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Abnormal pupillary activity in a brainstem-dead patient
British Journal of Anaesthesia 86 (5): 717±20 (2001)
CASE REPORTS Abnormal pupillary activity in a brainstem-dead patient D. Shlugman1*, M. Parulekar2, J. S. Elston2 and A. Farmery3 1
Neuro Intensive Care Unit,
2
Department of Ophthalmology and 3Nuf®eld Department of Anaesthetics, Radcliffe In®rmary, Oxford OX2 6HE, UK *Corresponding author
The pupils in brainstem-dead patients are classically ®xed and dilated. We present a case of a brainstem-dead patient whose pupils displayed persistent asynchronous pupillary constriction and dilatation independent of external physical stimuli. Central causes for the phenomenon were excluded leaving an unexplained peripheral cause as the most likely explanation. Early recognition of this phenomenon prevents delay in the diagnosis of brainstem death, lessening to some extent the distress for the family, and facilitating earlier organ donation and allowing the better use of resources. Br J Anaesth 2001; 86: 717±20 Keywords: brain, brainstem death; eye, pupillary re¯ex Accepted for publication: January 4, 2001
We present a unique case of abnormal pupillary movements in a patient who otherwise ful®lled the criteria for brainstem death. The consequences are far reaching. For the relatives, the delay in diagnosis results in undue distress. Organ donation, where applicable, is delayed and may affect the suitability of organs for transplantation. Finally, it is important that brainstem death is recognized early to ensure the most ef®cient use of limited intensive care unit resources.
Case report A 35-yr-old woman, with a history of alcohol abuse and depression, for which she had been prescribed amitryptiline, was referred by her general practitioner to the accident and emergency department with a provisional diagnosis of subarachnoid haemorrhage. The previous evening she had drunk one and a half bottles of wine and had complained of a sudden frontal headache. The following morning, she again complained of a sudden headache and collapsed 30 min later. On admission, she was unresponsive to command with a Glasgow Coma Score of 4/15, and required immediate tracheal intubation and mechanical ventilation of the lungs. The left pupil was ®xed and dilated and the right pupil middilated and reacting sluggishly to light. A computed tomography (CT)-scan showed a large left subdural
haematoma with signi®cant midline shift (Fig. 1). Mannitol and vitamin K were administered and she was referred to a regional neurosurgical centre. On arrival at the neurosurgical centre, 3 h after the ®rst presentation, both pupils were ®xed and dilated, with absent cough and gag re¯exes. In view of these ®ndings, and a signi®cantly deranged clotting pro®le frequently seen in head injuries (APTT 87 s, INR 3.3), a decision was made not to proceed with surgery. After excluding potentially reversible causes for coma, the ®rst set of brainstem death tests were performed approximately 6 h after admission. All the brainstem re¯exes as laid down in the UK guidelines1±4 were absent apart from the pupillary responses: the pupils were recorded as reacting to light with a consensual response. It was decided to re-test the patient after a 12 h interval. On retesting, the pupils were found to be active, but not in response to light. They were continuously observed for a period of 10 min and recorded on video. The pupils were mid-dilated and unequal, with the left pupil being larger. They displayed continuous and independent cyclical constriction and dilatation. The constriction phase lasted 2.5 s, and the dilatation phase 10 s, giving a periodicity of 5 min±1, which was unrelated to ambient light. At the time when one pupil was constricted, the other pupil was almost maximally dilated and vice versa (Fig. 2). No mydriatics had been used at any point. An EEG showed no cerebral activity, even
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2001
Shlugman et al.
during stimulation. Subsequently, two further sets of brainstem tests were performed and the patient was declared brainstem dead more than 24 h after the ®rst set of brainstem death tests. Throughout this period, the pupils remained active, but unresponsive to light. The patient's organs were used for transplantation. Post-mortem examination revealed a 200 ml subdural haematoma over a swollen left cerebral hemisphere with cerebellar tonsillar herniation and necrosis.
Fig 1 CT-scan showing large left sided subdural haematoma with midline shift.
Discussion In 1976 and 1979, the Conference of Medical Royal Colleges and their Faculties in the UK introduced and developed the concept of brainstem death as being synonymous with the death of the individual, even in the presence of functioning organ systems. Death was de®ned as `the irreversible loss of the capacity for consciousness combined with the irreversible loss of the capacity to breathe'. Strict criteria were laid down for the diagnosis, which could con®dently be made at the bedside, without the need for special investigations such as an EEG or cerebral angiography. To make the diagnosis of brainstem death, a three-stage procedure must be applied. First, certain preconditions must be met showing the patient suffers from a condition that has led to irremediable brain damage. Second, reversible causes of coma such as drug intoxication, hypothermia, metabolic, and endocrine disturbances must be excluded. Third, the absence of brainstem re¯exes including the pupillary response to light must be demonstrated. The bulk of the cranial nerve nuclei lie in close proximity to each other in the brainstem allowing for testing of this structure level-by-level (Fig. 3).5 The ultimate test of brainstem function is the test for apnoea. If no respiratory effort is seen with a PaCO2 >6.65 kPa (50 mm Hg), it can be assumed the patient is brainstem dead. It is recommended that the tests are carried out twice, usually a few hours apart. Such tests, by virtue of their simplicity, objectivity, and reproducibility have served to remove ambiguity from a situation fraught with emotion and potential controversy. This patient had irremediable brain damage, which had been con®rmed on CT-scan, and the potential reversible causes for coma had been excluded. Her blood alcohol level on initial presentation the previous day was 80 mg%, the upper legal driving limit in the UK. However, liver
Fig 2 Spontaneous changes in pupillary size under constant illumination.
718
Abnormal pupillary activity in a brainstem-dead patient
dysfunction was evident. The bilirubin levels on previous admissions over the preceding 3 months ranged from 28 to 53 mmol litre±1 and the gamma glutamyl transpeptidase, a useful indicator of alcoholic liver disease, was between 289 and 456 iu (normal 7±32 iu). Albumin levels were within the normal range. Before brainstem death tests, the bilirubin was 22 mmol litre±1, blood glucose 5 mmol litre±1 and the renal function was normal. An amitryptiline-induced coma was unlikely from the history as it has a half life of 15 h with a range of 9±25 h. In alcoholics, a coagulopathy is a well-recognized phenomenon.6 Traumatic head injuries also are often associated with clotting abnormalities. Clotting studies in the context of head injuries are a useful predictor of outcome, with prolongation or shortening of the APTT correlating strongly with death but prothrombin time proving to be of little prognostic value.7 8 This was borne out by this case where the APTT was 87 s (control 40 s) and INR 3.3 but with a platelet count within normal limits. In this patient's previous admissions, in spite of signi®cant liver dysfunction, her APTT and INR were within the normal range. The coagulopathy was corrected with the administration of fresh frozen plasma. This patient presented a dilemma. She ful®lled the preconditions and exclusions for brainstem death. There was an absence of cranial nerve and respiratory function but in spite of this, spontaneous pupillary activity was still evident. The pupillary signs raised two important questions. What was the mechanism of the phenomenon, and what were the implications for the diagnosis of brainstem death?
The pupillary response to light requires the presence of an intact re¯ex arc that passes through the brainstem (Fig. 4). The afferent component is the anterior visual pathway from which ®bres pass to synapse in the pretectal nucleus in the mid-brain. The efferent ®bres pass to the Edinger-Westphal subnucleii of the oculomotor nerve nucleus, explaining why a bilateral direct and consensual light response is seen when light is shone into one eye. The efferent parasympathetic ®bres are a component of the oculomotor nerve, which synapse in the ciliary ganglion in the orbit with the postganglionic ®bres supplying the pupillary sphincter. A lesion of the efferent pathway results in loss of all ipsilateral pupillary responses, and the pupil is mid-dilated and `®xed'. Total absence of response to light can occur with total disruption of either afferent or efferent pathways, and with brainstem damage. There are two reasons why the pupils should be unresponsive to light in this case. First, both oculomotor nerves, the efferent arcs, were shown radiologically and at post-mortem to be compressed against the free edge of the tentorium by the herniating cerebellar tonsils. Second, in brainstem death all the sympathetic and parasympathetic in¯uences are lost and the pupil assumes its position of rest (semi-dilated and ®xed). What then was the mechanism of the pupillary activity? This occurred asynchronously and so is unlikely to be a
Fig 3 Antero-lateral view of the brainstem showing the close proximity of the cranial nerves (Patten 1996, with permission).
Fig 4 Schematic drawing of the pupillary re¯ex arc showing crossed bilateral efferent output.
719
Davies et al.
`central' response, which is typically synchronous and bilateral. Light-near dissociation with preservation of the near response only would also produce synchronous pupillary responses. Moreover, for a centrally originating stimulus to produce a pupillary response, requires an intact efferent pathway, which was not the case. As it was asynchronous, it did not represent exaggerated hippus, which is a bilateral, simultaneous ¯uctuation in pupil size re¯ecting spontaneous changes in the pupilloconstrictor and pupillodilator balance. Spontaneous pupillary activity has been described as a preterminal event produced by intermittent discharges of dying neurones along the efferent arc, similar to Cheyne-Stokes respiration seen in terminal brainstem damage. However, such activity is typically bilateral and synchronous.9 The pupillary activity must, therefore, be peripheral in origin, arising either in the ciliary ganglion or the pupillary sphincter. The ciliary ganglion does not have any capacity for spontaneous activity. The iris sphincter, although smooth muscle histologically, is functionally similar to skeletal muscle and does not display spontaneous rhythmicity. Denervated muscle can display supersensitivity to circulating neurotransmitters, but this is likely to be a bilateral synchronous response unlike this case. Moreover, since the phenomenon lasted over 12 h, this is unlikely. We cannot, therefore, fully explain this phenomenon, nor have we found any similar case report in the literature. This case, in which the spontaneous pupillary activity was initially misinterpreted as a response to
light and hence indicative of an intact re¯ex arc, highlights the importance of thorough technique when testing the pupils. A period of uninterrupted observation is important. This case also shows that pupillary activity in the absence of elicited reactivity does not preclude the diagnosis of brainstem death.
References 1 Working Group of Conferences of Medical Royal Colleges and their Faculties in the United Kingdom. Diagnosis of death. BMJ 1976; 2: 1187±8 2 Working Group of Conferences of Medical Royal Colleges and their Faculties in the United Kingdom. Diagnosis of death. BMJ 1979; 1: 332 3 Criteria for the diagnosis of brain stem death. J R Coll Physicians Lond 1995; 29: 381±2 4 Code of Practice for the Diagnosis of Brainstem Death. Department of Health. March 1998 5 Patten J. The brain stem. In: Neurological Differential Diagnosis. London: Springer-Verlag 1996; 162 6 Weisberg LA. Alcoholic intracerebral hemorrhage. Stroke 1988; 19: 1565±9 7 Olson JD, Kaufman HH, Moake J, et al. The incidence and signi®cance of homeostatic abnormalities in patients with head injuries. Neurosurgery 1989; 24: 825±32 8 Selladurai BM, Vickneswaran M, Duraisamy S, Atan M. Coagulopathy in acute head injury ± a study of its role as a prognostic indicator. Br J Neurosurg 1997; 11: 398±404 9 Loewenfeld IE. The light re¯ex. In: The Pupil: Anatomy, Physiology and Clinical Applications. Detroit, MI: Wayne State University Press, 1993; 1: 83±273
British Journal of Anaesthesia 86 (5): 720±3 (2001)
Subdural haematoma after dural puncture headache treated by epidural blood patch J. M. Davies1*, A. Murphy2, M. Smith2 and G. O'Sullivan1 1
Department of Anaesthetics, St Thomas' Hospital, Lambeth Palace Rd, London SE1 7EH, UK. Department of Anaesthetics, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK
2
*Corresponding author Subdural haematoma is a well-documented complication of accidental dural puncture, and is thought to be preventable by prompt treatment with an epidural blood patch. An accidental dural puncture occurred in a 39-yr-old primagravida during the siting of an epidural catheter for pain relief in labour. Twenty hours after the puncture, the mother developed a typical postdural puncture headache, which increased in severity over the subsequent 24 h. An epidural blood patch was performed at 48 h, and this initially relieved the headache. After discharge from hospital, and 14 days after the dural puncture, the headache recurred, together with
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2001
CASE REPORTS Abnormal pupillary activity in a brainstem-dead patient D. Shlugman1*, M. Parulekar2, J. S. Elston2 and A. Farmery3 1
Neuro Intensive Care Unit,
2
Department of Ophthalmology and 3Nuf®eld Department of Anaesthetics, Radcliffe In®rmary, Oxford OX2 6HE, UK *Corresponding author
The pupils in brainstem-dead patients are classically ®xed and dilated. We present a case of a brainstem-dead patient whose pupils displayed persistent asynchronous pupillary constriction and dilatation independent of external physical stimuli. Central causes for the phenomenon were excluded leaving an unexplained peripheral cause as the most likely explanation. Early recognition of this phenomenon prevents delay in the diagnosis of brainstem death, lessening to some extent the distress for the family, and facilitating earlier organ donation and allowing the better use of resources. Br J Anaesth 2001; 86: 717±20 Keywords: brain, brainstem death; eye, pupillary re¯ex Accepted for publication: January 4, 2001
We present a unique case of abnormal pupillary movements in a patient who otherwise ful®lled the criteria for brainstem death. The consequences are far reaching. For the relatives, the delay in diagnosis results in undue distress. Organ donation, where applicable, is delayed and may affect the suitability of organs for transplantation. Finally, it is important that brainstem death is recognized early to ensure the most ef®cient use of limited intensive care unit resources.
Case report A 35-yr-old woman, with a history of alcohol abuse and depression, for which she had been prescribed amitryptiline, was referred by her general practitioner to the accident and emergency department with a provisional diagnosis of subarachnoid haemorrhage. The previous evening she had drunk one and a half bottles of wine and had complained of a sudden frontal headache. The following morning, she again complained of a sudden headache and collapsed 30 min later. On admission, she was unresponsive to command with a Glasgow Coma Score of 4/15, and required immediate tracheal intubation and mechanical ventilation of the lungs. The left pupil was ®xed and dilated and the right pupil middilated and reacting sluggishly to light. A computed tomography (CT)-scan showed a large left subdural
haematoma with signi®cant midline shift (Fig. 1). Mannitol and vitamin K were administered and she was referred to a regional neurosurgical centre. On arrival at the neurosurgical centre, 3 h after the ®rst presentation, both pupils were ®xed and dilated, with absent cough and gag re¯exes. In view of these ®ndings, and a signi®cantly deranged clotting pro®le frequently seen in head injuries (APTT 87 s, INR 3.3), a decision was made not to proceed with surgery. After excluding potentially reversible causes for coma, the ®rst set of brainstem death tests were performed approximately 6 h after admission. All the brainstem re¯exes as laid down in the UK guidelines1±4 were absent apart from the pupillary responses: the pupils were recorded as reacting to light with a consensual response. It was decided to re-test the patient after a 12 h interval. On retesting, the pupils were found to be active, but not in response to light. They were continuously observed for a period of 10 min and recorded on video. The pupils were mid-dilated and unequal, with the left pupil being larger. They displayed continuous and independent cyclical constriction and dilatation. The constriction phase lasted 2.5 s, and the dilatation phase 10 s, giving a periodicity of 5 min±1, which was unrelated to ambient light. At the time when one pupil was constricted, the other pupil was almost maximally dilated and vice versa (Fig. 2). No mydriatics had been used at any point. An EEG showed no cerebral activity, even
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2001
Shlugman et al.
during stimulation. Subsequently, two further sets of brainstem tests were performed and the patient was declared brainstem dead more than 24 h after the ®rst set of brainstem death tests. Throughout this period, the pupils remained active, but unresponsive to light. The patient's organs were used for transplantation. Post-mortem examination revealed a 200 ml subdural haematoma over a swollen left cerebral hemisphere with cerebellar tonsillar herniation and necrosis.
Fig 1 CT-scan showing large left sided subdural haematoma with midline shift.
Discussion In 1976 and 1979, the Conference of Medical Royal Colleges and their Faculties in the UK introduced and developed the concept of brainstem death as being synonymous with the death of the individual, even in the presence of functioning organ systems. Death was de®ned as `the irreversible loss of the capacity for consciousness combined with the irreversible loss of the capacity to breathe'. Strict criteria were laid down for the diagnosis, which could con®dently be made at the bedside, without the need for special investigations such as an EEG or cerebral angiography. To make the diagnosis of brainstem death, a three-stage procedure must be applied. First, certain preconditions must be met showing the patient suffers from a condition that has led to irremediable brain damage. Second, reversible causes of coma such as drug intoxication, hypothermia, metabolic, and endocrine disturbances must be excluded. Third, the absence of brainstem re¯exes including the pupillary response to light must be demonstrated. The bulk of the cranial nerve nuclei lie in close proximity to each other in the brainstem allowing for testing of this structure level-by-level (Fig. 3).5 The ultimate test of brainstem function is the test for apnoea. If no respiratory effort is seen with a PaCO2 >6.65 kPa (50 mm Hg), it can be assumed the patient is brainstem dead. It is recommended that the tests are carried out twice, usually a few hours apart. Such tests, by virtue of their simplicity, objectivity, and reproducibility have served to remove ambiguity from a situation fraught with emotion and potential controversy. This patient had irremediable brain damage, which had been con®rmed on CT-scan, and the potential reversible causes for coma had been excluded. Her blood alcohol level on initial presentation the previous day was 80 mg%, the upper legal driving limit in the UK. However, liver
Fig 2 Spontaneous changes in pupillary size under constant illumination.
718
Abnormal pupillary activity in a brainstem-dead patient
dysfunction was evident. The bilirubin levels on previous admissions over the preceding 3 months ranged from 28 to 53 mmol litre±1 and the gamma glutamyl transpeptidase, a useful indicator of alcoholic liver disease, was between 289 and 456 iu (normal 7±32 iu). Albumin levels were within the normal range. Before brainstem death tests, the bilirubin was 22 mmol litre±1, blood glucose 5 mmol litre±1 and the renal function was normal. An amitryptiline-induced coma was unlikely from the history as it has a half life of 15 h with a range of 9±25 h. In alcoholics, a coagulopathy is a well-recognized phenomenon.6 Traumatic head injuries also are often associated with clotting abnormalities. Clotting studies in the context of head injuries are a useful predictor of outcome, with prolongation or shortening of the APTT correlating strongly with death but prothrombin time proving to be of little prognostic value.7 8 This was borne out by this case where the APTT was 87 s (control 40 s) and INR 3.3 but with a platelet count within normal limits. In this patient's previous admissions, in spite of signi®cant liver dysfunction, her APTT and INR were within the normal range. The coagulopathy was corrected with the administration of fresh frozen plasma. This patient presented a dilemma. She ful®lled the preconditions and exclusions for brainstem death. There was an absence of cranial nerve and respiratory function but in spite of this, spontaneous pupillary activity was still evident. The pupillary signs raised two important questions. What was the mechanism of the phenomenon, and what were the implications for the diagnosis of brainstem death?
The pupillary response to light requires the presence of an intact re¯ex arc that passes through the brainstem (Fig. 4). The afferent component is the anterior visual pathway from which ®bres pass to synapse in the pretectal nucleus in the mid-brain. The efferent ®bres pass to the Edinger-Westphal subnucleii of the oculomotor nerve nucleus, explaining why a bilateral direct and consensual light response is seen when light is shone into one eye. The efferent parasympathetic ®bres are a component of the oculomotor nerve, which synapse in the ciliary ganglion in the orbit with the postganglionic ®bres supplying the pupillary sphincter. A lesion of the efferent pathway results in loss of all ipsilateral pupillary responses, and the pupil is mid-dilated and `®xed'. Total absence of response to light can occur with total disruption of either afferent or efferent pathways, and with brainstem damage. There are two reasons why the pupils should be unresponsive to light in this case. First, both oculomotor nerves, the efferent arcs, were shown radiologically and at post-mortem to be compressed against the free edge of the tentorium by the herniating cerebellar tonsils. Second, in brainstem death all the sympathetic and parasympathetic in¯uences are lost and the pupil assumes its position of rest (semi-dilated and ®xed). What then was the mechanism of the pupillary activity? This occurred asynchronously and so is unlikely to be a
Fig 3 Antero-lateral view of the brainstem showing the close proximity of the cranial nerves (Patten 1996, with permission).
Fig 4 Schematic drawing of the pupillary re¯ex arc showing crossed bilateral efferent output.
719
Davies et al.
`central' response, which is typically synchronous and bilateral. Light-near dissociation with preservation of the near response only would also produce synchronous pupillary responses. Moreover, for a centrally originating stimulus to produce a pupillary response, requires an intact efferent pathway, which was not the case. As it was asynchronous, it did not represent exaggerated hippus, which is a bilateral, simultaneous ¯uctuation in pupil size re¯ecting spontaneous changes in the pupilloconstrictor and pupillodilator balance. Spontaneous pupillary activity has been described as a preterminal event produced by intermittent discharges of dying neurones along the efferent arc, similar to Cheyne-Stokes respiration seen in terminal brainstem damage. However, such activity is typically bilateral and synchronous.9 The pupillary activity must, therefore, be peripheral in origin, arising either in the ciliary ganglion or the pupillary sphincter. The ciliary ganglion does not have any capacity for spontaneous activity. The iris sphincter, although smooth muscle histologically, is functionally similar to skeletal muscle and does not display spontaneous rhythmicity. Denervated muscle can display supersensitivity to circulating neurotransmitters, but this is likely to be a bilateral synchronous response unlike this case. Moreover, since the phenomenon lasted over 12 h, this is unlikely. We cannot, therefore, fully explain this phenomenon, nor have we found any similar case report in the literature. This case, in which the spontaneous pupillary activity was initially misinterpreted as a response to
light and hence indicative of an intact re¯ex arc, highlights the importance of thorough technique when testing the pupils. A period of uninterrupted observation is important. This case also shows that pupillary activity in the absence of elicited reactivity does not preclude the diagnosis of brainstem death.
References 1 Working Group of Conferences of Medical Royal Colleges and their Faculties in the United Kingdom. Diagnosis of death. BMJ 1976; 2: 1187±8 2 Working Group of Conferences of Medical Royal Colleges and their Faculties in the United Kingdom. Diagnosis of death. BMJ 1979; 1: 332 3 Criteria for the diagnosis of brain stem death. J R Coll Physicians Lond 1995; 29: 381±2 4 Code of Practice for the Diagnosis of Brainstem Death. Department of Health. March 1998 5 Patten J. The brain stem. In: Neurological Differential Diagnosis. London: Springer-Verlag 1996; 162 6 Weisberg LA. Alcoholic intracerebral hemorrhage. Stroke 1988; 19: 1565±9 7 Olson JD, Kaufman HH, Moake J, et al. The incidence and signi®cance of homeostatic abnormalities in patients with head injuries. Neurosurgery 1989; 24: 825±32 8 Selladurai BM, Vickneswaran M, Duraisamy S, Atan M. Coagulopathy in acute head injury ± a study of its role as a prognostic indicator. Br J Neurosurg 1997; 11: 398±404 9 Loewenfeld IE. The light re¯ex. In: The Pupil: Anatomy, Physiology and Clinical Applications. Detroit, MI: Wayne State University Press, 1993; 1: 83±273
British Journal of Anaesthesia 86 (5): 720±3 (2001)
Subdural haematoma after dural puncture headache treated by epidural blood patch J. M. Davies1*, A. Murphy2, M. Smith2 and G. O'Sullivan1 1
Department of Anaesthetics, St Thomas' Hospital, Lambeth Palace Rd, London SE1 7EH, UK. Department of Anaesthetics, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK
2
*Corresponding author Subdural haematoma is a well-documented complication of accidental dural puncture, and is thought to be preventable by prompt treatment with an epidural blood patch. An accidental dural puncture occurred in a 39-yr-old primagravida during the siting of an epidural catheter for pain relief in labour. Twenty hours after the puncture, the mother developed a typical postdural puncture headache, which increased in severity over the subsequent 24 h. An epidural blood patch was performed at 48 h, and this initially relieved the headache. After discharge from hospital, and 14 days after the dural puncture, the headache recurred, together with
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2001