoms, abnormal results of tests of tear and saliva production, and positive lip biopsy findings. Nonetheless, patients with Sjögren’s sensory neuronopathy usually do not have systemic extraglandular disease. MRI of the spinal cord often reveals bright signal intensity on the posterior columns on T2-weighted images.

Sjögren’s syndrome can cause branch trigeminal sensory neuropathies, unilaterally or bilaterally, with a predilection for the mandibular or maxillary divisions of the nerve. Pathology is probably inflammation of the gasserian ganglion, analogous to disease of the dorsal root ganglion in sensory neuronopathy, which sometimes accompanies the trigeminal neuropathy. Sjögren’s syndrome can also affect the olfactory, facial, and audiovestibular nerves.

Severe autonomic neuropathy with manifestations such as orthostatic syncope and nocturnal diarrhea is an unusual accompaniment of Sjögren’s syndrome. The autonomic neuropathy can be the sole neurological abnormality or can co-occur with sensory neuronopathy or peripheral neuropathy. When patients with Sjögren’s syndrome are questioned closely, they often reveal milder symptoms of autonomic dysfunction, such as orthostatic lightheadedness. Furthermore, detailed autonomic testing, such as tilt-table testing or comparison of heart rates during inspiration and expiration, often reveals asymptomatic autonomic dysfunction.

Mononeuritis multiplex is unusual in patients with Sjögren’s syndrome. When it does occur, systemic manifestations of Sjögren’s syndrome, such as cutaneous vasculitis or Raynaud’s phenomenon, are usually present. Many such patients have cryoglobulinemia. Nerve biopsy sometimes demonstrates evidence of vasculitis or nonspecific lymphocytic proliferation.

In rare cases, patients with Sjögren’s syndrome have prominent disease of α motor neurons, which differs from classic amyotrophic lateral sclerosis by the presence of other neurological changes such as CNS disease beyond the pyramidal tract.

Many patients with Sjögren’s syndrome complain of mild weakness or myalgias but have no serious muscle pathology. They usually have normal creatine kinase levels and electromyograms. Infrequently, Sjögren’s syndrome coexists with polymyositis or dermatomyositis. A rare complication of Sjögren’s syndrome is reversible hypokalemic paralysis caused by distal renal tubular acidosis.

Information on neurological responses to treatment is limited to uncontrolled observations in small series of patients. Steroids are rarely helpful in patients with axonal polyneuropathies.¹ The neuronopathy is poorly responsive to steroids or immunosuppression.^5,6 Myelopathy and other CNS syndromes are more likely to improve with steroid treatment. In patients with severe myelopathy or mononeuritis multiplex, cyclophosphamide in combination with steroid therapy sometimes yields apparent benefit.¹ Case reports suggest improvement in myelopathy treated with steroids and azathioprine or chlorambucil or in sensory neuronopathy treated with intravenous immunoglobulin. Responses to plasmapheresis have been mixed.⁷ A least one patient experienced improvement after treatment with the anti–tumor necrosis factor antibody infliximab.⁸

Headache

Neck or head pain, particularly occipital headache, is common among patients with rheumatoid arthritis. For some, this is independent of specific cervical spine pathology, but for others, pain is correlated with lateral subluxation of the atlantoaxial joint. In patients with severe intractable neck or occipital pain and demonstrable atlantoaxial joint lateral subluxation, surgical stabilization of the joint can decrease the pain.

Brown’s Syndrome

Tendonitis of the superior oblique tendon (Brown’s syndrome) can cause eye pain, intraorbital clicking with eye movement, and decreased eye elevation, especially when the eye is abducted. It is important to distinguish this rare complication of rheumatoid arthritis from neurological causes of impaired eye movement.

Atlantoaxial Disease

Rheumatoid arthritis can affect the cervical spine, where ligamentous inflammatory changes lead, in particular, to atlantoaxial joint subluxation (Fig. 119-1). Subluxation is usually anterior but can also occur vertically, laterally, or posteriorly. Anterior atlantoaxial subluxation was found in fewer than 3% of patients who had had rheumatoid arthritis for less than 5 years, 15% of those who had had the disease for 10 to 15 years, and 26% of those who had had the disease for more than 15 years.⁹ Once present, the subluxation may not increase; however, in a decade, at least 25% of those with subluxation have progression in subluxation, varying from 1 to 7 mm.

Figure 119-1 Lateral radiograph of the cervical spine, revealing anterior atlantoaxial dislocation, defined as movement of the atlas more than 3 mm forward from the axis. The odontoid and pedicle of C2 and elements of the ring of C1 are outlined.

(From Rosenbaum RB, Campbell SM, Rosenbaum JT: Clinical Neurology of Rheumatic Diseases. Boston: Butterworth-Heinemann, 1996, Figure 8.3B.)

Atlantoaxial subluxation is usually asymptomatic but can cause spinal cord compression. As compression worsens, signs of myelopathy, including sphincter disturbance, sensory deficits, extensor plantar responses, or weakness in legs or all extremities, can evolve. The risk of myelopathy increases as the atlantoaxial separation in flexion increases and as the diameter of the spinal canal at the C1 level decreases (Fig. 119-2). Soft tissue pannus, vascular compromise, and intermittent spinal cord compression during neck movement also influence the degree of myelopathy. The myelopathy usually evolves insidiously but can worsen suddenly. Arm and leg weakness is more common than weakness limited to the legs. Patients typically also have sensory findings, spasticity, sphincter dysfunction, and extensor plantar responses.

Figure 119-2 The prevalence of hyperreflexia in patients with rheumatoid atlantoaxial (A-A) joint separation is related to the distance of atlantoaxial separation (A) and to the sagittal diameter of the spinal canal at C1 (B).

(From Rosenbaum RB, Campbell SM, Rosenbaum JT: Clinical Neurology of Rheumatic Diseases. Boston: Butterworth-Heinemann, 1996, Figure 8.5.)

Vertical atlantoaxial subluxation can damage the brainstem. In addition to the spastic quadriparesis, sensory changes, and sphincter disturbances noted with horizontal subluxation, brainstem compression can cause bulbar palsy, trigeminal or high cervical patterns of sensory loss, ophthalmopareses and nystagmus, drop attacks, hydrocephalus, and sleep apnea. A less common mechanism of brainstem injury is vertebrobasilar stroke caused by distortion of the vertebral arteries in the subluxed neck.

Patients with atlantoaxial instability risk spinal cord compression during intubation or anesthesia. Patients with advanced rheumatoid arthritis should be assessed for atlantoaxial subluxation before surgery and have extra attention to neck protection during intubation and anesthesia.

Soft or hard cervical collars can alleviate head or neck pain associated with atlantoaxial subluxation but do not stabilize the spine or prevent neurological complications. A halo with cervical traction can stabilize the neck and can be used for preoperative stabilization or, less frequently, for chronic treatment.

The indications for surgery for atlantoaxial subluxation rely more on clinical signs of myelopathy or brainstem compression than on the measured extent of the subluxation. Spontaneous odontoid fracture is another indication for surgery. Among patients undergoing surgery, most do not regain lost neurological functions, but the subluxed segment is stabilized and progressive neurological deterioration is avoided.

Patients with rheumatoid arthritis, like all adults, are likely to develop degenerative cervical spondylosis below C1-C2 as they age. In addition, rheumatoid pannus can develop in the cervical epidural space and contribute to spinal stenosis. The pannus is usually enhanced on MRI scans.

Peripheral Neuropathy

Patients with chronic rheumatoid arthritis can develop a length-dependent symmetrical sensory neuropathy. Other peripheral nerve problems are autonomic neuropathy; nerve entrapments, exemplified by carpal tunnel syndrome; and mononeuritis multiplex.

The sensory neuropathy is usually mild, starting in the feet. In a population-based survey, it was noted in only about 2% of patients with rheumatoid arthritis. However, the incidence is higher in patients with more severe disease. No specific treatment is necessary. Nerve biopsy, if performed, sometimes reveals changes in epineurial blood vessels; nonetheless, this distal symmetrical neuropathy is not a harbinger of rheumatoid vasculitis or mononeuritis multiplex.

The peripheral neuropathy can include autonomic fibers, so that patients have impaired sweating in the regions of sensory loss. Some patients have other autonomic changes such as abnormal postural and cardiovascular reflexes, even in the absence of sensory neuropathy.

Carpal tunnel syndrome is the most common neurological manifestation of rheumatoid arthritis, occurring in 25% or more of patients, especially in those with hand flexor tenosynovitis. Successful anti-inflammatory treatment of the tenosynovitis can decrease the symptoms of carpal tunnel syndrome. When anti-inflammatory treatment does not succeed, patients usually respond well to carpal tunnel surgery, sometimes accompanied by tenosynovectomy. Other, less common nerve entrapments in patients with rheumatoid arthritis include ulnar nerve compression at the ulnar groove, radial or posterior interosseus nerve compression, compression of the peroneal or posterior tibial nerves by a Baker’s cyst in the popliteal region, tarsal tunnel syndrome, or digital neuropathies.

Multiple compression neuropathies should be distinguished from mononeuritis multiplex caused by vasculitic nerve infarcts. Nerve infarcts typically cause sudden, sometimes painful, mononeuropathies, often affecting the nerve proximally rather than at classic sites of compression. However, mononeuritis multiplex can also manifest more insidiously or more symmetrically. Development of rheumatoid vasculitis often heralds more aggressive inflammatory disease and is an indication for more aggressive therapy; therefore, patients with rheumatoid arthritis whose neuropathies exceed typical distal sensory neuropathy or carpal tunnel syndrome should undergo thorough evaluation.

Pachymeningitis

Pachymeningitis is a rare, late complication of rheumatoid arthritis. Patients can have a variety of symptoms caused by focal meningeal thickening or meningeal rheumatoid nodules. Symptoms include headache, seizures, and cranial neuropathies, such as optic or auditory neuropathies. MRI can demonstrate focal or multifocal meningeal thickening, which is often enhanced with gadolinium. CSF study can demonstrate high protein levels, low glucose levels, and mild pleocytosis; less frequently, CSF study reveals hundreds of white blood cells per centimeter, which is suggestive of leptomeningeal inflammation. Case reports describe mixed responses to high-dose corticosteroids or more aggressive immunosuppressive measures. Similar pachymeningitis can occur in Wegener’s granulomatosis, Sjögren’s syndrome, sarcoidosis, vasculitis, granulomatous infections, and malignancies.

Central Nervous System Manifestations

Peripheral Nervous System Manifestations

Acute Postoperative Encephalopathy (Coma, Failure to Awaken)

When patients do not fully awaken after transplantation, the differential diagnosis is extensive. They may have residual effects of the organ failure that necessitated the transplantation. Some, especially after heart or heart-lung transplantation, have acute postoperative brain injuries such as stroke or hypoxia-anoxia encephalopathy. Many of the drugs used for anesthetic management, such as benzodiazepines, opiates, thiopental, propofol, inhalation anesthetics, or neuromuscular blocking agents, can impair neurological function. Failure of the transplanted organ can cause metabolic disturbances that contribute to the encephalopathy.

Immunosuppressive drugs can have direct neurological toxicity (Table 119-3) or predispose to opportunistic CNS infections.

TABLE 119-3 Some Neurological Adverse Effects of Anti-inflammatory and Immunosuppressant Drugs

IVIg, intravenous immunoglobulin; TTP, thrombotic thrombocytopenic purpura.

Central pontine myelinolysis is another potential cause of coma or disturbed consciousness in patients in the acute postoperative period. Corticospinal and cranial nerve dysfunction can lead to quadriparesis, pseudobulbar palsy, and impaired eye movements, so that full assessment of consciousness can be difficult. Central pontine myelinolysis is most common after liver transplantation and is often but not invariably tied to rapid correction of hyponatremia. Acute demyelination may not be limited to the pons and can include other white matter sites such as the external and extreme capsules.

An acute encephalopathy, with manifestations such as headache, altered mental status, seizures, or coma, accompanying renal graft rejection, was described in the early 1980s.¹⁹ It is not easily explained by changes in blood pressure, medication toxicity, or electrolyte changes. It is more common when rejection is more severe and improves concomitantly with steroid therapy of the rejection episode.¹⁹ This syndrome has been neither reported in relation to nonrenal transplants nor examined in more detail in more recent series.

Seizures

Seizures affect between 2% and 40% of transplant recipients, particularly recipients of hearts or livers. The risk of seizures is highest in the first few days after transplantation. A common cause of seizures is toxicity of immunosuppressive drugs, especially cyclosporine, tacrolimus, or OKT3. Cyclosporine-associated seizures are more common in patients who also have hypomagnesemia, hypocholesterolemia, hypertension, hemolytic-uremic syndrome, total body irradiation, or treatment with busulfan and cyclophosphamide (see Wijdiks, 1999, p. 117).¹⁸ Seizures can also be caused by myriad metabolic possibilities, including low or high levels of sodium, calcium, or glucose and hepatic or renal failure. A number of drugs can cause seizures (Table 119-4), especially if drug levels are increased as a result of renal failure. Transplant recipients who suffer seizures must be evaluated for structural brain lesions such as ischemic or hemorrhagic strokes, cerebral vein thrombosis, opportunistic CNS infections, or posthypoxic encephalopathy. When seizures occur late after transplantation, metabolic causes are less common, but de novo malignancies and intracranial spread of malignancies (especially in patients who have undergone bone marrow transplantation for leukemia or lymphoma) must be considered.

TABLE 119-4 Examples of Drugs That May Cause Seizures in Transplant Recipients

Adapted from Wijdicks EFM, ed: Neurologic Complications in Organ Transplant Recipients. Boston: Butterworth-Heinemann, 1999, p 120.

Opportunistic Infections

Transplant recipients are at risk for opportunistic infections, particularly when they take medications to suppress T cell function. Diagnosis of these infections is aided by understanding the timing of susceptibility, the specific neurological infectious syndromes, and the most likely causative organisms. During the first month after transplantation, opportunistic infectious risks are relatively low, and infections that do occur are often typical problems of ill, hospitalized patients, such as pneumonia, catheter infections, wound infections, and viral hepatitis. The risk, for most patients, of opportunistic infection is highest between the first and sixth months after transplantation. After 6 months, most patients with successful transplants can take reduced dosages of immunosuppressants and are at lower infectious risks. Some patients at this stage have acquired chronic viral infections, such as hepatitis B or C or cytomegalovirus. The few who require continued aggressive immunosuppression to prevent rejection remain at risk for opportunistic infections.

The most clinically important entities causing opportunistic infections in transplant recipients are Listeria monocytogenes, Cryptococcus neoformans, and Aspergillus species, especially fumigatus. Listeria infection is usually acquired from contaminated foods, such as milk products, and produces an acute febrile gastrointestinal illness, which in some cases is then followed by CNS infection. The CNS disease may be an acute meningitis, chronic meningitis, or brainstem encephalitis (rhombencephalitis). Prophylactic treatment of immunosuppressed transplant recipients with trimethoprim-sulfamethoxazole decreases their risk of Listeria infection.

Chronic cryptococcal meningitis affects perhaps 1% to 2% of transplant recipients and is diagnosed an average of 2 years after transplantation, especially in patients who still require two or more immunosuppressant drugs. The risk is higher after heart or small bowel transplantation. Focal brain lesions are a much less common manifestation. The rate of mortality from cryptococcal meningitis in transplant recipients approaches 50%.²⁰ The differential diagnosis of chronic meningitis in transplant recipients includes other entities such mycobacterial infections, histoplasmosis, and coccidioidomycosis.

Aspergillus infection typically begins in the respiratory tract, causing bronchopneumonia or sinusitis, but the organisms can also enter the body where skin has been interrupted or as microscopic infection from the donor organ. They invade blood vessels, so that when they spread to the CNS, Aspergillus organisms can cause ischemic or hemorrhagic strokes or abscesses. Patients more often present with seizures or focal neurological findings than with nonspecific complaints such as fever and headache. The diagnosis is often supported by focal or multifocal abnormalities on brain MRI. The CSF does not invariably show inflammatory changes.

Brain abscess occurs in fewer than 1% of transplant recipients. Although Aspergillus is by far the most common organism, many other organisms bear consideration, including Candida, Mucorales, Toxoplasma, and Nocardia. The risk of pyogenic abscess is not increased in these patients. The abscess risk is higher in recipients of heart or heart-lung transplants. The rate of mortality among transplant recipients with brain abscess is more than 80%.²¹

The most common cause of acute meningitis in transplant recipients is Listeria infection. Another important cause of acute meningitis is Strongyloides stercoralis. In persons from endemic areas of the southern United States, Latin America, or Southeast Asia, the nematode S. stercoralis is a common asymptomatic colonizer of the gut. In immunosuppressed patients, the larvae can infect and penetrate the gut wall, not only spreading themselves but also promoting gram-negative infections. The result can be acute gram-negative bacterial meningitis or eosinophilic meningitis caused directly by the nematode.

Immunosuppressed transplant recipients are at increased risk for reactivation of herpes varicella-zoster infections and for primary varicella-zoster infection. The risk of the latter can be decreased by varicella vaccination of seronegative individuals before transplantation.

Many transplantation physicians accompany immunosuppression with prophylactic antibiotic therapies. Depending on the setting, this can include prophylaxis against Pneumocystic carinii, Listeria, Nocardia, Toxoplasma, and Strongyloides.

Immunosuppressed patients can also develop progressive multifocal leukoencephalopathy.

Central Nervous System Neoplasms

Immunosuppressed transplant recipients are at increased risk for developing malignancies, including brain tumors. The brain tumor risk is nearly equally divided between systemic and primary CNS lymphomas. There is no apparent increased risk of developing gliomas. Approximately half of the lymphomas are discovered within 1 year of transplantation, during the time of most aggressive immunosuppression. Bone marrow transplant recipients are at greatest risk. The lymphomas are part of a spectrum of post-transplantation lymphoproliferative disorders, many of which are related to Epstein-Barr virus infection. Other viruses such as cytomegalovirus and hepatitis C may play a role in some instances.

The manifestation is typically with focal or multifocal brain abnormalities. Although some CNS lymphomas have characteristic MRI appearances, the differential diagnosis often includes infections such as toxoplasmosis. Treatment with high-dose corticosteroids can lead to rapid but temporary tumor suppression and can obscure MRI and pathological findings. Unless the size of a brain mass necessitates urgent treatment, steroid therapy is best postponed until the diagnosis is established by biopsy. In addition to classic treatments with chemotherapy or radiation, options include reduction in immunosuppression. Antiviral drugs are sometimes used in cases associated with Epstein-Barr virus infection, but their value is debatable. Drugs such as anti–B cell monoclonal antibodies (rituximab), aimed at the altered immune response in these patients, must cross the blood-brain barrier if they are to be effective against CNS lymphoma.

Strokes

Transplant recipients can experience strokes in the perioperative and early postoperative periods. There are many potential sources, starting with any preexisting risk from the conditions that lead to transplantation. Patients undergoing heart or lung transplantation can suffer cardiogenic or air emboli. Anoxic or hypoxic encephalopathy can follow hypotension or hypoxia. The risk of hypertensive encephalopathy increases in patients taking cyclosporine or during renal graft rejection. Intravascular opportunistic infection, especially with Aspergillus, can cause multifocal strokes. Noninfectious thrombotic endocarditis is a potential risk factor for stroke after bone marrow transplantation.

Intracranial hemorrhages form a larger proportion of all strokes in transplant recipients than in the general population. These hemorrhages include strokes caused by coagulopathies, such as disseminated intravascular coagulation, endovascular infection, cerebral emboli, hypertension, and aneurysms.

Ischemic infarction of the distal spinal cord can occur if cord blood flow is disturbed during renal transplantation.²²

Neuropathy

Transplantation can be long and complex surgery. Patients are at risk of anesthesia-associated compression mononeuropathies at well-known sites of vulnerability such as the ulnar groove. In addition, technical surgical demands increase the risks for some patients. For example, like other patients undergoing open heart surgery, heart transplant and perhaps liver recipients have an increased incidence of postoperative brachial plexopathy. Phrenic neuropathy can occur as a complication of thoracotomy. Femoral neuropathy can follow renal and, less commonly, liver transplantation. Retroperitoneal hemorrhage can compress the lumbar plexus. Peroneal, sciatic, and saphenous neuropathies have been described.

Access catheters are another potential cause of nerve injury. Neuropathies in the arm can occur as a result of dialysis shunts or after placement of venous or arterial lines. Horner’s syndrome can be caused by internal jugular vein cannulation.

Transplant recipients are vulnerable to generalized weakness through a variety of mechanisms; the timing of the weakness in relation to the transplantation is helpful in establishing the differential diagnosis. Acute generalized weakness that persists after surgery can result from prolonged effects of neuromuscular blocking agents. Patients with liver failure may be slow to metabolize succinylcholine. Peripheral nerve stimulators are useful for assessing neuromuscular junction function in the unresponsive postoperative patient.

Acute illness myopathy causing proximal, more than distal, weakness can be evident in the early weeks after transplantation. It follows use of high-dose corticosteroids and neuromuscular blocking agents and affects a small percentage of patients after liver, heart, or lung transplantation.

Toxic myopathies should be considered in the differential diagnosis of patients with myalgias or proximal weakness. Considerations include the painless symmetrical proximal weakness of steroid myopathy; myopathy caused by cyclosporine; myalgias in patients taking cyclosporine or tacrolimus; and myalgias, weakness, or rhabdomyolysis caused by statins.

Like all critically ill patients, patients in the early weeks after transplantation are at risk for length-dependent axonal sensorimotor polyneuropathy.

Cyclosporine or tacrolimus is another potential cause of length-dependent neuropathy. Some patients complain of distal paresthesias or dysesthesias, but neuropathy severe enough to cause weakness or slow nerve conduction is unusual.

A few patients develop Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy days or months after bone marrow or solid organ transplantation. Almost all these patients are immunosuppressed, and they usually have serological evidence of cytomegalovirus infection. Treatment is with intravenous immunoglobulin or plasmapheresis, just as for inflammatory demyelinating neuropathies in patients not undergoing transplantation.²³ In cases associated with graft-versus-host disease or episodes of transplant rejection, more aggressive immunosuppression can help with both the neuropathy and transplant-associated immunological crisis.