Severe memory impairment following acute morphine intoxication Anne Landais PII: DOI: Reference:
S0022-510X(14)00365-7 doi: 10.1016/j.jns.2014.05.061 JNS 13238
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
4 February 2014 25 May 2014 29 May 2014
Please cite this article as: Landais Anne, Severe memory impairment following acute morphine intoxication, Journal of the Neurological Sciences (2014), doi: 10.1016/j.jns.2014.05.061
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
T
Title Page
IP
Severe memory impairment following acute morphine intoxication
SC R
Author : Anne LANDAIS, MD
NU
University Hospital of Pointe-à-Pitre/CHU de Pointe-à-Pitre
MA
Neurology Unit Route de Chauvel
TE
D
97139 ABYMES
CE P
France Tel : +3305 90 89 1430
AC
Fax : +330590891431
Mail : [email protected] Funding source : none Conflict of interest : none Article type : Letter to the Editor Key words : morphine intoxication, memory impairment, hippocampic syndrome, respiratory failure, hypoxemia, MRI hippocampic lesion
ACCEPTED MANUSCRIPT
T
To the Editor
IP
We report the case of a 40 year- old man without any past medical history, or
SC R
history of prior opioid use or abuse , who was first seen at his home by paramedics because of impaired consciousness that resulted from a high dose of
NU
morphine (five 200 mg ampoules) that was self administered in an attempt to commit suicide . On their arrival, the Glasgow Coma Scale rating was 8.
MA
Respiratory rate was severely depressed at 6/min. Oxygen saturation was 88%,
D
indicating hypoxemia. Blood pressure was 90/60 mmHg and pupillary
TE
assessment revealed tight, unresponsive miosis. Perfusion with isotonic saline,
CE P
and oxygen were initiated. Treatment with naloxone was immediately administered, and the patient was then transported to the emergency room where
AC
upon arrival the Glasgow Coma scale rating had improved to 12. The initial treatment regimen including intravenous naloxone was continued for 6 hours. Laboratory tests including serum glucose levels were normal. There were no signs of renal failure or rhabdomyolysis. Cardiovascular status, including the electrocardiogram, transthoracic echocardiography, Doppler studies of the cervical arteries was normal. After a 24 -hour stay in intensive care, having recovered normal consciousness, the patient was hospitalized in the psychiatric unit, where initial examination revealed temporo-spatial disorientation, a jovial behaviour, deemed inappropriate, given the context of a suicide attempt, and
ACCEPTED MANUSCRIPT emotional distance. The patient exhibited memory impairment by constantly asking the same questions and not remembering the answers. The clinical course
T
was favourable concerning the recollection of events prior to the suicide attempt,
IP
but eight days after the suicide attempt the patient continued to forget dates and
SC R
recent developments. He could not recall how long he had been hospitalized
NU
and was incapable of remembering new information.
Because of his persistence of memory disturbances, neuropsychological
MA
assessment was performed on Day 20. The assessment revealed no impairment in selective attention, mental flexibility or susceptibility to distraction. Working
TE
D
memory, logical reasoning, logical-mathematical reasoning and planning were preserved. Immediate memory was preserved, but there was significant
CE P
impairment of encoding, recovery of information and memory consolidation. Impairment in verbal and visual episodic memory suggested impairment in
AC
hippocampal functioning. Verbal episodic memory was assessed using the procedure of Free and Cued Selective Reminding Test (FCSRT) [1]. The FCSRT begins with a study phase designed to assess attention and cognitive processing. Patients identify pictured items (e.g, grapes, vest) in response to category cues (fruit, clothing). In the test phase, subjects are asked to recall the items they learned (free recall). The category cues are used to prompt recall of items not retrieved by free recall to generate a score termed cued recall. The sum of free and cued recall is termed total recall. The patient attained scores 2.15 to
ACCEPTED MANUSCRIPT 6.3 standard deviations below the expected mean for all free recalls. For total recall, scores were still pathologically low at 3.8 to 8.12 standard deviations
T
lower than the expected mean. The patient benefited from cueing and repetition
IP
of the material but not enough to obtain scores in the normal range. Free delayed
SC R
recall scores remained pathological at 5.5 standard deviations below the expected means. Total delayed recall showed an important decrease in the score,
NU
26.3 standard deviations below the expected mean.
MA
Visual episodic memory was evaluated using BEM 144 [2]. BEM144 is a
D
french test that enables an overall exploration of anterograde memory
TE
it is organised into two series of independent tests, designed in a strictly parallel
CE P
manner: the first consists of verbal material the second of visual material. Each of these series includes immediate and delayed recall, serial and associated
AC
learning, and an exercice in differed recognition. On the learning visual list, he obtained a pathological score 4.6 standard deviations below the expected mean. In attempts to recall the list, the patient scored 4.89 standard deviations below the expected mean.
His problem with visual episodic memory was further
confirmed by the recall of Rey's complex figure test, where he achieve a pathological score of 4.5, lower than 10 percentiles. Language assessment was found to be normal for oral denomination and categorical matching using DO 80 that is a picture naming test [3]. Moreover, the Beck Depression Scale score was relatively low but may have been biased
ACCEPTED MANUSCRIPT by the patient's apparent efforts to minimize his difficulties. The Spielberger anxiety scale revealed low scores for both state- and trait-
SC R
IP
T
anxiety.
NU
The neuropsychological assessment was repeated 4 months later and showed a
MA
general improvement in memory although a slight disturbance in memory recovery remained; efficient encoding was noted in free recall/cued recall tasks,
D
but spontaneous recovery remained deficient at 2.6 standard deviations below
TE
the expected mean. Cueing was required to move spontaneous recovery scores
CE P
into the normal range showing correct storage capacities. After delay, recovery of long-term memory remained impaired at 3.3 standard deviations below the
AC
expected mean, but cueing facilitated the restoration of performance to the normal range. Attention and executive functions were normal. The diffusion-, T2-, and fluid attenuated inversion recovery (FLAIR-) weighted images of the MRI of the brain obtained on Day 9 (text figure) revealed high signal intensity bilateral cortical hippocampic lesions that appeared hypointense in T1 weighted sequences. The basal ganglia were spared. There was a reduced apparent diffusion coefficient (ADC) at this level, probably related to edema of hypoxic or toxic origin.
ACCEPTED MANUSCRIPT A new MRI that was obtained 10 months later for comparison revealed the complete resolution of T2 and diffusion hyperintensity lesions.
IP
T
Discussion
SC R
To our knowledge, there is no other reported observation of such severe memory troubles following acute morphine intoxication. Moreover, our
NU
observation is remarkable because of the concurrent hippocampal involvement
MA
observed with MRI.
Several studies examined the acute and cumulative cognitive effects of opioids
D
in healthy volunteers, with assessment of cognitive performance: they generally
TE
show minimal impairment in cognitive functions [4]. Cognitive impairment,
CE P
when it occurred, was most often associated with parenteral opioids administered to opioid naïve individuals and was dose-related [4]. One study in
AC
healthy volunteers showed delayed recall impairment with all parenteral morphine sulphate (MS) levels tested [5]. Impaired encoding and processing of verbal information were noted with the highest MS levels [5]. Findings from studies that examined oral opioids are mixed, with some showing mild but significant dose related impairment. In one of those, RAVLT (Rey auditory verbal learning test) testing of verbal memory, revealed decreases in scores involving the highest oral dose-tested subjects [6]. By contrast, other studies found no significant impairment on any test for short and long term memory [4, 7, 8, 9]. Additionally, in a prospective study, memory scores obtained with the
ACCEPTED MANUSCRIPT FCSRT were in the normal range at baseline and were not significantly altered after 12 months of treatment with oral morphine [9]. Two studies even showed
T
that lorazepam consistently caused more impairment than opioids and that
SC R
IP
morphine was associated with improved cognition [8, 10].
There are a few cases that have reported evidence of the cerebral toxicity
NU
following methadone (synthetic opioid) and heroin overdose, showing in all cases bilateral cerebellar oedema and rarely lesions of the hippocampus [11-17].
MA
A leukoencephalopathy has also been described following high dose opiates that is characterized by spongiform changes on biopsy. The damage is attributed to
TE
D
the profound hypoxia that is associated with respiratory depression [16, 17], but a direct toxic effect or hypersensitivity to an additive or impurity may be
CE P
contributing factors.
AC
Sedlaczed reported on 26 patients suffering transient global amnesia (TGA), on brain MRI diffusion-weighted axial sequences, small punctate uni or bilateral high signal intensity lesions in the lateral part of the hippocampal formation. In our case, memory impairment persisted far too long to support the diagnosis of TGA [18]. The effects of this tragic event appear to be associated at least in part with alterations in the structure and function of the hippocampus. The hippocampus is located in the medial temporal lobe and is a major component of the limbic system. It has been shown to be essential for the acquisition of declarative or
ACCEPTED MANUSCRIPT explicit memory [19]. The results of imaging studies performed in this case are evidence of altered morphology and presumed function of the hippocampus in
T
this patient. Chronic opiate use has been shown to inhibit cell growth, trigger
IP
apoptosis and may impair regeneration of nerve cells [20, 21]. It has been
SC R
postulated that memory dysfunction and impaired learning after opiate exposure could be caused by the inhibition of adult neurogenesis as has been reported
NU
previously in adult rat hippocampus [22, 23, 24].
MA
A direct toxic effect of morphine on the hippocampi cannot be excluded in our case. The hippocampus is a region located in the limbic area of the brain. This
D
area has been shown to be required for the acquisition of declarative or explicit
TE
memory [19]. Neuropsychological studies on neurological patients, mainly
CE P
pioneered by Brenda Millner with the famous H.M. case, have shown that the multiple memory systems involve distinct brain areas and exhibit distinctive
AC
features. For example, explicit memory needs an intact medial temporal lobe (hippocampus) [19]. Chronic opiates have been demonstrated to inhibit cell growth and trigger apoptosis, and it is also suggested that opiate-induced toxicity may include impaired regeneration of nerve cells[20, 21] : memory dysfunctions after opiate exposure could be caused by decreased adult neurogenesis because opiates inhibit neurogenesis in the adult rat hippocampus[22, 23]. An impact of these adult-generated neurons on memory and learning is supported by the fact that
ACCEPTED MANUSCRIPT training on associative learning tasks doubles these neurons in the rat dentate gyrus [24].
IP
T
Another possible mechanism in our case could be hippocampal oligemia
SC R
induced by respiratory failure, which was provoked by the morphinic intoxication. The arterial supply to the hippocampus is characterized by an
NU
internal system of arcades that provide anastomoses between an upper and lower feeding artery [18]. The watershed area between the two feeding vessels is the
MA
hypoxia-susceptible sector of Sommer that is located in the lateral aspect of the hippocampus seen to be included in the area of high-signal intensity illustrated
TE
D
in the text figure. Hypoperfusion to this subcortical vascular borderzone could
CE P
be one of the mechanisms to explain this observation. REFERENCES
AC
1. Grober E, Buschke H. Genuine memory deficits in dementia. Dev Neuropsychol. 1987;3:13–36. 2. Signoret J.L. BEM 144 Paris: Fondation IPSEN. Collection esprit et cerveau (1991). 3. Deloche G, Hannequin D. DO80. Epreuve de Dénomination Orale D’images. Paris: Edition du centre de psychologie appliquée; 1997. 4. Ersek M, Cherrier M, Overmann SS, Irving GA. The cognitive effects of opioids. Pain mangement nursing 2004; 5(2):75-93.
ACCEPTED MANUSCRIPT 5.Kerr B, Hill H, Coda B, Calogero M, Chapman RC et al . Concentration related effects of morphine on cognition and motor control in human subjects.
IP
T
Neuropsychopharmacology. 1991; 5: 155-166
SC R
6. Cleeland CS, Nakamura Y, Howland EW, Morgan NR, Edwards KR et al. Effect of oral morphine on cold pressure tolerance time and neuropsychological
NU
performance. Neuropsychopharmacol, 1996; 15 : 252-62
7. Walker DJ, Zacny JP. Subjective, psychomotor, and analgesic effects of
MA
cumulative doses of oral codeine and morphine in healthy volunteers.
D
Psychopharmacol (Berl) 1998;140: 191-201.
TE
8. Hanks G, O’Neill W, Simpson P, Wesnes K. The cognitive and psychomotor
CE P
effects of opioids analgesics.II. : A randomized controlled trial of single doses of morphine, lorazepam and placebo in healthy subjects. Eur J Clin Pharmacol
AC
1995; 48: 455-460
9.Tassain V, Attal N, Fletcher D, Brasseur L , Dégieux P , Chauvin M et al. Long term effects of oral sustained release morphine on neuropsychological performance in patient with chronic non-cancer pain. Pain 2003; 104:389-400 10. O’Neill W, Hanks GW, Simpson P, Fallon MT, Jenkins E, Wesnes K. The cognitive and psychomotor effects of morphine on healthy subjects: A randomized controlled trial of repeated oral doses of dextropropoxyphene, morphine, lorazepam and placebo. Pain 2000; 85 : 209-215
ACCEPTED MANUSCRIPT 11. Wolters EC, Wijngarden GK, Stam FC, et al. Leucoencephalopathy after inhaling heroin pyrolysate. Lancet 1982; 2:1233-7,
IP
T
12. Zanin A, Masiero S, Severino MS, Calderone M, Da Salt L, Lavarda AM. A
SC R
delayed methadone encephalopathy: clinical and neuroradiological findings. J Child Neurol . Epub 2009 Oct 6.
NU
13. Mills F, MacLennan SC, Devile CJ, Saunders DE. Severe cerebellitis
MA
following methadone poisoning. Pediatric Radiol.2008 ; 38(2) :227-9 14. Anselmo M, Campos Rainho A, Do Carno Vale M, et al. Methadone
D
intoxication in a child : toxic encephalopathy ? J Child Neurol 2006; 21(7) :
TE
618-20
CE P
15. Celius EG, Anderson S. Leucoencephalopathy after inhalation of heroin : a case report. J Neurol Neurosurg Psychiatry.1996 ; 60(6) :694-5
AC
16. Robertson AS, Jain S, O’Neil RA. Spongiform leucoencephalopathy following intravenous heroin abuse: radiological and histopathological findings.Australas Radiol .2001; 45(3) : 390-2 17. Rizzuto N, Morbin M, Ferrari S, et al.Delayed spongiform leucoencephalopathyafter heroin abuse.Acta neuropathol 1997; 94(1):87-90 18. Sedlaczek O, Hirsh JG, Grips E, Peters CNA, Gass A, Wöhrle J, Hennrici M. Detection of delayed focalMR changes in the lateral hippocampus in transient global amnesia. Neurology 2004; 62 : 2165-2170.
ACCEPTED MANUSCRIPT 19. Benfenati F. Synaptic plasticity and the neurobiology of learning and
IP
T
memory. Acta Biomed. 2007;78(Suppl 1):58–66. [PubMed]
SC R
20. Yin D, et al. Morphine promotes Jurkat cell apoptosis through proapoptotic FADD/P53 and antiapoptotic PI3K/Akt/NK-κB pathways. J Neuroimmunol.
NU
2006;174:101–107. [PubMed]
MA
21. Mao J, Sung B, Ji RR, Lim G. Neuronal apoptosis associated with morphine tolerance: Evidence for an opioid-induced neurotoxic mechanism. J Neurosci.
TE
D
2002;22:7650–7661. [PubMed]
22. Eisch AJ, Barrot M, Schad CA, Self DW, Nestler EJ. Opiates inhibit
CE P
neurogenesis in the adult rat hippocampus. Proc Natl Acad Sci USA. 2000;97:7579–7584. [PMC free article] [PubMed]
AC
23. Eisch AJ, Harburg GC. Opiates, psychostimulants, and adult hippocampal neurogenesis: Insights for addiction and stem cell biology. Hippocampus. 2006;16:271–286. [PubMed]
24. Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci. 1999;2:260–265. [PubMed]
ACCEPTED MANUSCRIPT
Legend
AC
CE P
TE
D
MA
NU
SC R
IP
T
Axial Diffusion (A) and FLAIR(B) MRI sequences of the brain showing bilateral and symetrically increased signal intensity in the hippocampus.
AC
CE P
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
S0022-510X(14)00365-7 doi: 10.1016/j.jns.2014.05.061 JNS 13238
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
4 February 2014 25 May 2014 29 May 2014
Please cite this article as: Landais Anne, Severe memory impairment following acute morphine intoxication, Journal of the Neurological Sciences (2014), doi: 10.1016/j.jns.2014.05.061
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
T
Title Page
IP
Severe memory impairment following acute morphine intoxication
SC R
Author : Anne LANDAIS, MD
NU
University Hospital of Pointe-à-Pitre/CHU de Pointe-à-Pitre
MA
Neurology Unit Route de Chauvel
TE
D
97139 ABYMES
CE P
France Tel : +3305 90 89 1430
AC
Fax : +330590891431
Mail : [email protected] Funding source : none Conflict of interest : none Article type : Letter to the Editor Key words : morphine intoxication, memory impairment, hippocampic syndrome, respiratory failure, hypoxemia, MRI hippocampic lesion
ACCEPTED MANUSCRIPT
T
To the Editor
IP
We report the case of a 40 year- old man without any past medical history, or
SC R
history of prior opioid use or abuse , who was first seen at his home by paramedics because of impaired consciousness that resulted from a high dose of
NU
morphine (five 200 mg ampoules) that was self administered in an attempt to commit suicide . On their arrival, the Glasgow Coma Scale rating was 8.
MA
Respiratory rate was severely depressed at 6/min. Oxygen saturation was 88%,
D
indicating hypoxemia. Blood pressure was 90/60 mmHg and pupillary
TE
assessment revealed tight, unresponsive miosis. Perfusion with isotonic saline,
CE P
and oxygen were initiated. Treatment with naloxone was immediately administered, and the patient was then transported to the emergency room where
AC
upon arrival the Glasgow Coma scale rating had improved to 12. The initial treatment regimen including intravenous naloxone was continued for 6 hours. Laboratory tests including serum glucose levels were normal. There were no signs of renal failure or rhabdomyolysis. Cardiovascular status, including the electrocardiogram, transthoracic echocardiography, Doppler studies of the cervical arteries was normal. After a 24 -hour stay in intensive care, having recovered normal consciousness, the patient was hospitalized in the psychiatric unit, where initial examination revealed temporo-spatial disorientation, a jovial behaviour, deemed inappropriate, given the context of a suicide attempt, and
ACCEPTED MANUSCRIPT emotional distance. The patient exhibited memory impairment by constantly asking the same questions and not remembering the answers. The clinical course
T
was favourable concerning the recollection of events prior to the suicide attempt,
IP
but eight days after the suicide attempt the patient continued to forget dates and
SC R
recent developments. He could not recall how long he had been hospitalized
NU
and was incapable of remembering new information.
Because of his persistence of memory disturbances, neuropsychological
MA
assessment was performed on Day 20. The assessment revealed no impairment in selective attention, mental flexibility or susceptibility to distraction. Working
TE
D
memory, logical reasoning, logical-mathematical reasoning and planning were preserved. Immediate memory was preserved, but there was significant
CE P
impairment of encoding, recovery of information and memory consolidation. Impairment in verbal and visual episodic memory suggested impairment in
AC
hippocampal functioning. Verbal episodic memory was assessed using the procedure of Free and Cued Selective Reminding Test (FCSRT) [1]. The FCSRT begins with a study phase designed to assess attention and cognitive processing. Patients identify pictured items (e.g, grapes, vest) in response to category cues (fruit, clothing). In the test phase, subjects are asked to recall the items they learned (free recall). The category cues are used to prompt recall of items not retrieved by free recall to generate a score termed cued recall. The sum of free and cued recall is termed total recall. The patient attained scores 2.15 to
ACCEPTED MANUSCRIPT 6.3 standard deviations below the expected mean for all free recalls. For total recall, scores were still pathologically low at 3.8 to 8.12 standard deviations
T
lower than the expected mean. The patient benefited from cueing and repetition
IP
of the material but not enough to obtain scores in the normal range. Free delayed
SC R
recall scores remained pathological at 5.5 standard deviations below the expected means. Total delayed recall showed an important decrease in the score,
NU
26.3 standard deviations below the expected mean.
MA
Visual episodic memory was evaluated using BEM 144 [2]. BEM144 is a
D
french test that enables an overall exploration of anterograde memory
TE
it is organised into two series of independent tests, designed in a strictly parallel
CE P
manner: the first consists of verbal material the second of visual material. Each of these series includes immediate and delayed recall, serial and associated
AC
learning, and an exercice in differed recognition. On the learning visual list, he obtained a pathological score 4.6 standard deviations below the expected mean. In attempts to recall the list, the patient scored 4.89 standard deviations below the expected mean.
His problem with visual episodic memory was further
confirmed by the recall of Rey's complex figure test, where he achieve a pathological score of 4.5, lower than 10 percentiles. Language assessment was found to be normal for oral denomination and categorical matching using DO 80 that is a picture naming test [3]. Moreover, the Beck Depression Scale score was relatively low but may have been biased
ACCEPTED MANUSCRIPT by the patient's apparent efforts to minimize his difficulties. The Spielberger anxiety scale revealed low scores for both state- and trait-
SC R
IP
T
anxiety.
NU
The neuropsychological assessment was repeated 4 months later and showed a
MA
general improvement in memory although a slight disturbance in memory recovery remained; efficient encoding was noted in free recall/cued recall tasks,
D
but spontaneous recovery remained deficient at 2.6 standard deviations below
TE
the expected mean. Cueing was required to move spontaneous recovery scores
CE P
into the normal range showing correct storage capacities. After delay, recovery of long-term memory remained impaired at 3.3 standard deviations below the
AC
expected mean, but cueing facilitated the restoration of performance to the normal range. Attention and executive functions were normal. The diffusion-, T2-, and fluid attenuated inversion recovery (FLAIR-) weighted images of the MRI of the brain obtained on Day 9 (text figure) revealed high signal intensity bilateral cortical hippocampic lesions that appeared hypointense in T1 weighted sequences. The basal ganglia were spared. There was a reduced apparent diffusion coefficient (ADC) at this level, probably related to edema of hypoxic or toxic origin.
ACCEPTED MANUSCRIPT A new MRI that was obtained 10 months later for comparison revealed the complete resolution of T2 and diffusion hyperintensity lesions.
IP
T
Discussion
SC R
To our knowledge, there is no other reported observation of such severe memory troubles following acute morphine intoxication. Moreover, our
NU
observation is remarkable because of the concurrent hippocampal involvement
MA
observed with MRI.
Several studies examined the acute and cumulative cognitive effects of opioids
D
in healthy volunteers, with assessment of cognitive performance: they generally
TE
show minimal impairment in cognitive functions [4]. Cognitive impairment,
CE P
when it occurred, was most often associated with parenteral opioids administered to opioid naïve individuals and was dose-related [4]. One study in
AC
healthy volunteers showed delayed recall impairment with all parenteral morphine sulphate (MS) levels tested [5]. Impaired encoding and processing of verbal information were noted with the highest MS levels [5]. Findings from studies that examined oral opioids are mixed, with some showing mild but significant dose related impairment. In one of those, RAVLT (Rey auditory verbal learning test) testing of verbal memory, revealed decreases in scores involving the highest oral dose-tested subjects [6]. By contrast, other studies found no significant impairment on any test for short and long term memory [4, 7, 8, 9]. Additionally, in a prospective study, memory scores obtained with the
ACCEPTED MANUSCRIPT FCSRT were in the normal range at baseline and were not significantly altered after 12 months of treatment with oral morphine [9]. Two studies even showed
T
that lorazepam consistently caused more impairment than opioids and that
SC R
IP
morphine was associated with improved cognition [8, 10].
There are a few cases that have reported evidence of the cerebral toxicity
NU
following methadone (synthetic opioid) and heroin overdose, showing in all cases bilateral cerebellar oedema and rarely lesions of the hippocampus [11-17].
MA
A leukoencephalopathy has also been described following high dose opiates that is characterized by spongiform changes on biopsy. The damage is attributed to
TE
D
the profound hypoxia that is associated with respiratory depression [16, 17], but a direct toxic effect or hypersensitivity to an additive or impurity may be
CE P
contributing factors.
AC
Sedlaczed reported on 26 patients suffering transient global amnesia (TGA), on brain MRI diffusion-weighted axial sequences, small punctate uni or bilateral high signal intensity lesions in the lateral part of the hippocampal formation. In our case, memory impairment persisted far too long to support the diagnosis of TGA [18]. The effects of this tragic event appear to be associated at least in part with alterations in the structure and function of the hippocampus. The hippocampus is located in the medial temporal lobe and is a major component of the limbic system. It has been shown to be essential for the acquisition of declarative or
ACCEPTED MANUSCRIPT explicit memory [19]. The results of imaging studies performed in this case are evidence of altered morphology and presumed function of the hippocampus in
T
this patient. Chronic opiate use has been shown to inhibit cell growth, trigger
IP
apoptosis and may impair regeneration of nerve cells [20, 21]. It has been
SC R
postulated that memory dysfunction and impaired learning after opiate exposure could be caused by the inhibition of adult neurogenesis as has been reported
NU
previously in adult rat hippocampus [22, 23, 24].
MA
A direct toxic effect of morphine on the hippocampi cannot be excluded in our case. The hippocampus is a region located in the limbic area of the brain. This
D
area has been shown to be required for the acquisition of declarative or explicit
TE
memory [19]. Neuropsychological studies on neurological patients, mainly
CE P
pioneered by Brenda Millner with the famous H.M. case, have shown that the multiple memory systems involve distinct brain areas and exhibit distinctive
AC
features. For example, explicit memory needs an intact medial temporal lobe (hippocampus) [19]. Chronic opiates have been demonstrated to inhibit cell growth and trigger apoptosis, and it is also suggested that opiate-induced toxicity may include impaired regeneration of nerve cells[20, 21] : memory dysfunctions after opiate exposure could be caused by decreased adult neurogenesis because opiates inhibit neurogenesis in the adult rat hippocampus[22, 23]. An impact of these adult-generated neurons on memory and learning is supported by the fact that
ACCEPTED MANUSCRIPT training on associative learning tasks doubles these neurons in the rat dentate gyrus [24].
IP
T
Another possible mechanism in our case could be hippocampal oligemia
SC R
induced by respiratory failure, which was provoked by the morphinic intoxication. The arterial supply to the hippocampus is characterized by an
NU
internal system of arcades that provide anastomoses between an upper and lower feeding artery [18]. The watershed area between the two feeding vessels is the
MA
hypoxia-susceptible sector of Sommer that is located in the lateral aspect of the hippocampus seen to be included in the area of high-signal intensity illustrated
TE
D
in the text figure. Hypoperfusion to this subcortical vascular borderzone could
CE P
be one of the mechanisms to explain this observation. REFERENCES
AC
1. Grober E, Buschke H. Genuine memory deficits in dementia. Dev Neuropsychol. 1987;3:13–36. 2. Signoret J.L. BEM 144 Paris: Fondation IPSEN. Collection esprit et cerveau (1991). 3. Deloche G, Hannequin D. DO80. Epreuve de Dénomination Orale D’images. Paris: Edition du centre de psychologie appliquée; 1997. 4. Ersek M, Cherrier M, Overmann SS, Irving GA. The cognitive effects of opioids. Pain mangement nursing 2004; 5(2):75-93.
ACCEPTED MANUSCRIPT 5.Kerr B, Hill H, Coda B, Calogero M, Chapman RC et al . Concentration related effects of morphine on cognition and motor control in human subjects.
IP
T
Neuropsychopharmacology. 1991; 5: 155-166
SC R
6. Cleeland CS, Nakamura Y, Howland EW, Morgan NR, Edwards KR et al. Effect of oral morphine on cold pressure tolerance time and neuropsychological
NU
performance. Neuropsychopharmacol, 1996; 15 : 252-62
7. Walker DJ, Zacny JP. Subjective, psychomotor, and analgesic effects of
MA
cumulative doses of oral codeine and morphine in healthy volunteers.
D
Psychopharmacol (Berl) 1998;140: 191-201.
TE
8. Hanks G, O’Neill W, Simpson P, Wesnes K. The cognitive and psychomotor
CE P
effects of opioids analgesics.II. : A randomized controlled trial of single doses of morphine, lorazepam and placebo in healthy subjects. Eur J Clin Pharmacol
AC
1995; 48: 455-460
9.Tassain V, Attal N, Fletcher D, Brasseur L , Dégieux P , Chauvin M et al. Long term effects of oral sustained release morphine on neuropsychological performance in patient with chronic non-cancer pain. Pain 2003; 104:389-400 10. O’Neill W, Hanks GW, Simpson P, Fallon MT, Jenkins E, Wesnes K. The cognitive and psychomotor effects of morphine on healthy subjects: A randomized controlled trial of repeated oral doses of dextropropoxyphene, morphine, lorazepam and placebo. Pain 2000; 85 : 209-215
ACCEPTED MANUSCRIPT 11. Wolters EC, Wijngarden GK, Stam FC, et al. Leucoencephalopathy after inhaling heroin pyrolysate. Lancet 1982; 2:1233-7,
IP
T
12. Zanin A, Masiero S, Severino MS, Calderone M, Da Salt L, Lavarda AM. A
SC R
delayed methadone encephalopathy: clinical and neuroradiological findings. J Child Neurol . Epub 2009 Oct 6.
NU
13. Mills F, MacLennan SC, Devile CJ, Saunders DE. Severe cerebellitis
MA
following methadone poisoning. Pediatric Radiol.2008 ; 38(2) :227-9 14. Anselmo M, Campos Rainho A, Do Carno Vale M, et al. Methadone
D
intoxication in a child : toxic encephalopathy ? J Child Neurol 2006; 21(7) :
TE
618-20
CE P
15. Celius EG, Anderson S. Leucoencephalopathy after inhalation of heroin : a case report. J Neurol Neurosurg Psychiatry.1996 ; 60(6) :694-5
AC
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Axial Diffusion (A) and FLAIR(B) MRI sequences of the brain showing bilateral and symetrically increased signal intensity in the hippocampus.
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