ABSTRACT. New-onset epileptic seizures occur in patients with Alzheimer's disease (AD), but the nature and underlying rea- sons for these seizures are unclear ...
Seizures in Alzheimer’s Disease: Clinicopathologic Study Mario F. Mendez, MD, PhD, Peter Catanzaro, BA, Robert C. DOSS,BS, Raul Arguello, MD and William H. Frey 11, PhD
ABSTRACT New-onset epileptic seizures occur in patients with Alzheimer’s disease (AD), but the nature and underlying reasons for these seizures are unclear. We identified new-onset, nonsymptomatic seizures in 77 (17%) of 446 patients with uncomplicated, definite AD on autopsy. Among these seizure patients, 69 had generalized tonic-clonic seizures, and 55 had less than three total seizures. The seizure patients had a younger age of dementia onset than did the remaining AD patients; however, at seizure.onset, they averaged 6.8 years into their AD and had advanced dementia. When further compared to 77 AD controls, matched for age of onset and duration, the seizure patients did not differ on medical illnesses, amount of medications, and degree of focal neuropathology. We conclude that a few unprovoked generalized seizures frequently occur late in the course ofAD, and that AD patients with a younger age of dementia onset are particularly susceptible to seizures. ( J Geriatr Psychiatry Neurol 1994;7:230-233).
Most estimates of the frequency of new-onset seizures amongAlzheimer’s disease (AD) patients range from 9% to 26%,I4but the reasons €or their seizures are unclear. The occurrence of seizures may define a subgroup ofAD patients. For example, seizures could follow concentrations of the neuropathologic changes of AD in specific brain regions. Alternatively, ongoing medical problems or multiple medications may result in undetected epileptogenic lesions or covert symptomatic seizures. Prior studies have not established the reasons for seizures in AD, in part due to their small sample sizes: less than 20 patients in most studies.’-’ Moreover, there has been no systematic evaluation of clinical and neuropathologic variables in a controlled study of definite AD patients with neiv-onset seizures. We analyzed the clinicopathologicrecords of all patients in a large, dementia brain bank who had only AD on neuropathology, and identified those with nonsymptomatic seizures. First, we characterized the seizures in terms of prevalence, type, frequency, electroencephalographic (EEG) findings, and anticonvulsant drug therapy. Second, we characterized the AD in terms of
Received March 29,1993. Received revised June 3,1993.Accepted for publication July 1,1993. From the Department of Neurology, St. Paul-Ramsey hledical Center, and The University of hlinnesota, St. Paul, Minnesota. Reprint requests:Dr. h1.F. hlendez, NeurobehaviouralUnit (69Y116AF) West Los Angeles VA hIedical Center, 11301 Wilshire Blvd., Los Angeles, CA 90073.
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age of onset, duration of illness, and duration and severity a t the time of the seizures. Finally, we matched the seizure patients with nonseizure controls, based on age of onset and duration of t h e m and then compared the groups on medical variables and neuropathologic features. METHODS Subjects This study included records from the Ramsey FoundationAlzheimer’s Treatment and Research Center Brain Bank, St. Paul, Minnesota. These autopsies were requested by families for research participation and confirmation of the dementia diagnosis. We identified patients with evidence on their medical records of a n acquired, sustained, and dysfunctional cognitive decline, and neuropathologic criteria for AD. We excluded cases with lesions other than those compatible with AD.
Pathology Areas examined with Bielschowsky silver staining included: (1) frontal cortex, (2) temporaI cortex, (3) parietal cortex, and (4) hippocampus (subiculum-Hl). Areas examined with hematoxylin and eosin stdining included: (1)parietal cortex, (2) occipital cortex, (3) hippocampus, (4)nucleus basalis of Meynert, (5)locus ceruleus,and (6)substantia n i p . Pathologic criteria for AD were based on an age-adjusted, moderate-tosevere number of neuritic plaques in the neocortex similar to proposed criteria!.’ All neuropathologically diagnosed AD patients had moderate-to-severe neurofibrillary tangles in the hippocampus and lacked evidence of any other dementing illness.
Seizures in Alzheimer's Disease I Mendez et a1
Seizure Characteristics \Ve identified AD patients who had a new-onset seizure during the course of their AD. The seizure history was obtained from the accompanying physician and nursing home records, and from a detailed medical history questionnaire administered to family members. The attending physicians diagnosed seizures based on the presence of brief spells or convulsions of probable epileptiform origin. The medical records were reviewed for the accuracy of their seizure diagnoses and to exclude acute, symptomatic causes for seizures. After this review, we included only those who met established criteria for unprovoked, generalized, or partial seizures.l0Finally, we characterized the number and type of seizures, the EEG findings, and the presence of anticonvulsant drug therapy.
AD Characteristics We characterized the AD features of the patients with unprovoked seizures and definite AD. The AD variables included age of onset, overall duration of AD, and age and dementia severity at the onset of seizures. Dementia severity was evaluated retrospectively with the Clinical Dementia Rating (CDR) Scale, a reliable measure of stage of dementia based on the presence of both functional and cognitive disturbances."J2 Matched Study Each AD patient with seizures was matched by sex, age of onset of AD (within three years), and duration of AD (within three years) to a n AD patient without known evidence of seizures. The groups were compared for chronic, underlying medical illnesses, the number of medications a t the time of the seizures (exclusive of prn laxatives, analgesics, and sedativehypnotics), and the presence of specific foci of microscopic neuropathology. The neuropathologist characterized the microscopic neuropathology on a 5-point scale (O=none, l=mild, 2=moderate, 3=moderately-severe, 4=severe) based on amounts of neuritic plaques, neurofibrillary tangles, and neuronal loss per high power field.
Statistical Analysis For the matched samples, comparisons were made using McNemar xz for the medical data, and the 'Wilcoxon signedrank test for the neuropathologic data.
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RESULTS Seizure Characteristics
Of a total of 446 patients with definitem, 77 (17.3%) had seizure(s) without an acute, identifiable, symptomatic cause (Table l).Among these seizure patients, 24 (31.2%) had only one seizure and 55 (71.4%)had one or two seizures. Anticonvulsant drugs were used in 65 (84.4%)patients, including 18 who had only one seizure, and consisted of phenytoin in 63,carba-mazepine in 1, phenobarbital in 4, and two drugs in 3 patients. EEGs were obtained within a few days of seizures in 52 patients and showed focal or generalized slowing in 39, slowing with sharp waves in 4,periodic complexes in 2, spike waves and epileptiform changes in 2, and normal activity in 5 patients. Most patients had generalized tonic-clonic seizures (TCS);however, the ictal events in 9 of the patients were partial, complex or partial, simple seizures. The partial seizures were unresponsive staring spells in 3, abnormal motor movements and/or myoclonus in 2, blackouts with postictal confusion i n 2, blackouts with automatisms in 1,and syncope with nonfluent aphasia in 1patient. AD Characteristics
The seizure patients (47 women; 30 men) had a younger age of onset ofAD than did the remaining 369 patients (205 women; 164 men) without seizures (see Table l).At the onset ofseizures, they averaged 6.8years into theirAD and had moderately advancedm and CDR scores. The typical patient was institutionalized, had severe memory loss, was unable to solve problems, had little independent function, and required a great deal of assistance in activities of daily living. Matched Study
No group differences were found. First, there were no significant differences for medical illnesses or for medication (Table 2). The seiiure patients took 3.5+ 2.7 drugs vs 4.2 -+ 2.6 for the controls. No patient was on epileptogenic psychotropic drugs, such as clozapine or
Table 1. Alzheimer's Disease (AD) and Seizure (SZ) Characteristics n
AD-NO SZS
Controls'
AD-SZS
General' Partial'
Age o f A D Onset
Duration ofAD
369 77
67.1 f 9.1' 65.5 f 9.6
10.0 f 9.1 10.8 f 8.2
77 69 9
64.1 f 8.8' 64.2 f 8.9 63.9 -+ 1.9
11.1 f. 8.1 11.1 f 7.9
11.1 f 9.1
*Clinical Dementia Rating Scale. 'APNo SZs vs AD-SZs in age of A 0 onset: t = 2.613, P = .009. 'Matched with AD-SZs patients on age of onset, duration, and sex. 'All generalized tonic-clonic seizures (TCSI. 'Partial seizure episodes are described i n text; one patient had both TCS and partial episodes.
Age of SZ Onset
CDR* at SZOnset
Number of SZs
C
71.0 f 9.1 71.1 f 9.0 70.2 _+ 10.1
2.7 f 1.1 2.7 f 1.2 3.1 -+ 0.4
2.8 f 2.3 2.3 f 1.6 6.5 k 7.5
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Journal of Geriatric Psychiatry and Neurology I Vol. 7,October-December 1994
Table 2. Background Medical Factors: Alzheimer's Disease (AD) Patients With and Without Seizures (SZ) AD-SZs (n = 77) n (%I Familial dementia. Hypertension Heart disease' Cerebrovascular* Pulmonary diseases* Alcohol abuse Diabetes Prior head trauma1 Other medical illnesses'
23 23 22 15 7 5 3 2 11
(29.9%) (29.9%) (28.6%) (19.5%) (9.1%) (6.5%) (3.9%) (2.6%) (14.3%)
AD-No SZs In = 71) n (%I 25 20 16 16
8
11 5 5 12
(32.5%) (26.0%) (20.8%) (20.8%) (10.4%) (14.3%) (6.5%) (6.5%) (15.6%)
'Includes first-degreerelatives. Myocardial infarctions, angina pectoris. cardiomyopathies. 'Transient ischemic attacks, strokelike events, carotid bruits. 'Does not include terminal pulmonaryconditions. 'Head injury accompanied by loss of consciousness. 'Miscellaneous renal, endocrine, hematologic, gastrointestinal, vascular and rheumatologicdisorders exclusive of degenerative arthritis.
buproprion. Second, there were no significant differences on neuropathology. Mean scores for seizure group vs controls were: Frontal 0.9 & 0:8 vs 1.4 k 1.1; temporal 1.5 f 1.1vs 1.6 f 1.0; parietal 0.8 f 0.9 vs 1.2 f 1.0; occipital 0.5 f 0.6 vs 0.8 k 0.8; hippocampus 1.9 f 1.5 vs 1.9 f 1.3; nucleus basalis 1.5 f 0.8 vs 1.6 f 0.8; locus ceruleus 1.1k 1.1vs 1.4 f 1.0; and substantia nigra 0.6 f 0.9 vs 0.6 k 0.9; DISCUSSION
In this clinicopathologic investigation of definite AD, 17%of 446AD patients developed nonsymptomatic seizures after the onset of their dementia. One or two generalized seizures commonly occurred about seven years into the course ofAD when patients were institutionalized and incapacitated, and these seizures often resulted in anticonvulsant therapy. When further compared to AD patients without seizures, those with seizures had a younger age of onset of their dementia but did not differ in medical illnesses, amount of medications, or degree of focal neuropathology. Our findings suggest that AD patients with a younger age of onset are particularly susceptible to seizures. Although new-onset seizures are common in the normal elderly popu1ation,'"l6 they are even more common in those with AD. In a clinicopathologic study of AD, Hauser et all found 8 (10%)of 81 patients with newonset seizures, 10 times that expected for a n aged control group. They projected a cumulative risk for unprovoked seizures in AD of 11%by 10 years and 26% by 15 years. In the only controlled prospective study, Romanelli et a15followed 44AD patients and 58 controls over a 90 month period and found that 7 (16%)AD patients and none of the controls developed seizures. Most clinical studies of probable AD patients have found similar frequencies of new-onset However, some selected patient samples, followed longitudinally until
death, showed seizure development in more than half of the patients ~ t u d i e d . ~Additionally, J~ 5% to 15% of Down's syndrome patients have seizures, usually in adulthood after developing the pathologic changes of AD.18Althoughone study proposed that "minor attacks" are common in AD early in its course,'jJ9most studies report a preponderance of generalized TCS in 79% to 100% of their AD patients.'~~.~J~ Similar to our findings, these seizures occurred 6.5 years or more after onset of AD, or 6 months to 3 years prior to death.1~2.5~7*19 Also, similar to our mean CDR score of 2.7, one prior prospective study found that all of their seizure patients had a n advanced CDR score of 3 a t the time of seizure onset.5 Our findings suggest that seizures occur in a subgroup of AD patients who have a younger age of onset. Similar to our findings, Sulkava*Oreported seizures in 11% of those with onset of dementia before age 65, compared to 6% for those with a later onset. McAreavey et a13also found a younger age of onset of dementia if seizures were present; however, their study involved psychiatric inpatients with mixed dementias. Seizures in AD are not clearly related to underlying medical illness or medications. Romanelli et alj also failed to find increased stroke-like events, alcohol use, hypertension, or medications in AD patients with seizures. Moreover, there are no obvious differences in focal concentration of neuritic plaques, neurofibrillary tangles, or neuronal loss. There are several potential mechanisms for seizures in AD. first, seizures could result from the neuronal, glial, or other pathologic change< 'in the hippocampus and elsewhere, present in AD. A possible selective loss of inhibitory neurons may encourage the occurrence of seizures. These mechanisms may also explain the reported increased frequency of myoclonus in AD patients with seizure^.^*.^ Second, seizures could result from coincidental, non-AD lesions. Although the cause of new-onset seizures rhay be unidentified in 50% or more of elderly patients,21about one-third have a cerebrovascular ~ a u s e , ' and ~ . ~small ~ vascular changes occur more commonly in the elderly with unexplained seizures than in controls.23Therefore, occult vascular lesions could explain some seizures in AD. Third, seizures could result from a chemically induced, epileptic susceptibility caused by a greater reduction of choline acetyl transferase, by alterations in dopaminergic or inhibitory transmitters, or by other neuroendocrine and neuromodulator changes. Our findings raise several methodological considerations. First, the incidence of unprovoked seizures in AD may be underestimated in our study. Undoubtedly, we missed seizures that went undetected or unreported, particularly partial seizures, which are difficult to recognize in advanced dementia. However, we minimized this problem by our extensive evaluation of medical records, by our matched design, and by applying estab-
Seizures in Alzheimer’s Disease 1 bfendez et a1
lished criteria for partial seizures. In contrast, prior studies may have overestimated seizures by including many nonepileptiform spells as partial-seizure events. Second, the lack of significant differences on medical and neuropathologic variables in this study could not entirely exclude the presence of true group differences. This preliminary study should Iead to a more detailed assessment of some of these variables. In conclusion, this clinicopathologicstudy corroborates the increased risk for unprovoked seizures in AD. Our findings suggest that AD patients with a younger age of dementia onset are a t particular risk for seizures. Moreover, the frequent occurrence of one or two seizures in advanced dementia often leads to unnecessary treatment with anticonvulsant medications. Further work is needed to establish whether nonsymptomatic seizures in this AD subgroup result from primary epileptogenicity of AD pathology, from occult non-AD pathology, or from other causes. Acknowledgment Supported in part by the Robert Wood Johnson J962 Charitable Trust, Ramsey Foundation, the State ofMinnesota, and theAlice M.OBnen Foundation.
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