Brain (1976), 99, 673-694

THE NEUROLOGICAL COMPLICATIONS OF CARDIAC TRANSPLANTATION by JOHN R. HOTSON and TIMOTHY A. PEDLEY (From the Department of Neurology, Stanford Medical Center, Stanford, California 94305, USA)

IN selected cases, cardiac transplantation is an accepted treatment for patients with terminal heart disease (Graham, Stinson, Rider, Shumway and Harrison, 1974). Since introduction of the procedure in 1968, about 300 patients world wide have received cardiac homografts. Though 50 per cent of patients now survive operations by at least one year (Graham et al, 1974), post-operative complications remain a major problem. A variety of neurological disorders have been recognized in patients following kidney transplantation. These include occlusive and haemorrhagic cerebrovascular disease, infections of the central nervous system, lymphoreticular malignancy, central pontine myelinolysis, progressive multifocal leukoencephalopathy, metabolic encephalopathy, myopathy and peripheral neuropathy (Manz, Dinsdale and Morrin, 1971; Schneck, 1971). Some of these (for example, infections of the CNS) are undoubtedly the consequence of suppressed immune defence mechanisms. In others, the underlying factors are less clear, and may relate in part to the presence of pre-existing uraemia, electrolyte disturbances, hypertension and general malnutrition. Similar detailed information is not available from individuals who have received cardiac transplants. The experience at Stanford University Medical Center over the past seven years furnishes a unique opportunity to review the neurological syndromes seen in patients who have undergone cardiac transplantation. Neuropathological findings in 31 cases have been reported previously (Schober and Herman, 1973). Since effective treatment of these disorders requires prompt and accurate diagnosis, the major emphasis in this paper will be on the incidence and clinical presentations of the neurological complications. In addition, however, study of transplant patients may provide useful information about the effects of acquired immunosuppression on normal brain function. Such knowledge is of clinical importance since manipulation of immune responsiveness has been proposed for the treatment of collagen-vascular disease (Sztejnbok, Stewart, Diamond and Kaplan, 1971), polymyositis (Currie and Walton, 1971), multiple sclerosis (Neumann and

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Ziegler, 1972), myasthenia gravis (Rowland, 1971) and post-infectious polyradiculitis (Yuill, Swinburn and Liversedge, 1970). Furthermore, some degree of immunosuppression is frequently seen in patients with cancer as a side effect of chemotherapy.






No. of patients


Age (years) 15-39 40-64

19 64

23 77

Primary cardiac disease Arteriosclerotic cardiovascular disease Cardiomyopathy Rheumatic heart disease

56 23 4

67 28 5

Neurological complications Patients with one complication Patients with two complications Neurological illness as terminal event

45 32 13 17

54 38 16 20


Immunosuppression Regimen All patients were treated according to a standard protocol. Though detailed information is not available about the patients' pre-operative immune responsiveness, screening tests for immunological competence including blood counts, immunoglobulin assays and delayed hypersensitivity reactions to mumps or Candida antigen were normal before operation. The protocol specified post-operative immunosuppression and anticoagulation regimens in detail, and also established criteria for the diagnosis and treatment of cardiac rejection crises. Immunosuppression was begun with methylprednisolone 1 500 mg, azathioprine 8 mg/kg or cyclophosphamide 5 mg/kg, and antilymphocyte or antithymocyte globulin. Immunosuppression was maintained with prednisone 0-5-1-0 mg/kg/day and azathioprine 2-0-2-5 mg/kg/day. Coumadin and persantine were given routinely in the first postoperative week in an attempt to reduce the incidence of coronary vessel occlusion during cardiac rejection (Graham et al., 1974). Acute cardiac rejection usually presented as a reduction in EKG voltage, cardiac arrhythmias, change in heart sounds, and/or congestive heart failure. Treatment of acute rejection crises was with heparin, methylprednisolone 1 500 mg, actinomycin 400-500 mg and antithymocyte globulin given for three days.

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Information was gained retrospectively by reviewing medical records and, where appropriate, autopsy material (Table 1). Eighty-three patients received cardiac transplants between January 1968 and June 1975 because of intractable heart failure from cardiomyopathy, rheumatic heart disease or arteriosclerotic cardiovascular disease. Of these, 28 were alive in June 1975. Forty-five patients (54 per cent) had at least one neurological complication, and 13 (16 per cent) had more than one. In 17 patients (20 per cent), the neurological complications were the cause of death.




The neurological complications in these patients can be grouped into eight broad categories based upon clinical, laboratory and, in many instances, neuropathological findings. These are listed in Table 2 with the frequency of occurrence. Each of the categories will be discussed and illustrated with representative case histories. TABLE 2. CLASSIFICATION OF NEUROLOGICAL COMPLICATIONS IN 83 PATIENTS WITH CARDIAC TRANSPLANTS


neurological complications 17 34 9 12 14 12 2

A. Operative Morbidity Ten patients showed impaired neurological function in the immediate postoperative period (Table 3). Four of these patients had recurrent focal motor seizures occurring four to thirty-six hours after operation. In each, there was an associated hemiparesis ipsilateral to the seizure activity. Both seizures and weakness resolved, the former within forty-eight hours, the latter sometimes taking up to two weeks. Ischaemic infarction of the contralateral cerebral cortex was found in 2 of the cases examined post mortem. Severe anoxic brain damage following a post-operative cardiac arrest occurred in only one patient. Another patient had transient worsening of a pre-existing hemiparesis, the result of an earlier cerebrovascular occlusion. A reversible organic brain syndrome manifested by disorientation, somnolence and agitation occurred in 3 patients. One also had bilateral cerebellar ataxia. Two of these patients died from other causes within two weeks of operation. Severe, widespread arteriosclerosis of the intracerebral vessels and ischaemic neuronal changes were found on neuropathological examination. The focal infarcts were probably the result of air emboli from the chambers of the transplanted heart, inadequate cerebral perfusion during the operation, or embolization of paniculate matter (Gilman, 1965). The more diffuse changes in cerebral function which occurred in the immediate post-operative period may have resulted from generalized cerebral ischaemia sustained during a transient fall in the mean cardiopulmonary bypass (CPB) pressure. Stockard, Bickford and Schauble (1973) have shown a significant correlation between CPB pressures of less than 50 mmHg and the subsequent development of neurological complications.

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Operative morbidity CNS infection Cerebrovascular disorders Metabolic encephalopathy Vertebral fracture Acute psychosis Neoplasm

No. of patients 10 20 5 7 8 7 1



They recommended maintaining a mean bypass pressure greater than 70 mmHg especially in patients with cerebral arteriosclerosis. In support of this hypothesis it is noteworthy that the majority of our patients with operative morbidity had had CPB pressures below 50 mmHg (Table 3). TABLE 3. OPERATIVE MORBIDITY IN 43 CARDIAC RECIPIENTS Stanford series Age No. (years) 37 48

Neurological manifestation

L. hemiparesis resolving in one week

Not recorded

L. focal seizures; confusion L. focal seizures; confusion L. focal seizures

L. hemiparesis and disorientation resolving over two weeks L. hemiparesis and disorientation resolving over two weeks L. hemiparesis resolving in one week Disorientation; agitation; unable to follow simple commands; no focal neurological deficits; terminal cardiac arrest one week after transplant Disorientation; paranoid ideation; somnolence improving over two weeks Disorientation, truncal and bilat. appendicular ataxia, and dysarthria resolving over a month Not evaluated in detail

40 mmHg for 18 min. 50-60 mmHg








Confusion and delirium






Confusion and gait disorder


Not evaluated in detail between recurrent cardiac arrests Exacerbation of residual L.-sided weakness due to old cerebrovascular accident Coma and generalized seizures after prolonged cardiac arrest




35 mmHg for 30 min. Not recorded

Not recorded

Laboratory investigations and neuropathological findings EEG-lateralized epileptiform discharges in R. temporal region; 2 cm R. temporal, 1 cm R. occipital infarcts; no emboli found

R. frontal micro-infarct: no emboli found EEG-right temporal epileptiform focus Severe cerebral arteriosclerosis; 0-5 cm R. temporal and occipital infarcts; no emboli found

Severe cerebral arteriosclerosis; mild anoxic changes

60-70 mmHg

Not recorded

Multiple fat emboli and multiple focal infarcts; incidental lint embolus

L. hemiparesis and athetosis

Not recorded

Multiple old microinfarcts in R. basal ganglia and thalamus

Coma with impaired extraocular movements; no improvement over one month

40-25 mmHg for 30 min.

EEG-difluse delta with periodic spike-sharp waves progressing to anterior 'pseudo-alpha'

Lowest cardio-pulmonary bypass pressure; duration is added when below 50 mmHg.

B. Infection CNS infection by opportunistic organisms was the most common neurological complication seen in patients with cardiac transplants. Infections were more frequently caused by fungi or viruses than bacteria or protozoa (Table 4). Fungal infections.

Fungal invasion of the CNS occurred in 9 patients, 8 of whom had evidence of extracranial disease. Aspergillus was isolated in over half of the cases and appears to have a particular predilection for transplant recipients (Remington,

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L. focal seizures



Neurological findings

CPB pressure* (mmHg)



Gaines, Griepp and Shumway, 1972; Rifkind, Marchioro, Schneck and Hill, 1967). In contrast, Candida albicans, the most frequent cause of deep fungal infection in all patients at Stanford University Hospital, was found in only one patient. TABLE 4. CLASSIFICATION OF CNS INFECTIONS IN 20 OF 83 PATIENTS WITH CARDIAC TRANSPLANTS

Candidiasis Cryptococcosis Viral Cytomegalovirus Herpes simplex Herpes zoster Bacterial Listeria monocytogenes Protozoan Toxoplasmosis

No. with systemic infections infections


Nature of CNS involvement Multiple intracerebral abscesses Nasal-orbital; cerebral vasculitis and abscess Meningoencephalitis Meningitis

5 2

25 10

5 0

1 1

5 5

1 0

3 3 2

15 15 10

3 3 2








Disseminated intracerebral pseudocysts

Encephalitis Encephalitis Meningitis-ventriculitis; plexitis; myelitis


1. Aspergillosis. Disseminated aspergillosis is rare, usually occurring in individuals with altered immunological defences (Young, Bennett, Vogel, Carbone and DeVita, 1970). In most instances, the cerebral lesions are assumed to be metastatic from the lungs through hsematogenous dissemination. All 5 of our patients had multiple abscesses with adjacent meningeal involvement. Case 1 {Stanford Series No. 34). A 52-year-old man suffering from severe coronary artery disease and intractable congestive heart failure received a cardiac transplant in August 1971. The operation was uneventful, and post-operatively his cardiovascular function improved dramatically. Three episodes of acute cardiac rejection occurred in the 13th, 24th and 30th post-operative days. On the 26th day he was found to have a pulmonary infiltrate. He was placed on methicillin, penicillin, gentamicin and chloramphenicol. On the 38th day he complained of generalized headache, impaired memory, unsteadiness of gait and difficulty in writing. Over the next four days he developed a language disturbance, and became increasingly confused and disorientated. Neurological examination revealed global dysphasia, a right hemiparesis sparing the face, and a right homonymous hemianopsia. Laboratory studies included a WBC of 1000 with 3 per cent lymphocytes and 97 per cent polymorphonuclear leukocytes, a platelet count of 175 000, haematocrit of 36 per cent and a prothrombin time 10 per cent of control. Serum sodium was 125 mEq/1 but the remaining chemical screening tests were normal. Lung tomograms demonstrated multiple nodular lesions, one of which was cavitary.

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Infection Fungal Aspergillosis Phycomycosis

No. of patients



The EEG was diffusely slowed without focal abnormalities. Skull films and brain scan were normal. Lumbar puncture revealed clear fluid with an opening pressure of 120 mm H 2 O. The protein and glucose were normal, and no cells were found. Cultures of multiple tracheal aspirates, however, grew Aspergillus fumigatus, but CSF examination and cultures for fungi were negative. The patient was started on intravenous amphotericin B and coumadin was discontinued. Over the next six days he became progressively more obtunded and the right hemiparesis worsened. Repeat brain scan and lumbar puncture were unremarkable. On the forty-eighth hospital day his neurological status abruptly deteriorated with the appearance of signs compatible with uncal herniation and brainstem compression. He died shortly thereafter. At necropsy, there was no evidence of cardiac rejection. Systemic aspergillosis involved lungs, kidney and myocardium. Neuropathological examination revealed a large left fronto-parietal fungal abscess with an associated intracerebral haemorrhage. Smaller abscesses were found in the right frontal and occipital lobes, and in the left cerebellar hemisphere. Meningeal involvement was limited to focal areas adjacent to the abscesses.

2. Phycomycosis (mucormycosis). In contrast to aspergillosis where the primary lesion is almost always pulmonary, the most common site of involvement in phycomycosis is cranio-facial (Landau and Newcomer, 1962; Straatsma, Zimmerman and Gass, 1962). Classically, phycomycosis accompanies diabetes mellitus, but the increased use of corticosteroids and the longer survival of patients with acquired immune deficiencies has led to a higher incidence of this fungal infection with other chronic and debilitating illnesses (Meyer, Rosen and Armstrong, 1972). Case 2 (Stanford Series No. 9). A 48-year-old man received a cardiac homograft in November 1968 because of a progressive idiopathic cardiomyopathy with intractable congestive heart failure. His past medical history included diabetes mellitus of adult onset which had been treated with diet and tolbutamide. The operation was uneventful, but two episodes of acute rejection occurred on the fifth and fifteenth post-operative days. Three weeks following transplantation, the patient complained of diplopia on downward gaze and loss of sensation about the right cheek and nose.

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Comment. All our patients had early symptoms such as headaches or changes in mental state which at the time were considered non-specific. Focal symptoms and signs referable to the sites of the mass lesions developed later but these could be singularly unimpressive. In 2 of the cases the diagnosis was not suspected during life because of significant concurrent metabolic derangements and the paucity of focal neurological findings. Though tracheal aspirates have been invariably positive for aspergillus in our patients, CSF studies have been either normal or nondiagnostic, and in none of our cases was aspergillus cultured from the spinal fluid. This has also been the experience of others and probably means that brain involvement was principally parenchymal with only focal extension to the meninges. The organisms have a tendency to invade blood vessel walls with subsequent formation of mycotic aneurysms which may rupture into the subarachnoid space or brain substance. Associated intracranial haemorrhage is thus not uncommon and occurred in 2 of our cases.



Neurological examination showed paresis of the right superior oblique muscle, diminished sensation in the first and second divisions of the right trigeminal nerve, a right Homer's syndrome with anhidrosis and paralysis of the right side of the face. Laboratory studies revealed a glucose of 220 mg per cent without acidosis and .a WBC of 19 000. The EEG and results of lumbar puncture were normal. He developed pain in the right eye, and periorbital inflammation and chemosis were observed. Sinus films showed mucosal thickening and bony erosion in the right maxillary sinus. A necrotic mass was found in the right middle turbinateand biopsied. Cultures of the biopsy specimen grew rhizopus and histological examination showed fungal invasion of nasal tissue. Treatment was begun with intravenous amphotericin (total dose 2 700 mg). Repeated debridement of necrotic nasal tissue was performed. Over the next two months his neurological signs improved markedly and finally resolved completely. He did well for the next eight months leading a virtually normal life, but died suddenly of a cardiac arrest in association with late cardiac rejection. Pathological examination revealed no evidence of phycomycosis.

3. Cryptococcosis A single case of cryptococcal meningitis occurred in our series. This patient presented with neck stiffness, headache and fever followed by confusion.-Lumbar puncture revealed-10 lymphocytes/mm3 and 19 cryptococcal organisms/mm3. CSF glucose was 50 mg per cent (serum glucose 137 mg per cent) and the protein was 56 mg per cent. The peripheral leukocyte count was normal. He was started on intravenous amphotericin and 5-fludruracil but died one week later of Klebsiella pneumonia.

4. Candidiasis Candida meningoencephalitis occurred in association with disseminated Candida albicans in one patient. He developed a progressive deterioration in his mental state in association with renal and respiratory insufficiency. His neurological deterioration was attributed to metabolic abnormalities, and the CNS infection was discovered only at post-mortem examination.

Viral infections Viral infection of the central nervous system occurred in 8 patients (Table 5). Three criteria were required for the diagnosis of viral encephalitis: (1) clinical evidence of a diffuse encephalopathy; (2) isolation of a virus from the brain, or cerebrospinal fluid, or a fourfold rise in a specific viral antibody titre; and (3) pathological demonstration of microglial nodule formation and, in 3 cases, nuclear inclusions. Additional histological findings often associated with encephalitis, such as perivascular aggregates of inflammatory cells, neuronophagia, haemorrhage and necrosis, were minimal or absent.

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Comment. The early recognition of phycomycosis is important since successful therapy and cure can be accomplished. If untreated, the infection spreads from the nasal and paranasal sinuses to the orbit with subsequent proptosis and complete ophthalmoplegia with loss of corneal and facial sensation. Other cranial nerves, especially the facial, are often involved. Cavernous sinus and carotid artery thrombosis may occur because of a mycotic vasculitis. In our other patient with phycomycosis the diagnosis was not made during life. This individual eventually developed bilateral orbital necrosis with intracranial extension to both frontal lobes.


Stanford Onset Series Isolated or (days after presumed virus transplant) Clinical findings No. 60 Cytomegalovirus 69 Disorientation; paranoid ideation; visual hallucinations; seizures; chorioretinitis




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Laboratory findings WBC 3 000/mm3 EEG diffuse slowing CSF normal viral cultures: negative CMV Titres: > fourfold rise CMV cultured from lung biopsy

Clinical course Improved after one month with residual memory deficit and intermittent confusion

Neuropathologicalfindings* (395 days) Dissem. microglial nodules; no perivascular inflammation or neuronophagia; retinal nuclear and cytoplasmic inclusions

Progressive confusion and obtundation; Gramnegative sepsis

WBC 1 800/mm3 BUN 65 mg/dl CMV Titres: > fourfold rise CMV cultured from lungs

Progression to terminal coma

(315 days) Dissem. microglial nodules with neuronal nuclear inclusions

Progression to terminal coma

(64 days) Dissem. microglial nodules; minimal perivascular inflammation




Progressive confusion and obtundation; Gramnegative sepsis

WBC 2 200/mm3 BUN 45-100 mg/dl CMV Titres: > fourfold rise


Herpes simplex


Progressive obtundation; dissem. herpes simplex

Progression to preWBC 1 400/mm3 CSF 819 RBC/mm 3 ; 657 WBC/ terminal coma 3 mm (90 per cent lymphocytes) ; protein 580 mg/dl;



(45 days) Dissem. microglial nodules; no perivascular inflammation or haemorrhages

CSF viral culture: negative Herpes simplex isolated from skin vesicles, tracheal aspirate, and pleural fluid 61

Herpes simplex


Progressive confusion and obtundation; dissem. herpes simplex

WBC 1 000/mm3 Herpes simplex isolated from skin vesicles and urine Aspergillus cultured from tracheal aspirate

Progression to terminal coma

o o

(127 days) Herpes simplex isolated from brain post-mortem; dissem. microglial nodules; no perivascular inflammation; multiple abscesses from aspergillus


"8 ffl



Herpes simplex



Herpes zoster



Herpes zoster


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Progressive confusion and obtundation; oral and pulmonary herpes simplex

WBC 300/mm3 SGPT 420 IU/L Protime 24 per cent of control Bilirubin 3 mg/dl Herpes simplex isolated from oral vesicles

Progression to terminal coma; sepsis

(55 days) Dissem. microglial nodules; one neuronal nuclear inclusion; no perivascular inflammation

T9-10 herpes zoster with dissem.; disorientation; ataxia; myoclonus

WBC 1 800/mm3 CSF 182 RBC/mm 3 ; 12 WBC/ mm 3 (68 per cent polymorphonuclear); protein 152 mg/dl; glucose 60 mg/dl Varicella zoster isolated from CSF

Developed episodes of apnoea and unresponsiveness, then respiratory arrest

(177 days) Thoracic dorsal root ganglionitis; meningitis and ventriculitis; rare microglial nodules

C5 herpes zoster followed by deltoid and biceps weakness; R. Babinski; disorientation and hallucinations


WBC 10 000/mm CSF 120 RBC, 5 WBC (80 per cent polymorphonuclear); protein 73 mg/dl; glucose 56 mg/dl EEG diffuse slowing Brain scan normal Herpes zoster isolated from skin vesicles

Improved after three weeks; residual R. C5 weakness and impaired memory

(278 days) Old R. C3-6 ganglionitis; demyelination R. brachial plexus; 'neurogenic atrophy' R. deltoid; C4-5 focal myelopathy with microglial nodules; vacuolization; gliosis

O O •v r

o > H o z oo


m > H

Parentheses indicate time of necropsy in relation to transplantation procedure.

Z oo

z > O




1. Cytomegalovirus. The clinical and pathological findings in cytomegalovirus encephalitis have recently been extensively reviewed (Dorfman, 1973; Schneck, 1965). The following case is representative.

Comment. As in other published reports the diagnosis of CMV encephalitis in this case was based upon circumstantial evidence. This included the occurrence of a diffuse encephalopathy in the setting of proved systemic CMV, and the findings at post-mortem examination of cerebral microglial nodules and inclusion body chorioretinitis. Two other patients also appeared to have CMV infection. To our knowledge the virus has not been isolated from either brain or cerebrospinal fluid. 2. Herpes simplex. Three patients developed an encephalitis in association with disseminated herpes simplex but the virus was isolated from the brain in only one case. This patient also had multiple abscesses due to cerebral aspergillosis. All patients presented with behavioural changes and alterations in mental status which were progressive. No seizures were observed, and neurological examination failed to disclose focal abnormalities. Spinal fluid examination revealed lymphocytosis and raised protein content. The pathological findings were similar to CMV

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Case 3 {Stanford Series No. 60). A 47-year-old man received a cardiac allograft in August 1973 because of severe coronary artery disease and intractable congestive heart failure. Episodes of acute cardiac rejection occurred on the tenth, fifteenth, twentieth, and forty-sixth post-operative days. Each was successfully treated according to protocol. On the sixty-ninth day he became withdrawn and non-communicative and spent the next four days lying in bed staring vacantly. Neurological examination found him mute, with grossly diminished spontaneous motor activity. No focal abnormalities or pathological reflexes could be demonstrated. Laboratory data included a WBC of 3000 and normal metabolic studies. Examination of the CSF on two occasions was unremarkable. An EEG demonstrated diffuse slowing over both cerebral hemispheres. A brain scan was normal. CMV serum antibody titres rose from less than 1:8 to 1:132. CMV was isolated from a lung biopsy but viral cultures of the CSF were sterile. On the seventy-ninth day he developed visual hallucinations and had a generalized major motor seizure. Diphenylhydantoin and phenobarbitone were started. Neurological examination disclosed bilateral grasp reflexes, snout and rooting responses and marked 'gegenhalten' bilaterally. Diminished visual acuity was noted bilaterally and ophthalmoscopic examination revealed bilateral chorioretinitis consistent with a viral aetiology (fig. 1A). Over the next two and a half months his mental state gradually improved. He could speak fluently, maintain self-care and follow complex commands. However, he remained intermittently disorientated and inappropriate with paranoid ideation. Over the next twelve months no new neurological symptoms appeared. He then developed respiratory insufficiency in association with pneumonia, and died of cardio-respiratory arrest. General pathological examination showed evidence of widespread cytomegalovirus infection. Microscopic sections of the retina showed focal necrosis, minimal inflammation and numerous nuclear inclusions (fig. 1B). The brain was grossly normal. Histological examination, however, demonstrated abundant microglial nodules disseminated throughout the cortex and brain-stem. There was no associated perivascular infiltrate or leptomeningeal inflammation, and no neuronal nuclear inclusions were identified. Viral cultures were not made.



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FIG. 1. Case 3 (Stanford Series No. 60). A, fundus photograph of the left eye showing cytomegalic viral retinitis with diffuse white lesions, B, photomicrograph of the retinal lesion shown in A demonstrating inclusion body (arrow) and minimal inflammatory reaction. Photograph courtesy of Drs. A. R. Rosenthal and P. Egbert, Department of Ophthalmology, Stanford University Hospital.



encephalitis: disseminated microglial nodules, rare perivascular inflammatory infiltrate and no evidence of haemorrhage or necrosis.

Protozoan infection A single patient was found to have CNS toxoplasmosis. His post-operative course was complicated by repeated episodes of cardiac rejection followed by progressive confusion and obtundation. Metabolic studies were only minimally abnormal and not consistent with his degree of somnolence. Serum titres to CMV rose from 1:16 to 1:256 but serological tests for toxoplasmosis were not done. This patient died one week after the onset of his neurological symptoms. Examination of the brain revealed disseminated toxoplasma pseudocysts and microglial nodules. This case was reported previously by Schober and Herman (1973). Toxoplasmosis may present with evidence of a diffuse encephalopathy (as in this patient), as a more fulminant meningoencephalitis or as a space-occupying lesion (Ruskin and Remington, 1976; Townsend, Wolinsky, Baringer and Johnson, 1975). Since the CNS infection is treatable with pyrimethamine and sulfadiazine, suspicion of this organism must be high in susceptible individuals. A presumptive diagnosis may be made from results of the Sabin-Feldman Dye Test and indirect fluorescent antibody studies. Bacterial infections Bacterial infections of the CNS occurred in only 2 patients. They presented with characteristic meningeal signs including headache, nuchal rigidity and photophobia. CSF examination showed a polymorphonuclear pleocytosis with a normal or doubtfully low sugar content. Listeria monocytogenes was the causative organism in both cases and was readily cultured from the CSF. One of the patients had a focal lesion resulting in a transient left hemiparesis and neglect of left visual space. He had left-sided focal motor seizures associated with lateralized pseudoperiodic epileptiform discharges on the EEC A brain scan showed increased

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3. Herpes zoster. Encephalopathy following segmental herpes zoster occurred in 2 patients. The first had a T9_10 radiculopathy which was followed by obtundation, coma and death. Herpes zoster was isolated from the CSF. Neuropathological examination revealed a thoracic ganglionitis and diffuse meningitis with ventriculitis. (Edema and rare microglial nodules were present in the cortex. The other patient initially had a C5 radiculopathy and focal myelopathy. He subsequently developed behavioural changes and prominent impairment of recent memory. He eventually recovered with only residual weakness of the arm and mild difficulty with memory. He died ten months later of cardiac rejection. Examination of the spinal cord showed vacuolization, demyelination and microglial nodules in the cervical region. The brain was normal.



uptake in the right parietal region; a cerebral arteriogram was normal. Both patients were successfully treated with intravenous penicillin and had no residual neurological impairment. While both our patients had a CSF pleocytosis, Listeria meningitis may occur without a cellular response (Schneck, 1971). Gram stains and cultures of the spinal fluid are usually positive at this stage.

D. Metabolic Encephalopathy Seven patients developed metabolic encephalopathies characterized by global blunting of higher intellectual function and depression of consciousness. Two had hepatic failure from hepatitis, and one had renal failure from acute tubular necrosis. In the other 4 patients, there was evidence of multiple organ failure, usually in association with sepsis, and as part of the terminal illness. A virtually identical clinical syndrome occurred in 4 additional patients who also had significant metabolic derangements, but in each of these cases, a cerebral fungal infection was discovered which was not suspected during life. In 2 of these patients, progressive obtundation continued in spite of correction of renal insufficiency by haemodialysis. E. Vertebral Fractures Osteoporosis from chronic corticosteroid administration was present in most patients surviving longer than six months. Eight individuals developed vertebral compression fractures one-half to three years after operation. The presenting complaint was invariably low back pain, usually without a radicular

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C. Cerebrovascular Disorders Cerebrovascular complications occurred sporadically 22-470 days after cardiac transplantation. Three cases presented with acute focal neurological deficits followed rapidly by clinical signs of mesial temporal lobe herniation. In 2 of these cases the cause was an intracerebral haemorrhage into the basal ganglia with intraventricular extension. One patient was hypertensive (170/110) and the other had a prothrombin time less than 10 per cent of normal. In the third case, there was occlusion of the left internal carotid artery with extensive infarction of the left cerebral hemisphere. A left atrial mural thrombus was found at necropsy. Transient cerebral ischaemia occurred in an additional 2 cases. One patient developed recurrent episodes of right facial weakness and non-fluent dysphasia lasting one-half to two hours. These occurred in association with acute cardiac rejection and resolved after heparinization and increased immunosuppression. A second patient developed recurrent syncopal attacks due to an atrioventricular conduction defect two and a half years after transplantation; these episodes resolved with placement of a permanent cardiac pacemaker.



component. All patients were obviously Cushingoid, but except for local tenderness and mild diffuse proximal muscle weakness, results of neurological examination were unremarkable. Radiological examination of these patients revealed multiple compression fractures. The low thoracic and high lumbar vertebrae were involved most frequently. In 2 patients, the back pain developed at a time when x-rays demonstrated only severe osteoporosis. Both subsequently developed compression fractures at the site of the pain.

G. Neoplasm In a review of organ transplant recipients, Schneck and Penn reported 22 patients who developed lymphomas, usually reticulum cell sarcomas, in a series of 5 000 recipients of renal transplants and 170 patients with cardiac homografts (Schneck and Penn, 1971). Eleven cases involved the brain primarily while the others had evidence of systemic involvement. One of our patients developed a cerebellar reticulum cell sarcoma but died from cerebellar tonsillar herniation before a diagnosis could be made and radiotherapy given. The details of this case have been reported previously (Schober and Herman, 1973). Another individual was found to have a disseminated lymphoreticular tumour, but the nervous system was not involved.

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F. Acute Psychosis Acute psychotic episodes, characterized by bizarre or inappropriate behaviour, paranoid ideation and hallucinations, occurred in 7 patients. In all instances, the psychosis was completely reversible, clearing gradually between four to thirty days. These episodes occurred within the first two months after transplantation, and the majority during thefirstthirty days. In 3 cases, disorientation and confusion accompanied the abnormal behaviour. Six of 7 patients had pre-operative behavioural abnormalities: 4 had symptoms compatible with chronic personality disorders; the other 2 had pre-operative confusion which improved after transplantation. The acute psychosis is probably the result of several coexisting factors including pre-morbid personality, situational stress and medications, particularly corticosteroids and sedatives. A similar clinical presentation occurred in 4 other patients. Each of these, however, developed progressive neurological dysfunction which was later proved to be the result of CNS infection. Some features that partially distinguish this group include a later onset of symptoms (usually beyond the first post-operative month), the absence of pre-operative personality disturbances, and the invariable accompaniment of confusion and disorientation. None the less, the initial differentiation between the patient with an acute reversible psychotic reaction and the patient in whom the psychosis is the first symptom of a more serious, progressive disorder, is difficult.




The vast majority of patients receiving cardiac homografts today experience a marked and often dramatic improvement in cardiac performance. At the same time, rejection crises are being more successfully treated. Increasingly, it is the complications related to necessary immunosuppression that determine the length and quality of survival. These complications frequently involve the nervous system, and in 20 per cent of our patients, this involvement of the CNS led to death.

12 io


< a. LL O £C



3 Z




EPISODES OF CARDIAC REJECTION FIG. 2. Relationship between infectious neurological complications and the number of acute cardiac rejections during the first four post-operative months.

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Comparison with Renal Transplantation The neurological manifestations of cardiac transplantation are similar to those seen following renal transplantation. In contrast to the patients with end-stage renal disease, however, individuals receiving cardiac homografts are usually not significantly hypertensive and have not had long-standing specific metabolic abnormalities (for example, uraemia) prior to transplantation. Thus, in most instances, the neurological syndromes encountered in the present series are directly related to the surgical procedure, to cardiac rejection or to immunosuppression. Infection is the most common cause of neurological manifestations in both the renal and cardiac recipients. Multiple types of organisms are involved, but generally they are of low pathogenicity. With the exception of phycomycosis, brain involvement is typically part of a systemic infection (Table 4). Of the 20 patients who developed infections of the CNS, 15 presented during the first four post-operative months. The probability of infection could be roughly correlated with the.number of acute rejection crises during, that period. Fig. 2 illustrates that neurological disorders developing after three episodes of homograft rejection were consistently found to be of infectious aetiology. The absence of cardiac



Effects of Immunosuppression on the Nervous System Immunosuppression sufficient to prevent graft rejection is associated with three major side effects: (1) the patient is rendered susceptible to infection by ubiquitous organisms of low pathogenicity; (2) the host's response to infective agents is altered; and (3) neoplasms may appear de novo. Susceptibility to opportunistic organisms is enhanced because defences against infection are impaired in several ways (for review see Harris and Bagai (1974) and Hersch (1974)). Antigen uptake by the lymphoreticular system is defective. At the same time, antibody formation is decreased by selective killing of lymphocytes, reduction in numbers of germinal centres in lymph nodes and spleen and depression of bone marrow. Azathioprine and corticosteroids suppress the inflammatory response and adversely affect delayed hypersensitivity. Both steroids and antilymphocyte globulin depress interferon production. The patient's ability to fight infection is further hindered if significant leukopenia develops. Finally, vigorous use of antibiotics eliminates more common bacterial pathogens. Thus, under these circumstances viruses, fungi, protozoa and unusual bacteria will be selected for and even encouraged to flourish. It is also not unexpected that some patients are found to be infected with more than one organism, and that infectious complications frequently develop in association with allograft rejection, a time when immunosuppression is most extreme. In uraemic patients receiving kidney transplants, there is the additional factor of impaired immune

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rejection, or only one acute episode, favoured a non-infectious aetiology for the CNS dysfunction. It is likely that the increased use of immunosuppressive agents necessitated by frequent bouts of acute rejection enhances the likelihood for development of widespread infection. To date, we have not encountered either central pontine myelinolysis or progressive multifocal leuko-encephalopathy, both reported in patients with transplanted kidneys. Schneck (1966) described 3 cases of central pontine myelinolysis in 34 patients who died following renal transplantation. The selectivity implied by the absence of central pontine myelinolysis in our material, and its relative rareness in renal transplant recipients, suggests that its development is probably due to the confluence of several pathological processes which affect the myelin sheath rather than to a single causative factor such as immunosuppression. Since progressive multifocal leuko-encephalopathy is typically seen in patients with long-standing chronic systemic diseases, particularly if there is altered immune responsiveness, it is natural to expect this disease as a complication of cardiac transplantation. The absence of progressive multifocal leukoencephalopathy from the present series may simply reflect the fact that the life expectancy of cardiac transplant patients has been, until now, less than the time necessary for its virus to cause discernible disease. If this hypothesis is correct, we would predict that with longer survival time, this 'slow virus' demyelinating disease will be reported in patients who have undergone cardiac transplantation.



Diagnosis of the Transplant Recipient with Neurological Manifestations The diagnostic problems presented by the cardiac transplant recipient who develops a neurological syndrome may serve as a model for approaching any patient with acquired immunological deficiency. Making a firm neurological diagnosis in these patients is critical, yet often extraordinarily difficult. In our

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responsiveness related to the chronic disease which antedates the iatrogenic immunosuppression (Merrill, 1968). This pre-existing altered state of immunity (at least as judged by delayed hypersensitivity and immunoglobulins) is not seen in patients receiving cardiac homografts. In addition to enhancing susceptibility to opportunistic organisms, immunosuppression alters the host's response to the infective agent. This is best illustrated by considering the clinical and neuropathological findings in transplant patients with presumed viral encephalitis. An outstanding feature of these cases is the paucity of symptoms or signs classically seen in sporadic or acute epidemic encephalitis. Few of the patients had an illness characterized by abrupt onset, fever, seizures or focal neurological deficits. They presented instead with a slow deterioration in mental status. On microscopical examination at necropsy, there was no inflammatory perivascular infiltrate; neuronophagia was not prominent; and necrosis was infrequent. The hallmark pathologically was abundant microglial nodule formation mainly in grey matter. The third consequence of a defective immunological response is the increased risk of neoplasia. Schneck and Penn (1970) have reported an incidence of 6 per cent if the patient lives more than four months. These neoplasms appear to have a predilection for the nervous system, as over half have involved the brain, sometimes primarily. The vast majority of these are reticulum cell sarcomas, and may appear multicentric in origin (Barnett and Schwartz, 1974; Schneck and Penn, 1970, 1971; Schober and Herman, 1973). The most attractive theory to date relates the development of neoplastic disease in these patients to suppression of an 'immunological surveillance system.' In terms of this hypothesis, the immunesuppressed host has limited ability to recognize new antigens as foreign. Thus, aberrant cells, whether the result of metaplasia caused by oncogenic viruses (Schwartz and Andre-Schwartz, 1968) or chromosomal damage by cytotoxic agents (Jensen, 1970), may proliferate with relative impunity. What role the allograft itself might play in inducing neoplasia by providing continuous antigenic stimulation of the immune system is unknown (Walford, 1966). The brain may be especially vulnerable as a site for neoplastic transformations since it normally has weak rejection potential, probably because of the absence of lymphatics and lymphoid tissue, and is considered an immunologically privileged site. The unusual intracerebral origin for many of the tumours reported in transplant patients, therefore, may be the outcome of foreign antigenic material residing in the CNS without opposition, at a time when the extracerebral immune system, even though suppressed, retains some ability to repress tumour formation.



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experience, the bedside examination alone can rarely be relied upon to differentiate accurately among the various a;tiological possibilities. There are, however, several exceptions. In the immediate post-operative period, recurrent focal seizures with or without neurological deficit are most likely to be the result of focal cerebral infarction. Post-operative delirium and confusion which subsequently improve are probably related to transient, diffuse cerebral ischaemia and are unlikely to be infectious in origin. The acute or subacute onset of pain in the back, even in the absence of trauma, is likely to be due to compression fractures of one or more vertebral bodies. Finally, ophthalmoplegia, periorbital inflammation and numbness about the eye and nose suggest phycomycosis. The greatest problem arises in assessing the patient who develops mild and often vague symptoms of mental impairment after the immediate post-operative period. In our series, the single most common error in diagnosis was to attribute a deterioration in mental status to 'metabolic encephalopathy' or 'intensive care unit psychosis' when it was in fact due to infection. Since host response may be severely attenuated in this group of patients, the infectious agent can be firmly entrenched and already widespread by the time neurological symptoms appear. It is important that every patient who develops neurological manifestations, regardless of how vague and non-specific, be suspected of harbouring an infection and investigated appropriately and urgently. We emphasize that this is irrespective of any concomitant metabolic disturbances. Similarly, the absence of fever does not exclude infection in this group of patients. Some points which are helpful in making an accurate diagnosis include the following. Consideration of pulmonary and systemic infections present at the time neurological symptoms appear is essential. Every case of cerebral aspergillosis and CMV infection was associated with pulmonary involvement. Suspicion of a CNS viral or fungal infection should lead to meticulous ophthalmoscopic examination (see, for example, Case 3). The Sabin-Feldman Dye Test for toxoplasmosis should be requested routinely. Lumbar puncture is of obvious importance in attempting to find evidence of a CNS infection, but a normal CSF examination never excludes this possibility. Aspergillosis, for example, causes a severe necrotizing encephalitis and vasculitis with little or no meningeal reaction. Consequently, the CSF may be entirely normal (Case 1). Improved serological techniques now permit early and accurate diagnosis of cryptococcal infection even when the CSF is otherwise normal. Electroencephalography has generally been of limited value. Almost without exception, multiple cerebral lesions have been associated with non-specific EEG changes which have no focal or lateralizing features. This has also been the case with widespread viral infection. The EEG has been useful in defining epileptiform foci in patients with recurrent focal seizures. It has also accurately indicated a focal abnormality in the presence of an acute destructive lesion, for example intracerebral haemorrhage.




Review of the neurological complications encountered in 83 patients who received cardiac homografts over a seven-year period leads to the following conclusions: (1) Neurological disorders are common in transplant recipients, occurring in over 50 per cent of patients. (2) Infection was the single most frequent cause of the neurological dysfunction, being responsible for one-third of all CNS 1 Since completing this review, a second patient developed cryptococcal meningitis. The infection has been cured with repeated cisternal and intravenous infusions of amphotericin, and the patient is neurologically normal at present. F

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Computed axial tomographic (CAT) scanning was not available at the time these patients were under investigation. It is our present practice to obtain CAT scans routinely in any transplant patient who develops neurological symptoms. Experience to date suggests that introduction of this new technique improves diagnostic accuracy considerably, particularly in differentiating between structural brain disease and metabolic encephalopathy. For example, we now make a presumptive diagnosis of cerebral aspergillosis in immunologically compromised individuals if the CAT scan reveals characteristic multiple lesions in a patient with proved pulmonary aspergillosis and an undiagnosed neurological syndrome. Without brain biopsy, though, it is not possible to implicate a specific organism as the unequivocal cause of an abscess, nor has it always been possible to distinguish accurately between brain abscess and cerebral neoplasm. While therapeutic alternatives are limited, there is no justification for a nihilistic approach. Bacterial meningitis, even when caused by obscure organisms, should respond to appropriate antibiotics. Phycomycosis, if recognized early, can be cured with a combination of thorough debridements and amphotericin (Case 3). Our single case of cryptococcal meningitis died of unrelated complications before a response to antifungal therapy could be determined.1 Pyrimethamine and sulfadiazine are effective in treating toxoplasmosis (Ruskin and Remington, 1976). Cerebral reticulum cell sarcomas may go into remission for extended periods with radiotherapy (Schneck and Penn, 1970). There is little doubt, however, that treatment of infectious complications remains generally unsatisfactory. At the present time, amphotericin is the only antifungal drug in widespread use. Apart from a number of severely toxic side effects, its major disadvantage lies in its being fungistatic rather than fungicidal. This is especially significant for the transplant recipient whose host defences, impaired by immunosuppression, are unable to assist in the elimination of fungal pathogens. The current therapy of viral infections has even less to offer. The effectiveness of idoxyuridine, cytarabine and amantadine has been disappointing, and their use remains largely experimental (Weinstein and Chang, 1973). Attempts to stimulate and take advantage of the host's own interferons have so far met with only limited success (Weinstein and Chang, 1973).



ACKNOWLEDGEMENTS We appreciate the support of Dr. Norman Shumway and the members of his cardiac transplant team. Our colleagues in neuropathology, Drs. Mary Herman and Lysia Forno, contributed substantially to the final shaping of the manuscript and Dr. Leslie Dorfman made many valuable suggestions.

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complications. (3) The infective organisms were typically those considered to be usually of low pathogenicity: fungi, viruses, protozoa and an uncommon bacterial strain. (4) Other clinical neurological syndromes were related to vascular lesions, often apparently from cerebral ischaemia or infarction occurring during the surgical procedure, metabolic encephalopathies, cerebral microglioma, acute psychotic episodes and back pain from vertebral compression fractures. (5) The infectious complications and probably the development of neoplasms de novo, are related to immunosuppressive therapy which impairs virtually all host defence mechanisms and alters the nature of the host's response to infective agents or other foreign antigens. (6) Because neurological symptoms and signs were usually those of behavioural changes or deterioration in intellectual performance, the neurological examination was often of little value in diagnosing the nature or even the anatomical site of the neuropathological process. (7) The possibility of an infectious origin of the neurological manifestations must be aggressively pursued even in the absence of fever and a significantly abnormal spinal fluid examination. The diagnostic error made most frequently was to ascribe neurological symptoms erroneously to metabolic disturbances or to 'intensive care unit psychosis' when they were in fact due to unrecognized CNS infection. (8) Maintenance of mean cardiopulmonary bypass pressures above 70 mmHg, particularly in patients with known arteriosclerosis, may reduce operative morbidity. (9) Though increased diagnostic accuracy is possible with routine use of a variety of radiological and laboratory techniques, two further requirements probably must be met before a significant reduction in the frequency of neurological complications will occur: the advent of greater immunospecificity in suppressing rejection of the grafted organ while preserving defences against infection; and a more effective armamentarium of antiviral and antifungal drugs.



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The neurological complications of cardiac transplantation.

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