BRIEF COMMUNICATIONS
Intracerebral Hemorrhage Related to Cerebral Amyloid Angiopathy and t-PA Treatment -
William W. Pendlebury, MD, Elizabeth D. Iole, MD, Russell P. Tracy, PhD, and Barbara A. Dill, BA
Tissue plasminogen activator (t-PA) has been approved as thrombolytic therapy for the treatment of acute myocardial infarction, but this agent can cause serious bleeding complications including intracerebral hemorrhages. Mechanisms underlying the development of these hemorrhages have not been clarified. We report a patient who developed two intracerebral hemorrhages shortly after receiving t:PA for the treatment of an acute myocardial infarction, and who wa. found to have cerebral amyloid angiopathy at autopsy. Staining of cortical sections with Congo red and an antibody directed against beta amyloid protein (A4 peptide) disclosed specific involvement of most of the subarachnoid and superficial cortical vessels in the region of the two hemorrhages. Based on the findings in this patient and in 6 additional patients reported recently, it is likely that cerebral amyloid angiopathy plays a pathogenic role in some intracerebral hemorrhages associated with the administration of t-PA. The cautious use of t-PA with heparin in patients who are elderly or demented may be advisable. Pendlebury WW, Iole ED, Tracy RP, Dill BA. lntrdcerebrd hemorrhage related to cerebral amyloid angiopathy and t-PA treatment. Ann Neurol 1991;29:210-213
Tissue plasminogen activator (t-PA) has been approved by the Food and Drug Administration for use in the management of acute myocardial infarction (AMI) 11). Hemorrhagic complications related to t-PA administration include bleeding at vascular access sites, gastrointestinal and retroperitoneal bleeding, and bleeding into the central nervous system (CNS) [2, 31. Intracerebral hemorrhages (ICH), hemorrhagic brain infarctions, and subdural hematomas occur with a combined frequency of 0.0 to 1.7%) in patients receiving t-PA for the treatment of AM1 14-71. The incidence of CNS hemorrhages appears to be related to the dose of t-PA given and the concomitant aclministration of heparin
From the Department of Pathology, University of Vermont, Medical Alumni Building, Burlington, VT. Received Jul 20, 1990, and in revised form Aug 28. Accepted for publication Aug 30, 1990. Address correspondence to Dr Pendlebury, Department of Pathology, University of Vermont, Medical Alumni Building, Burlington, VT 05405.
210
[8}. In a previous report of ICH associated with t-PA administration 191, the mechanism or mechanisms underlying the generation of the hemorrhages was not clear. To shed light on this issue, we report the case of a 60-year-old woman who suffered fatal ICHs after the use of t-PA in the management of an AMI. Autopsy examination of the brain disclosed multifocal cerebral amyloid angiopathy (CAA) of leptomeningeal and superficial cortical vessels, and in particular, the vessels in the area of the two hemorrhages were extensively involved.
Patient Report A cognitively normal, 60-year-old white woman without prior cardiac, hypertensive, or cerebrovascular disease was admitted to the Medical Center Hospital of Vermont with severe substernal chest pain and electrocardiographic (EKG) changes consistent with acute inferior wall ischemia. At the time of her admission, she was taking no medications including aspirin. General physical examination disclosed a blood pressure of 1601100 mm Hg and an S4 cardiac sound but was otherwise unremarkable. Neurological examination gave normal findings. Initial laboratory results included a fibrinogen of 3.4 gm/L (340 mgidl), a partial thromboplastin time (PTT) of 30 seconds, and a prothrombin time of 11.4 seconds. The patient had no apparent contraindications to the use of t-PA and after the diagnosis of AMI, t-PA administration was begun approximately 2.5 hours after the onset of chest pain. She received a 6-mg bolus of t-PA followed by an infusion of 54 mgihr for 1 hour, 20 mgihr for the next hour, and 5 mgihr for the next 4 hours for a total dose of 100 mg. The t-PA protocol also included boluses of lidocaine hydrochloride (75 mg) and heparin (5,000 U) (both given with the initial bolus of t-PA) followed by a heparin infusion of 1,000 Uihr. Approximately 10 minutes after t-PA was initiated, the patient experienced a pronounced decrease in chest pain and by 40 minutes she was pain free. A followup EKG showed almost complete resolution of ischemic changes. Six hours after the initiation of t-PA therapy, the patient developed nausea, vomiting, and lethargy. Blood pressure ranged from 94/60 mm Hg to 124188 mm Hg. Lethargy and confusion progressed, and 4 hours later, she developed a brief episode of apnea and became unresponsive except to pain. Blood pressure ranged from 148190 mm Hg to 1801 110 mm Hg. Laboratory analysis at the time of her clinical deterioration revealed a fibrinogen of 2.86 gm/L (286 mgidll and a P T T greater than 100 seconds. Neurological examination gave no focal findings, and all medications were discontinued. The patient subsequently developed weakness, conjugate gaze preference, and a Babinski response all on the right. An emergent cranial computerized tomographic scan identified two areas of I C H within the right frontal and left temporal lobes (Fig 1). She was immediately given protamine and intubated for the purpose of hyperventilation, and the P M decreased to 3 1 seconds. H e r neurological status deteriorated, and she expired approximately 32 hours after admission. Serial platelet counts were normal throughout her course. Fibrin split products and D-dimer values were not obtained.
Copyright 0 1991 by the American Neurological Association
Fig 2. Coronal section of the fmntal lobes showing the gross appearance of the right fTontal lobe hemorrhage. Note the super$cia/ location of the lesion with rupture into the subarachnoid space.
Fig 1 . Computerized tomographicscanof the brain without intraoenous enhancement showing a large right frontul lobe intracerebral hemorrhage and a smaller left temporal lobe hemorrhage. The temporallobe leJ ion has an amciated hypoitrnse area corresponding to necrosis.
Pathological Findings The brain weight after fixation was 1,320 gm. Multifocal subarachnoid hemorrhages were present over the right hemisphere, involving primarily the posterior frontal lobe. There was diffuse gyral flattening and sulcal obliteration. Clotted blood emanated through 2 x 4-cm defects in the lateral aspect of the right frontal pole and inferior left temporal lobe. Bilateral uncal grooving was present. Coronal sections of 1-cm thickness showed ventricles filled with clotted blood. Within the right frontal lobe there was a 5 x 4-cm hemorrhage located superficially and laterally, and extending posteriorly from the frontal pole to the genu of the corpus callosum (Fig 2). Within the left temporal lobe there was a 4 x 4-cm, superficial hemorrhage extending posteriorly from the level of the anterior commissure to the splenium of the corpus callosum. The cerebellum and brainstem were unremarkable. Histopathological examination of paraffinembedded, hematoxylin-and-eosin-stained sections of brain disclosed acute ICHs of the right frontal and left temporal lobes. Many small blood vessels within the leptomeninges and gray matter had patent lumens with walls thickened by an amorphous hyaline material within the media. Staining with Congo red disclosed the intramural deposits to have salmon pink coloration by light microscopy and apple green birefringence
Fig 3. High-power photomicrogruph of leptomeninges after StrepAvidin immunoprocessingwith an antibody directed against beta amyloid (A4peptide). Note positive .rtaining of medium-sized vessels. (Magnification, x 500 before photographic reduction.)
when polarized, characteristic of amyloid. Blood vessels containing amyloid were present within both hemorrhagic and intact areas of the brain. The antigenic nature of the amyloid deposits was confirmed by positive staining after immunoprocessing with an antibody directed against beta amyloid protein (A4 peptide) [ 101 (Fig 3). Bielschowsky silver stain disclosed small numbers of neuritic plaques within the cerebral cortex of the frontal and temporal lobes. In addition, occasional neurofibrillary tangles were present in neurons of layer 5 of the temporal cortex. The number of these lesions was insufficient to establish the pathological diagnosis of Alzheimer’s disease { 111.
Discussion Hemorrhagic complications associated with t-PA use mandate that patients at high risk for such complica-
Brief Communication: Pendlebury et
al:
Intracerebral Hemorrhages and t-PA
21 1
tions be identhed before treatment. In particular, the incidence of ICH is reported to be in the range of 0.4 to 1.3% (70% of these lobar in location), depending on the dosage of t-PA used [S]. It has been suggested that patients at high risk for intracranial bleeding, including those with recent stroke or known intracranial lesion, be excluded from receiving t-PA therapy [12]. Although there are few studies that address the role of heparin in hemorrhagic events during thrombolytic therapy, heparin cannot be excluded as a factor contributing to this patient’s ICH. She had received a 5,000-U heparin bolus and was receiving an intravenous infusion of 1,000 U heparin per hour at the time of her intracerebral hemorrhagic events. The P T T was prolonged at greater than 100 seconds. CAA is a vasculopathy associated with aging, Alzheimer’s disease, and Down’s syndrome 1131, and has been implicated as an etiological factor in patients suffering superficial, lobar ICH in the absence of other risk factors such as hypertension r141. Although our patient had no history of dementia or retardation, she had CAA present in hemorrhagic and intact areas of her brain. The lobar nature of the ICHs is compatible with both CAA and t-PA administration f3, 8, 141. Evidence of other causes of lobar hemorrhage, including arteriovenous malformation and malignancy, was not present. The patient had intermittently elevated blood pressures during her hospital course but had no clinical history of hypertension. Signs of prolonged systemic hypertension, including left ventricular hypertrophy, arteriolonephrosclerosis, and intracerebral lacunar infarctions were not present at autopsy. CAA has been suspected but not directly implicated in the pathogenesis of ICHs associated with t-PA treatment. Kase and colleagues 191reported the clinical and radiological findings in 6 patients suffering ICH after treatment with t-PA for AMI. All the patients were older than the age of 65 years, and 2 of them were demented. The hemorrhages were lobar and in 2 of the patients, multifocal. In 1 patient who underwent evacuation of the hematoma, no evidence of CAA was found by Congo red staining. Considering these patients and others {S], the similarity between ICHs associated with t-PA and those associated with CAA is remarkable. Both patient groups tend to be older and the ICHs tend to be lobar, superficial, and multifocal. The fact that CAA was not demonstrated in the 1 patient examined in the previous study {9] is not surprising given its multifocal and at times sparse nature in the CNS vasculature. We feel that our patient’s underlying CAA placed her at increased risk for developing ICH when treated with a fibrinolytic agent and heparin. There are at least two possible mechanisms that might explain the genesis of ICHs in this setting. First, because it is known that CAA is a predisposing factor for ICH in the ab212
Annals of Neurology Vol 29 No 2 February 1991
sence of thromobolytic therapy, it may have been this patient’s misfortune to develop a hemorrhagic event by chance (or through some as yet undefined mechanism) during thrombolytic therapy. Results of the lytic state, such as factor V inactivation and fibrinogen degradation product generation, along with heparin, may have impaired the hemostatic response. Alternately, although no new hemorrhagic event may have occurred during therapy, the presence of CAA may predispose to the generation of subclinical, microscopic hemorrhages, one of which may have occurred in the recent past in our patient. The hemostatic response to that event would have resulted in the formation of a physiological clot at the site with subsequent lysis during thrombolytic therapy. These hypotheses are supported by the following two key elements: first, the presence of CAA increases the frequency with which ICH occurs, and second, the combination of thrornbolytic therapy and adjunctive heparin therapy compromises the hemostatic response by blocking clot formation and enhancing clot Iysis regardless of the pathological or physiological nature of the clot. In summary, clinical features that signal the presence of CAA include Alzheimer’s disease, Down’s syndrome, uncharacterized dementia, and increasing age. We conclude that patients with a clinical history of dementia or Down’s syndrome, or who are extremely old, should be viewed cautiously as candidates for t-PA treatment. We thank George Perry, PhD, Institute of Pathology, Case Western Reserve University, Cleveland, OH, for his generous donation of the beta amyloid protein (A4 peptide) antibody.
References 1. Zeller FP, Spinler SA. Alteplase: a tissue plasminogen activator for acute myocardial infarction. Drug Intell Clin Pharm 1988; 22:6-14 2. Califf RM, Topol EJ, George BS, et al. Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of amre myocardial infarction. Am J Med 1988;85:353-359 3. Roa AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial-phase 1: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;ll:l-11 4. Braunwald E, Knatterud GL, Passamani ER, Robertson TL.Announcement of protocol change in Thrombolysis in Myocardial Infarction Trial. J Am Coll Cardiol 1987;9:467 5. Braunwald E, Knatterud GL, Passamani ER, et al. Update from the Thrombolysis in Myocardial Infarction Trial. J Am Coll Cardiol 1987;10:970 6. Carlson SE, Aldrich MS, Greenberg HS, Topol EJ. Intracerebral hemorrhage complicating intravenous tissue plasminogen activator treatment. Arch Neurol 1988;45:1070-1073 7. Gore J, Sloan M, Price T, ec al. Intracranial hemorrhage after rt-PA and heparin for acute myocardial infarction-the TIMI I1 pilot and randomized trial combined experience. J Am Coll Cardiol 1990;15(suppl A):15A
8 Sloan MA, Price TR, Randall AM, ec al. Inuacerebral hemorrhage after a-PA and heparin for acute myocardial infarction: the TIM1 I1 pilot and randomized trial combined experience. Stroke 199O;21:182 9 Kase CS, ONeal AM, Fisher M, et al. Intracranial hemorrhage after use of tissue plasminogen activator for coronary thrombolysis. Ann Intern Med 1990;112:17-21 10. Cras P, Kawai M, Siedlak S, et al. Neutonal and microglial involvement in B-amyloid protein deposition in Alzheimer's dis-
ease. Am J Pathol 1990;137:241-246 11. Khachamian ZS. Diagnosis of Alzheimer's disease. Arch Neurol 1985;42:1097-1105 12. Mark DB, Hlatky MA, OConnor CM, et al. Administration of thrombolytic therapy in the community hospital: established principles and unresolved issues. J Am Coll Cardiol 1988;12: 32A-43A 13. Vinters HV. Cerebral amyloid angiopathy a critical review. Stroke 1987;18:311-324 14. Ishii N, Nishihara Y, Horie A. Amyloid angiopathy and lobar cerebral hemorrhage. J Neurol Neurosurg Psychiatry 1984; 47:1203-1210
Myoclonus in Adult Huntington's Disease Caryn M. Vogel, MD," Ivo Drury, MB, HCh," L. Cass Terry, MD, PhD,t and Anne B. Young, MD, PhD*
Two brothers with clinically definite adult Huntington's disease developed disabling myoclonus years after t h e first signs of the disease. T h e i r electroencephalograms were consistent with a primary generalized epilepsy, although neither man had seizures. The rnyoclonus was controlled with valproic acid therapy. Vogel CM, Drury I, Terry LC, Young AB. Myoclonus in adult Huntington's disease. Ann Neurol 1991;29:213-215
Myoclonus is an uncommon clinical feature in H u n t ington's disease (HD). The prominent movement disorder in affected adults is chorea, whereas in juvenile patients, the clinical picture is o n e of parkinsonism { 1, 2). O n l y 3 patients with myoclonus complicating adult HD have b e e n reported [2-43, although t h e prevalence of m y o d o n u s may be greater in patients with juvenile onset C1, 51. The patients described here illus-
From the *Department of Neurology, Universiry of Michigan Medical School, Ann Arbor, MI, and the ?Department of Neurology, Medical College of Wisconsin, Milwaukee, WI. Received Mar 19, 1990, and in revised form Jd 31. Accepted for publication Aug 2, 1990. Address correspondcncc to Dr Vogcl, University of Michigan Med-
ical Center, Department of Neurology, 1915 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0322.
trate that myoclonus can be a disabling but treatable feature in a subset of patients with adult HD.
Patient Histories T.T. was first evaluated at age 28 years, 2 years after the onset of cognitive decline and incoordination. The diagnosis of HD was supported by findings of dementia and choreiform movements, and a definite family history of adult onset dementia and chorea previously diagnosed as HD (Fig 1). Neuropsychometric testing revealed a full scale I Q (FSIQ) of 72, and positron emission tomography (PET) demonstrated hypometabolism in the caudate nuclei. Ceruloplasmin, serum and urine copper levels, electroencephalogram (EEG), head computed tomographic (CT) scan, and cerebrospinal fluid (CSF) analysis were normal. Serial examinations over the next 5 years demonstrated only a mild cognitive decline until he presented with a I-month history of uncontrollable brief, rapid jerking movements. Examination revealed frequent generalized myoclonic jerks involving axial and appendicular muscle groups, exacerbated by any attempt at movement, and prominent rigidity. Benztropine mesylare and haloperidol had been started after the onset of the myoclonus. These drugs were discontinued without clinical change. A head C T scan showed prominent caudate atrophy. An EEG demonstrated generalized bisynchronous polyspike waves, at times associated with myoclonic jerks, without loss of consciousness and enhanced by photic stimulation (Fig 2). The myoclonus, as recorded by surface electromyography over the right forearm, consisted of 40 to 80-msec bursts. The cortical component of short latency somatosensory evoked responses (SSERs) was not enlarged. An eccrine sweat gland biopsy for inclusion bodies, a periodic acid-Schiff stain for inclusion bodies in lymphocytes, an ophthalmological examination for a cherry red spot, and a lysosomal enzyme screen were negative. He did not cooperate with formal neuropsychometric testing. Valproic acid was instituted daily with a pronounced reduction in myoclonus and a return to his previous level of function. Follow-up examination 5 months later revealed rare myoclonus and no polyspike-wave activity on EEG. W.T., the older brother ofT.T., was diagnosed with HD at age 30 years, 2 years after the onset of cognitive decline and involuntary movements. His initial evaluation was similar to his brother's except for caudate atrophy on head CT scan. Five years later, his caretakers reported a progressive decline in ambulation and recent onset of jerking movements that were worse on awakening. O n neurological examination, any attempt to walk brought out myoclonic movements, which were otherwise infrequent. An EEG showed bisynchronous polyspike waves enhanced by photic stimulation. These appeared both independent of and concomitant with the myoclonus. The cortical component of the SSERs was not enlarged. Skin and rectal biopsies for inclusion bodies were negative by light and electron microscopy. Repeat neuropsychometric testing revealed a FSIQ of 64, with a pronounced decline in motor speed and dexterity. Five months after starting valproic acid therapy, he could walk unassisted; however, the remainder of his neurological examination, including the chorea, was unchanged. Follow-up EEG continued to show generalized polyspike waves. An EEG and SSERs were normal in a clinically unaffected brother.
Copyright 0 1991 by the American Neurological Association
213
Intracerebral Hemorrhage Related to Cerebral Amyloid Angiopathy and t-PA Treatment -
William W. Pendlebury, MD, Elizabeth D. Iole, MD, Russell P. Tracy, PhD, and Barbara A. Dill, BA
Tissue plasminogen activator (t-PA) has been approved as thrombolytic therapy for the treatment of acute myocardial infarction, but this agent can cause serious bleeding complications including intracerebral hemorrhages. Mechanisms underlying the development of these hemorrhages have not been clarified. We report a patient who developed two intracerebral hemorrhages shortly after receiving t:PA for the treatment of an acute myocardial infarction, and who wa. found to have cerebral amyloid angiopathy at autopsy. Staining of cortical sections with Congo red and an antibody directed against beta amyloid protein (A4 peptide) disclosed specific involvement of most of the subarachnoid and superficial cortical vessels in the region of the two hemorrhages. Based on the findings in this patient and in 6 additional patients reported recently, it is likely that cerebral amyloid angiopathy plays a pathogenic role in some intracerebral hemorrhages associated with the administration of t-PA. The cautious use of t-PA with heparin in patients who are elderly or demented may be advisable. Pendlebury WW, Iole ED, Tracy RP, Dill BA. lntrdcerebrd hemorrhage related to cerebral amyloid angiopathy and t-PA treatment. Ann Neurol 1991;29:210-213
Tissue plasminogen activator (t-PA) has been approved by the Food and Drug Administration for use in the management of acute myocardial infarction (AMI) 11). Hemorrhagic complications related to t-PA administration include bleeding at vascular access sites, gastrointestinal and retroperitoneal bleeding, and bleeding into the central nervous system (CNS) [2, 31. Intracerebral hemorrhages (ICH), hemorrhagic brain infarctions, and subdural hematomas occur with a combined frequency of 0.0 to 1.7%) in patients receiving t-PA for the treatment of AM1 14-71. The incidence of CNS hemorrhages appears to be related to the dose of t-PA given and the concomitant aclministration of heparin
From the Department of Pathology, University of Vermont, Medical Alumni Building, Burlington, VT. Received Jul 20, 1990, and in revised form Aug 28. Accepted for publication Aug 30, 1990. Address correspondence to Dr Pendlebury, Department of Pathology, University of Vermont, Medical Alumni Building, Burlington, VT 05405.
210
[8}. In a previous report of ICH associated with t-PA administration 191, the mechanism or mechanisms underlying the generation of the hemorrhages was not clear. To shed light on this issue, we report the case of a 60-year-old woman who suffered fatal ICHs after the use of t-PA in the management of an AMI. Autopsy examination of the brain disclosed multifocal cerebral amyloid angiopathy (CAA) of leptomeningeal and superficial cortical vessels, and in particular, the vessels in the area of the two hemorrhages were extensively involved.
Patient Report A cognitively normal, 60-year-old white woman without prior cardiac, hypertensive, or cerebrovascular disease was admitted to the Medical Center Hospital of Vermont with severe substernal chest pain and electrocardiographic (EKG) changes consistent with acute inferior wall ischemia. At the time of her admission, she was taking no medications including aspirin. General physical examination disclosed a blood pressure of 1601100 mm Hg and an S4 cardiac sound but was otherwise unremarkable. Neurological examination gave normal findings. Initial laboratory results included a fibrinogen of 3.4 gm/L (340 mgidl), a partial thromboplastin time (PTT) of 30 seconds, and a prothrombin time of 11.4 seconds. The patient had no apparent contraindications to the use of t-PA and after the diagnosis of AMI, t-PA administration was begun approximately 2.5 hours after the onset of chest pain. She received a 6-mg bolus of t-PA followed by an infusion of 54 mgihr for 1 hour, 20 mgihr for the next hour, and 5 mgihr for the next 4 hours for a total dose of 100 mg. The t-PA protocol also included boluses of lidocaine hydrochloride (75 mg) and heparin (5,000 U) (both given with the initial bolus of t-PA) followed by a heparin infusion of 1,000 Uihr. Approximately 10 minutes after t-PA was initiated, the patient experienced a pronounced decrease in chest pain and by 40 minutes she was pain free. A followup EKG showed almost complete resolution of ischemic changes. Six hours after the initiation of t-PA therapy, the patient developed nausea, vomiting, and lethargy. Blood pressure ranged from 94/60 mm Hg to 124188 mm Hg. Lethargy and confusion progressed, and 4 hours later, she developed a brief episode of apnea and became unresponsive except to pain. Blood pressure ranged from 148190 mm Hg to 1801 110 mm Hg. Laboratory analysis at the time of her clinical deterioration revealed a fibrinogen of 2.86 gm/L (286 mgidll and a P T T greater than 100 seconds. Neurological examination gave no focal findings, and all medications were discontinued. The patient subsequently developed weakness, conjugate gaze preference, and a Babinski response all on the right. An emergent cranial computerized tomographic scan identified two areas of I C H within the right frontal and left temporal lobes (Fig 1). She was immediately given protamine and intubated for the purpose of hyperventilation, and the P M decreased to 3 1 seconds. H e r neurological status deteriorated, and she expired approximately 32 hours after admission. Serial platelet counts were normal throughout her course. Fibrin split products and D-dimer values were not obtained.
Copyright 0 1991 by the American Neurological Association
Fig 2. Coronal section of the fmntal lobes showing the gross appearance of the right fTontal lobe hemorrhage. Note the super$cia/ location of the lesion with rupture into the subarachnoid space.
Fig 1 . Computerized tomographicscanof the brain without intraoenous enhancement showing a large right frontul lobe intracerebral hemorrhage and a smaller left temporal lobe hemorrhage. The temporallobe leJ ion has an amciated hypoitrnse area corresponding to necrosis.
Pathological Findings The brain weight after fixation was 1,320 gm. Multifocal subarachnoid hemorrhages were present over the right hemisphere, involving primarily the posterior frontal lobe. There was diffuse gyral flattening and sulcal obliteration. Clotted blood emanated through 2 x 4-cm defects in the lateral aspect of the right frontal pole and inferior left temporal lobe. Bilateral uncal grooving was present. Coronal sections of 1-cm thickness showed ventricles filled with clotted blood. Within the right frontal lobe there was a 5 x 4-cm hemorrhage located superficially and laterally, and extending posteriorly from the frontal pole to the genu of the corpus callosum (Fig 2). Within the left temporal lobe there was a 4 x 4-cm, superficial hemorrhage extending posteriorly from the level of the anterior commissure to the splenium of the corpus callosum. The cerebellum and brainstem were unremarkable. Histopathological examination of paraffinembedded, hematoxylin-and-eosin-stained sections of brain disclosed acute ICHs of the right frontal and left temporal lobes. Many small blood vessels within the leptomeninges and gray matter had patent lumens with walls thickened by an amorphous hyaline material within the media. Staining with Congo red disclosed the intramural deposits to have salmon pink coloration by light microscopy and apple green birefringence
Fig 3. High-power photomicrogruph of leptomeninges after StrepAvidin immunoprocessingwith an antibody directed against beta amyloid (A4peptide). Note positive .rtaining of medium-sized vessels. (Magnification, x 500 before photographic reduction.)
when polarized, characteristic of amyloid. Blood vessels containing amyloid were present within both hemorrhagic and intact areas of the brain. The antigenic nature of the amyloid deposits was confirmed by positive staining after immunoprocessing with an antibody directed against beta amyloid protein (A4 peptide) [ 101 (Fig 3). Bielschowsky silver stain disclosed small numbers of neuritic plaques within the cerebral cortex of the frontal and temporal lobes. In addition, occasional neurofibrillary tangles were present in neurons of layer 5 of the temporal cortex. The number of these lesions was insufficient to establish the pathological diagnosis of Alzheimer’s disease { 111.
Discussion Hemorrhagic complications associated with t-PA use mandate that patients at high risk for such complica-
Brief Communication: Pendlebury et
al:
Intracerebral Hemorrhages and t-PA
21 1
tions be identhed before treatment. In particular, the incidence of ICH is reported to be in the range of 0.4 to 1.3% (70% of these lobar in location), depending on the dosage of t-PA used [S]. It has been suggested that patients at high risk for intracranial bleeding, including those with recent stroke or known intracranial lesion, be excluded from receiving t-PA therapy [12]. Although there are few studies that address the role of heparin in hemorrhagic events during thrombolytic therapy, heparin cannot be excluded as a factor contributing to this patient’s ICH. She had received a 5,000-U heparin bolus and was receiving an intravenous infusion of 1,000 U heparin per hour at the time of her intracerebral hemorrhagic events. The P T T was prolonged at greater than 100 seconds. CAA is a vasculopathy associated with aging, Alzheimer’s disease, and Down’s syndrome 1131, and has been implicated as an etiological factor in patients suffering superficial, lobar ICH in the absence of other risk factors such as hypertension r141. Although our patient had no history of dementia or retardation, she had CAA present in hemorrhagic and intact areas of her brain. The lobar nature of the ICHs is compatible with both CAA and t-PA administration f3, 8, 141. Evidence of other causes of lobar hemorrhage, including arteriovenous malformation and malignancy, was not present. The patient had intermittently elevated blood pressures during her hospital course but had no clinical history of hypertension. Signs of prolonged systemic hypertension, including left ventricular hypertrophy, arteriolonephrosclerosis, and intracerebral lacunar infarctions were not present at autopsy. CAA has been suspected but not directly implicated in the pathogenesis of ICHs associated with t-PA treatment. Kase and colleagues 191reported the clinical and radiological findings in 6 patients suffering ICH after treatment with t-PA for AMI. All the patients were older than the age of 65 years, and 2 of them were demented. The hemorrhages were lobar and in 2 of the patients, multifocal. In 1 patient who underwent evacuation of the hematoma, no evidence of CAA was found by Congo red staining. Considering these patients and others {S], the similarity between ICHs associated with t-PA and those associated with CAA is remarkable. Both patient groups tend to be older and the ICHs tend to be lobar, superficial, and multifocal. The fact that CAA was not demonstrated in the 1 patient examined in the previous study {9] is not surprising given its multifocal and at times sparse nature in the CNS vasculature. We feel that our patient’s underlying CAA placed her at increased risk for developing ICH when treated with a fibrinolytic agent and heparin. There are at least two possible mechanisms that might explain the genesis of ICHs in this setting. First, because it is known that CAA is a predisposing factor for ICH in the ab212
Annals of Neurology Vol 29 No 2 February 1991
sence of thromobolytic therapy, it may have been this patient’s misfortune to develop a hemorrhagic event by chance (or through some as yet undefined mechanism) during thrombolytic therapy. Results of the lytic state, such as factor V inactivation and fibrinogen degradation product generation, along with heparin, may have impaired the hemostatic response. Alternately, although no new hemorrhagic event may have occurred during therapy, the presence of CAA may predispose to the generation of subclinical, microscopic hemorrhages, one of which may have occurred in the recent past in our patient. The hemostatic response to that event would have resulted in the formation of a physiological clot at the site with subsequent lysis during thrombolytic therapy. These hypotheses are supported by the following two key elements: first, the presence of CAA increases the frequency with which ICH occurs, and second, the combination of thrornbolytic therapy and adjunctive heparin therapy compromises the hemostatic response by blocking clot formation and enhancing clot Iysis regardless of the pathological or physiological nature of the clot. In summary, clinical features that signal the presence of CAA include Alzheimer’s disease, Down’s syndrome, uncharacterized dementia, and increasing age. We conclude that patients with a clinical history of dementia or Down’s syndrome, or who are extremely old, should be viewed cautiously as candidates for t-PA treatment. We thank George Perry, PhD, Institute of Pathology, Case Western Reserve University, Cleveland, OH, for his generous donation of the beta amyloid protein (A4 peptide) antibody.
References 1. Zeller FP, Spinler SA. Alteplase: a tissue plasminogen activator for acute myocardial infarction. Drug Intell Clin Pharm 1988; 22:6-14 2. Califf RM, Topol EJ, George BS, et al. Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of amre myocardial infarction. Am J Med 1988;85:353-359 3. Roa AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial-phase 1: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;ll:l-11 4. Braunwald E, Knatterud GL, Passamani ER, Robertson TL.Announcement of protocol change in Thrombolysis in Myocardial Infarction Trial. J Am Coll Cardiol 1987;9:467 5. Braunwald E, Knatterud GL, Passamani ER, et al. Update from the Thrombolysis in Myocardial Infarction Trial. J Am Coll Cardiol 1987;10:970 6. Carlson SE, Aldrich MS, Greenberg HS, Topol EJ. Intracerebral hemorrhage complicating intravenous tissue plasminogen activator treatment. Arch Neurol 1988;45:1070-1073 7. Gore J, Sloan M, Price T, ec al. Intracranial hemorrhage after rt-PA and heparin for acute myocardial infarction-the TIMI I1 pilot and randomized trial combined experience. J Am Coll Cardiol 1990;15(suppl A):15A
8 Sloan MA, Price TR, Randall AM, ec al. Inuacerebral hemorrhage after a-PA and heparin for acute myocardial infarction: the TIM1 I1 pilot and randomized trial combined experience. Stroke 199O;21:182 9 Kase CS, ONeal AM, Fisher M, et al. Intracranial hemorrhage after use of tissue plasminogen activator for coronary thrombolysis. Ann Intern Med 1990;112:17-21 10. Cras P, Kawai M, Siedlak S, et al. Neutonal and microglial involvement in B-amyloid protein deposition in Alzheimer's dis-
ease. Am J Pathol 1990;137:241-246 11. Khachamian ZS. Diagnosis of Alzheimer's disease. Arch Neurol 1985;42:1097-1105 12. Mark DB, Hlatky MA, OConnor CM, et al. Administration of thrombolytic therapy in the community hospital: established principles and unresolved issues. J Am Coll Cardiol 1988;12: 32A-43A 13. Vinters HV. Cerebral amyloid angiopathy a critical review. Stroke 1987;18:311-324 14. Ishii N, Nishihara Y, Horie A. Amyloid angiopathy and lobar cerebral hemorrhage. J Neurol Neurosurg Psychiatry 1984; 47:1203-1210
Myoclonus in Adult Huntington's Disease Caryn M. Vogel, MD," Ivo Drury, MB, HCh," L. Cass Terry, MD, PhD,t and Anne B. Young, MD, PhD*
Two brothers with clinically definite adult Huntington's disease developed disabling myoclonus years after t h e first signs of the disease. T h e i r electroencephalograms were consistent with a primary generalized epilepsy, although neither man had seizures. The rnyoclonus was controlled with valproic acid therapy. Vogel CM, Drury I, Terry LC, Young AB. Myoclonus in adult Huntington's disease. Ann Neurol 1991;29:213-215
Myoclonus is an uncommon clinical feature in H u n t ington's disease (HD). The prominent movement disorder in affected adults is chorea, whereas in juvenile patients, the clinical picture is o n e of parkinsonism { 1, 2). O n l y 3 patients with myoclonus complicating adult HD have b e e n reported [2-43, although t h e prevalence of m y o d o n u s may be greater in patients with juvenile onset C1, 51. The patients described here illus-
From the *Department of Neurology, Universiry of Michigan Medical School, Ann Arbor, MI, and the ?Department of Neurology, Medical College of Wisconsin, Milwaukee, WI. Received Mar 19, 1990, and in revised form Jd 31. Accepted for publication Aug 2, 1990. Address correspondcncc to Dr Vogcl, University of Michigan Med-
ical Center, Department of Neurology, 1915 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0322.
trate that myoclonus can be a disabling but treatable feature in a subset of patients with adult HD.
Patient Histories T.T. was first evaluated at age 28 years, 2 years after the onset of cognitive decline and incoordination. The diagnosis of HD was supported by findings of dementia and choreiform movements, and a definite family history of adult onset dementia and chorea previously diagnosed as HD (Fig 1). Neuropsychometric testing revealed a full scale I Q (FSIQ) of 72, and positron emission tomography (PET) demonstrated hypometabolism in the caudate nuclei. Ceruloplasmin, serum and urine copper levels, electroencephalogram (EEG), head computed tomographic (CT) scan, and cerebrospinal fluid (CSF) analysis were normal. Serial examinations over the next 5 years demonstrated only a mild cognitive decline until he presented with a I-month history of uncontrollable brief, rapid jerking movements. Examination revealed frequent generalized myoclonic jerks involving axial and appendicular muscle groups, exacerbated by any attempt at movement, and prominent rigidity. Benztropine mesylare and haloperidol had been started after the onset of the myoclonus. These drugs were discontinued without clinical change. A head C T scan showed prominent caudate atrophy. An EEG demonstrated generalized bisynchronous polyspike waves, at times associated with myoclonic jerks, without loss of consciousness and enhanced by photic stimulation (Fig 2). The myoclonus, as recorded by surface electromyography over the right forearm, consisted of 40 to 80-msec bursts. The cortical component of short latency somatosensory evoked responses (SSERs) was not enlarged. An eccrine sweat gland biopsy for inclusion bodies, a periodic acid-Schiff stain for inclusion bodies in lymphocytes, an ophthalmological examination for a cherry red spot, and a lysosomal enzyme screen were negative. He did not cooperate with formal neuropsychometric testing. Valproic acid was instituted daily with a pronounced reduction in myoclonus and a return to his previous level of function. Follow-up examination 5 months later revealed rare myoclonus and no polyspike-wave activity on EEG. W.T., the older brother ofT.T., was diagnosed with HD at age 30 years, 2 years after the onset of cognitive decline and involuntary movements. His initial evaluation was similar to his brother's except for caudate atrophy on head CT scan. Five years later, his caretakers reported a progressive decline in ambulation and recent onset of jerking movements that were worse on awakening. O n neurological examination, any attempt to walk brought out myoclonic movements, which were otherwise infrequent. An EEG showed bisynchronous polyspike waves enhanced by photic stimulation. These appeared both independent of and concomitant with the myoclonus. The cortical component of the SSERs was not enlarged. Skin and rectal biopsies for inclusion bodies were negative by light and electron microscopy. Repeat neuropsychometric testing revealed a FSIQ of 64, with a pronounced decline in motor speed and dexterity. Five months after starting valproic acid therapy, he could walk unassisted; however, the remainder of his neurological examination, including the chorea, was unchanged. Follow-up EEG continued to show generalized polyspike waves. An EEG and SSERs were normal in a clinically unaffected brother.
Copyright 0 1991 by the American Neurological Association
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