Causes of Death in Patients With Tuberous Sclerosis

Causes of Death in Patients With Tuberous Sclerosis

CHARLES W. SHEPHERD, M.D.,* Department ofNeurology; MANUEL R. GOMEZ, M.D., Section ofPediatric Neurology; J. T. LIE, M.D., Section ofMedical Pathology; CYNTHIA S. CROWSON, BoA., Section of Biostatistics Of the 355 patients with tuberous sclerosis complex (TSC) examined at the Mayo Clinic, 49 had died (9 of causes other than TSC). We attempted to determine what pattern oforgan involvement occurred most often in the 40 patients who died of TSC. One baby died of cardiac failure due to cardiac rhabdomyomas, and one child died of rupture of an aneurysm of the thoracic aorta. Eleven patients died of renal disease, which was the commonest cause of death. Ten patients died as a result of brain tumors, and four patients (who were 40 years of age or older) died of lymphangiomyomatosis of the lung. Thirteen patients with severe mental handicaps died of either status epilepticus or bronchopneumonia; in all but one of these patients, the only source of information was the death certificate. Survival curves show a decreased survival for patients with TSC in comparison with that for the general population. Patients with TSC need lifelong follow-up for early detection of potentially life-threatening complications.

Tuberous sclerosis complex (TSC) is an autoso- volvement causes severe symptoms, disability, mal dominant disease characterized by the pres- or even death. As part of a review of the medical records of all ence of hamartias and the growth of hamartomas in every organ, except possibly the skeletal Mayo Clinic patients with TSC, the cause of and muscles and the peripheral nerves. The TSC age at death were determined in those patients gene or genes are expressed with various pheno- known to have died. We have attempted to types,' even within the same family. The result document which organ involvement was most depends on which organ or organs are involved often fatal for these patients. We hope that this and the extent of involvement. In some organs- information will help prevent early deaths from for example, the eye-the hamartomas almost TSC. never cause symptoms," but in other organs-for example, the brain-the hamartomas may cause METHODS intracranial hypertension. In some patients, no All patients with TSC examined at the Mayo symptoms occur and only signs ofthe disease are Clinic were identified by a computer search of disclosed, whereas in other patients, the in- the medical records. TSC was diagnosed on the basis of published criteria. 3 We reviewed the medical records of all patients with TSC to *Current address: Craigavan Hospital, Lurgan, Co Ar- determine their current clinical signs and sympmagh, Northern Ireland. toms related to TSC. Further information about the patient's current clinical status was obtained Address reprint requests to Dr. M. R. Gomez, Section of by using a standard questionnaire. When a Pediatric Neurology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 66:792-796,1991

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patient's death was reported, the cause was ascertained by reviewing the autopsy report and pathologic materials if available, outside medical records, and death certificate. A KaplanMeier survival curve" was plotted for all patients who had died, regardless of the cause of death.

RESULTS

Of the 355 patients with TSC who had been assessed at the Mayo Clinic, 49 (26 female and 23 male patients) were known to have died, and 50 had been lost to follow-up. The other 256 patients were directly contacted to establish their current health status. In 9 of the 49 patients who had died, the cause of death was considered not directly attributable to TSC. The distribution of ages of the 40 patients who died of TSC is shown in Figure 1, and the distribution of deaths by cause of death and by age ofthe patient is depicted in Figure 2. Cardiovascular deaths occurred in infancy or early childhood. Only one patient, a 3-day-old boy, died of cardiac rhabdomyomas that obstructed the atrial and mitral valves. In our series, ofthe 91 patients screened by echocardiography, 45 (49%) had cardiac rhabdomyomas. The other cardiovascular death was due to rupture of an aneurysm of the thoracic aorta in a 3year-old girl. Of the 11 patients (7 female and 4 male) who died of renal disease, all were 10 years of age or older, and the frequency of renal deaths increased with advancing age. Seven patients died of renal failure, two died of bleeding angiomyolipoma, and two died of renal cell carcinoma. Of the 148 patients screened for renal involvement in this series, 55 (37%) had angiomyolipomas, 10 (7%) had cysts, and 14 (9%) had both cysts and angiomyolipomas. Of the 216 patients who were screened in this study, 191 (88%) had evidence of subependymal nodules, and 21 (10%) had subependymal giant cell astrocytoma thought to arise from such nodules." In 10 patients (5 female and 5 male), death was either a result of the tumor (in 6 cases) or related to treatment (in 4 cases). In seven of these patients, the tumor was proved histologically to be a subependymal giant cell astrocy-

DEATH FROM TUBEROUS SCLEROSIS

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toma. In the three other patients, no histologic observations were available; however, the radiologic and clinical features were consistent with an intraventricular tumor. Deaths due to brain tumors were most common in the 10- to 19-yearold group. Deathfrom lymphangiomyomatosis ofthe lung occurred in patients who were 40 years of age or older. Of the 10 patients with biopsy-proven lung disease, 4 (3 female and 1 male) had died. In this series, 13 patients (7 female and 6 male) with severe mental handicaps due to TSC died; the cause of death was listed as status epilepticus in 9 and bronchopneumonia in 4. In 12 patients, the only information on the cause of death was from the death certificate; in 1 patient, additional information was obtained from the patient's mother. No autopsies were done on these patients. The survival curve for all the Mayo patients with TSC (regardless of cause of death) is plotted in Figure 3. For comparison, the survival curve for the white population of the United States in 1970 is also shown.

DISCUSSION Although 49% of our patients with TSC who are alive and who were examined by echocardiography (most ofwhom are children) had one or more rhabdomyomas, only 1 death in 40 could be attributed to this tumor (obstruction of the

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ventricular outflow tracts by intracavitary tumors in a 3-day-old baby). Rhabdomyomas can be embedded in the myocardium or can protrude into a cardiac cavity." Echocardiographic studies have shown that rhabdomyomas shrink as the patient ages.? Although a published study reported sudden death in a 10-yearold girl with rhabdomyomas embedded in the myocardium and compensatory hypertrophy of unaffected myocardium (it did not state that she had TSC), B rhabdomyoma apparently causes symptoms in only a small proportion of newborns with this tumor. Intrinsic disease of the medium-sized and large vessels in TSC is rare but often fatal. Larbre and associates" described a 21h -year-old boy and Freycon and colleagues!" described a 2year-old girl who both had TSC and an aneurysm of the abdominal aorta, and both patients died. The other known cause of an aortic aneurysm reported in infants is sepsis from catheterization of the umbilical artery. 11 Other investigators have reported the association of TSC with fibromuscular dysplasia of the aneurysmal vessel. 12,13 In our series, only one patient with TSC had an aneurysm of the ascending thoracic aor-

ta, and its rupture and the resultant hemothorax caused death. In our series, the most common cause of death was renal disease in the form of angiomyolipomas,':' cysts, or both. Angiomyolipomas are more common than renal cysts." The presence of numerous renal cysts may cause renal failure even in children, and this finding may be an initial clinical feature of TSC.16 Cysts that led to renal failure occurred in young patients; angiomyolipomas occurred in two older patients in our study group. Angiomyolipomas also were fatal in two patients because of a massive hemorrhage within the tumor."? Renal clear cell carcinoma is a malignant tumor that may be associated with angiomyolipomas.v" It originates in the same hyperplastic tubular epithelium seen only in TSC,20 which lines the renal cysts." In our study, two patients, including a 31-year-old man, died of this malignant lesion. Other investigators have found this tumor in young patients with TSC.22,23 The potentially fatal outcome in patients with TSC who have renal involvement warrants periodic examination with use of renal imaging and measurement of renal function.

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Fig. 3. Kaplan-Meier survival curves for patients with tuberous sclerosis complex (solid line) and for the white population of the United States in 1970 (broken line).

Subependymal giant cell astrocytoma, a tumor that we have found only in patients with other signs ofTSC, OCcurs in 6% ofthese patients.v' It arises from the subependymal nodules" and may grow sufficiently to block one or both foramina of Monro, which causes obstructive hydrocephalus." The histopathologic features of subependymal giant cell astrocytoma are identical to those of subependymal nodules." It grows slowly and rarely has a malignant appearance.P" In our series, six patients died as a direct result of this tumor-five because of increased intracranial pressure and one because of a hemorrhage into the tumor, an infrequent occurrence.29 In four other patients, complications of treatment of the tumor preceded death. Computed tomography can be used to detect the tumor before it becomes symptomatic." The recent trend of using regular computed tomography of the head in young patients with cerebral TSC facilitates early detection and treatment, which result in decreased mortality. Pulmonary involvement has been estimated to occur in less than 1% of all cases ofTSC.31 The pathologic features are similar to those oflymphangiomyomatosis of the lung32,33-cystic changes and focallymphangiomyomatosis. 34,35 The condition is almost always found in women of childbearing age; in our series of patients with TSC, only one male patient died of this lung disease. Ten of our patients had biopsy-proven lung in-

795

volvement from TSC, four of whom died. The prognosis associated with pulmonary TSC is less favorable than that associated with other organ involvement in TSC; a higher percentage of patients died ofTSC with lung disease than with heart, kidney, or brain involvement. Death certificates are often inaccurate for determining the cause of death, and they were the only available source of information for 12 of the 13 mentally handicapped patients who died of bronchopneumonia or status epilepticus. Bronchopneumonia is a frequent complication of all types of severe mental handicap. Death from bronchopneumonia was not the direct effect of the pathologic lesions of TSC, but severely mentally handicapped patients have a greater risk for this disease than does the rest of the population. Although status epilepticus or convulsions were the cause of death listed on the death certificates of nine patients, this number may be questioned and was not definitely established for our study. The survival curve for all patients with TSC in our study shows that, when analyzed collectively, patients with TSC have a decreased life expectancy in comparison with the overall population; however, by dividing the patients into groups according to the organs involved and the severity of involvement, prediction of survival can be more accurate.

REFERENCES 1. Gomez MR: Varieties of expression oftuberous sclerosis. Neurofibromatosis 1:330-338, 1988 2. Robertson DM: Ophthalmic findings. In Tuberous Sclerosis. Secondedition. EditedbyMRGomez. New York, Raven Press, 1988, pp 89-109 3. Gomez MR: Criteria for diagnosis. In Tuberous Sclerosis. Secondedition. Edited by MR Gomez. New York, Raven Press, 1988, pp 9-19 4. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457481, 1958 5. Fujiwara S, Takaki T, Hikita T, Nishio S: Subependymal giant-cell astrocytoma associated with tuberous sclerosis: do subependymal nodules grow? Childs Nerv Syst 5:43-44,1989 6. Fenoglio JJ Jr, McAllister HA Jr, Ferrans VJ: Cardiac rhabdomyoma: a clinicopathologic and electron microscopic study. Am J Cardiol 38:241-251, 1976

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