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J Am Coll Cardiol, 2005; 45:1840-1843, doi:10.1016/j.jacc.2005.02.060
© 2005 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: HEART RHYTHM DISORDER

Amnesia for Loss of Consciousness in Carotid Sinus Syndrome

Implications for Presentation With Falls

Steve W. Parry, MBBS, PhD, MRCP*,*, I. Nick Steen, PhD{dagger}, Mary Baptist, RN* and Rose Anne Kenny, MD, FRCP, FRCP(I)*

* Falls and Syncope Service and Institute for Ageing and Health, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
{dagger} Centre for Health Services Research, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom

Manuscript received September 27, 2004; revised manuscript received February 10, 2005, accepted February 14, 2005.

* Reprint requests and correspondence: Dr. Steve W. Parry, Royal Victoria Infirmary, Cardiovascular Investigation Unit, Victoria Wing, Newcastle upon Tyne, Tyne and Wear NE1 4LP, United Kingdom. (Email: steve.parry{at}nuth.northy.nhs.uk).


   Abstract
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OBJECTIVES: The goal of this study was to compare the clinical characteristics of patients with carotid sinus syndrome who presented with falls with those who presented with syncope.

BACKGROUND: Carotid sinus syndrome presents with both falls and syncope. The reasons for this differential presentation are unknown, but amnesia for loss of consciousness may be the underlying cause.

METHODS: Two groups of 34 consecutive patients with carotid sinus syndrome as the sole cause of falls and syncope were recruited. Cognitive function and clinical characteristics were compared between the two groups.

RESULTS: Syncopal subjects with carotid sinus syndrome were more likely to be older males (18 [53%] vs. 7 [21%] years; p = 0.006) with a longer duration of symptoms (27.9 vs. 13.3 months; p = 0.009) and more soft tissue injuries (19 [56%] vs. 9 [26%]; p = 0.03). Duration of asystole during carotid sinus massage was similar in both groups (5.1 vs. 5.4 s; p = 0.42), but witnessed amnesia for loss of consciousness was more frequent in fallers than those with syncope (21 [95%] vs. 4 [12%]; p < 0.001). Clinical characteristics and cognitive function were otherwise similar in both groups.

CONCLUSIONS: Patients with carotid sinus syndrome have similar rates of witnessed loss of consciousness during laboratory testing regardless of symptoms. However, those presenting with falls are far less likely to perceive any disturbance of consciousness than those with syncope, showing for the first time the manner in which such patients manifest symptoms. Cognitive impairment does not explain the amnesia for loss of consciousness seen in fallers with carotid sinus syndrome.

Abbreviations and Acronyms
  CICSS = cardioinhibitory carotid sinus syndrome
  CSM = carotid sinus massage
  LOC = loss of consciousness
  MMSE = mini-mental state examination
  RR = relative risk

Cardioinhibitory carotid sinus syndrome (CICSS) is traditionally associated with syncope, but has recently also been implicated in the genesis of falls in older patients (1–3). Both observational (2,3) and intervention (1) studies have demonstrated this causal role, but the reasons why patients present with falls rather than syncope are unclear. This is compounded by the frequent absence of witness accounts of falls; up to 60% of falls in older people are unwitnessed, making a corroborative history of loss of consciousness (LOC) less likely (2,4).

Amnesia for LOC is a well-described phenomenon in patients with epilepsy of all age groups and may be one explanation for CICSS presenting as falls in older persons. In our clinical practice, we noted that fallers often elicited amnesia for LOC during bradycardia induced in the laboratory. Our study objective was to compare the clinical characteristics of patients with CICSS who presented with falls with those who presented with syncope. We hypothesized that amnesia for LOC was an explanation for the difference in presentation and that this was due to cognitive impairment in patients who presented with falls.


   Methods
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Participants.   All patients gave informed consent, and the study was approved by our local research ethics committee. Two groups of patients were recruited. Consecutive patients over 60 years of age who were referred to the Falls and Syncope Service for investigation of recurrent, unexplained falls with no history of syncope, and consecutive patients with recurrent syncope with no history of falls, both of whom had CICSS as the only attributable cause of symptoms, were invited to participate.

Cardioinhibitory carotid sinus syndrome was defined as an asystolic response >3 s during 5 s of carotid sinus massage (CSM). Bilateral, sequential (right- then left-sided) CSM was performed initially supine and, if nondiagnostic, repeated in the head-up tilt position (at 70°) during phasic heart rate and blood pressure monitoring. The maximum asystolic response was the maximum R-R interval during CSM. The vasodepressor response was defined as the maximum associated drop in systolic blood pressure during CSM. After diagnostic massage, no further CSM was performed in order to minimize the possibility of neurological complications (5). A nurse and doctor independently noted whether patients lost consciousness, and only patients in whom both agreed that LOC had occurred were categorized as LOC. Subjects were not informed before the study that they were going to be asked whether they had lost consciousness. Immediately on recovery, patients were asked if they had lost consciousness. All were asked again when ambulant before leaving the clinic. Patients who had witnessed LOC but denied LOC were categorized as having "amnesia for LOC." The doctor responsible for interpreting the results of CSM was blinded to mode of symptom presentation.

Exclusions included any other attributable cause of symptoms or severe cognitive impairment (mini-mental state examination [MMSE] <15 of 30).

Investigations.   Before the attribution of CICSS as the cause of their symptoms, all subjects were investigated according to the European Society of Cardiology Task Force recommendations for syncope and the U.S./U.K. guidelines on falls management (6,7). All subjects had full cardiac and neurological clinical assessment, 12-lead surface electrocardiogram, repeated morning orthostatic blood pressure assessments, and head-up tilt tests. Where indicated, subjects also had two-dimensional echocardiography, intracardiac electrophysiology, exercise stress testing, Holter monitoring and/or external loop monitoring, and electroencephalography studies.

Cognitive function assessment.   All subjects had baseline cognitive function assessment using the MMSE (8). The MMSE is a standard 30-point questionnaire covering orientation, attention, executive function, and memory. Fifty of the participants agreed to more detailed cognitive assessment with the Cognitive Drug Research (CDR) computerized test battery—a touch-screen series of neuropsychological tests (9). The battery covers all aspects of cognition, providing a summary group of five primary cognitive variables, namely speed of memory processes, quality of episodic secondary memory, power of attention, continuity of attention, and quality of working memory. The battery was administered in an individual’s home by a neuropsychologist blinded to presenting symptoms.

Statistics.   The relative risk (RR) of a patient in the syncope group having the attribute has been calculated for all binary variables (for example presence or absence of a comorbid condition). For each of the continuous variables, means, SDs, and p values derived from t tests have been calculated, with 95% confidence intervals reported for the mean. Interval estimates of the difference between groups are provided to allow a judgement as to whether differences are not significant because of sample size or not significant because it is unlikely that there is a clinically relevant difference. An RR of 1 implies that both groups are equally likely to have a particular attribute or risk factor, while a value >1 implies higher risk in the syncopal group.


   Results
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Thirty-four participants were recruited to each group; their clinical characteristics are detailed in Table 1. Both groups were of similar age. Syncopal patients were more likely to be male, had been symptomatic for a longer period of time, and experienced more frequent soft tissue injuries (Table 1). Otherwise, the total number of episodes, the consequences of events, such as hospitalization rates and fractures, prescribed medications (including rates of polypharmacy and cardiovascular and psychoactive medications), and comorbidity were similar for fallers and syncopal patients with the exception of osteoarthritis, which was more common in fallers (Table 1).


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  		Table 1. Clinical Characteristics of Fallers and Syncopal Patients With Carotid Sinus Syndrome
 
The maximum asystolic response during CSM and the vasodepressor response during CSM was the same for both groups (Table 2). The hypersensitive response was right-sided in 85% (24 patients) of syncopal patients and 71% (29 patients) fallers (p = NS). In fallers, CSM was more often diagnostic in the head-up tilt position than when performed supine (Table 2). Loss of consciousness during diagnostic CSM was more common in fallers, with fallers who lost consciousness during CSM being much less likely to recall induced LOC than syncopal subjects (Table 2). There was no disagreement between nurse and doctor on the presence or absence of LOC during CSM.


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  		Table 2. Heart Rate and Blood Pressure Responses to Carotid Sinus Massage
 
Cognitive function.   There was no difference in the cognitive scores for MMSE assessments or more detailed CDR assessments between fallers and syncopal patients (Table 3). Thirty-four fallers and 16 syncopal patients agreed to CDR testing. There was no difference in clinical characteristics between these two groups.


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  		Table 3. Cognitive Function in Fallers and Syncopal Patients With Carotid Sinus Syndrome
 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
References
 
Amnesia for LOC is the most likely explanation for older persons with CICSS presenting with falls rather than syncope. Other differences in clinical characteristics were that fallers were more likely to be female, have a higher symptom burden, and suffer comorbid osteoarthritis. The higher prevalence of amnesia for LOC supports our hypothesis that fallers with CICSS experience a "microsyncopal" event leading to their collapse, and subsequently remember the fall but not the transient LOC that precipitated it. Amnesia for LOC is a well-recognized phenomenon in epilepsy, transient global amnesia, and concussion (10,11). It is postulated that the hippocampus and temporal lobes play key roles in disruption of the temporary memory store (12). The transitory memory disturbance in these disorders is attributed to ischemia, seizure discharge, migraine, or concussion, although clear causal pathophysiology is still lacking (12). As in our CICSS fallers, it is noteworthy that amnesia for LOC in these disorders is not associated with impairment of other aspects of cognitive function.

The ability of a neuron to transmit and store information is based on the speed and plasticity of its synopsis. The hippocampus is composed of "soft synopsis" neurons (i.e., those with greater plasticity), while the neocortex is composed of "hard synopsis" (12). A high degree of neuronal plasticity demands a high quality of metabolites and growth factors derived from surrounding blood vessels. During an ischemic event, the hippocampal neurons (particularly the CA1 neurons) are vulnerable to cell damage (12) particularly if cerebral autoregulation is abnormal (13,14). We hypothesize that the hippocampus momentarily loses its function due to reduced cerebral perfusion during CICSS-induced hypotension, which explains the transient loss of memory demonstrated in fallers with CICSS.

Differences in cognitive function clearly did not account for the amnesia for LOC seen more prominently in fallers. An alternative explanation may lie in altered cerebral autoregulation during bradyarrhythmia-induced symptoms, resulting in transient and selective differences in regional cerebral perfusion and consequent disturbance in awareness of consciousness. Our group have recently reported altered cerebral autoregulation in patients with CICSS (15). Cerebral autoregulation differed significantly between cases and controls for both dynamic and static indexes, while cerebrovascular resistance was significantly higher in patients with CICSS than in controls (15). The magnitude of the asystolic and vasodepressor responses and the laterality of the maximum asystolic response were similar in both groups, suggesting that the underlying pathology is similar. However, a higher proportion of fallers had their initial diagnostic test in the head-upright position, further supporting our hypothesis that compromised cerebral perfusion secondary to altered cerebral autoregulation underpins amnesia for LOC.

Syncopal subjects experienced symptoms for more than twice as long as fallers, and, while fractures and hospital admission rates were similar, the syncopal group suffered more soft tissue injuries requiring medical attention. The higher frequency of symptoms in fallers is a possible explanation for earlier referral.

Thus, patients with carotid sinus syndrome who present with falls rather than syncope are more likely to be female, have more frequent symptoms, and have a higher prevalence of CSM-induced asystole during testing in the upright position. Although more liable to experience witnessed LOC during laboratory testing, fallers are less likely to perceive any disturbance of consciousness after diagnostic CSM, showing clearly, for the first time, the manner in which such patients manifest their symptoms.


   Footnotes
 
Dr. Kenny has received funding for other research studies from Medtronic Inc. This study was funded by the British Heart Foundation.


   References
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  1. Kenny RA, Richardson DA, Bexton RS, et al. Cardiac pacing reduces falls in carotid sinus hypersensitivitythe SAFE-PACE trial. J Am Coll Cardiol 2001;38:1491-1496.[Abstract/Free Full Text]
  2. McIntosh S, daCosta D, Kenny RA. Outcome of an integrated approach to the investigation of dizziness, falls and syncope in elderly patients referred to a ’syncope’ clinic Age Ageing 1993;22:53-58.[Abstract/Free Full Text]
  3. Crilley JG, Herd B, Khurana CS, et al. Permanent cardiac pacing in elderly patients with recurrent falls, dizziness and syncope, and a hypersensitive cardioinhibitory reflex Postgrad Med J 1997;73:415-418.[Abstract]
  4. Cummings SR, Nevitt MC, Kidd S. Forgetting falls. The limited accuracy of recall of falls in the elderly J Am Geriatr Soc 1988;36:613-616.[ISI][Medline]
  5. Richardson DA, Bexton R, Shaw FE, et al. Complications of carotid sinus massage—a prospective series of older patients Age Ageing 2000;29:413-417.[Abstract/Free Full Text]
  6. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope Eur Heart J 2001;22:1256-1306.[Abstract/Free Full Text]
  7. American Geriatrics Society Guideline for the prevention of falls in older persons J Am Geriatr Soc 2001;49:664-672.[CrossRef][ISI][Medline]
  8. Folstein MF, Folstein SE, McHugh PR. "Mini mental state." A practical method for grading the cognitive state of patients for the clinician J Psychiatr Res 1975;12:189-198.[CrossRef][ISI][Medline]
  9. The CDR Computerised Cognitive Assessment System. Operating Manual. Reading, United Kingdom: Cognitive Drug Research Ltd; 1997.
  10. Pantoni L, Lamassa M, Inzitari D. Transient global amnesiaa review emphasizing pathogenic aspects. Acta Neurol Scand 2000;102:275-283.[CrossRef][ISI][Medline]
  11. Shaw NA. The neurophysiology of concussion Prog Neurobiol 2002;67:281-344.[CrossRef][ISI][Medline]
  12. Crepel VEJ, Ben-Ari Y. Ischemia induces short- and long-term remodelling of synaptic activity in the hippocampus(review) J Cell Mol Med 2003;7:401-407.[ISI][Medline]
  13. Zang R, Zuckerman JH, Giller CA, et al. Transfer function analysis of dynamic cerebral autoregulation in humans Am J Physiol 1998;274H233–41.
  14. Lipsitz LA, Ryan SM, Parker JA, et al. Haemodynamic and autonomic nervous system responses to mixed meal ingestion in healthy young and old subjects and dysautonomic patients with postprandial hypotension Circulation 1993;87:391-400.[Abstract/Free Full Text]
  15. Parry SW, Baptist M, Steen N, et al. Cerebral autoregulation in impaired inpatients with carotid sinus hypersensitivity presenting with drop attacks(abstr) Heart 2003;89(Suppl 1):A61A206.



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