Forensic Science International

102 (1999) 51–59

Hypoxic / ischaemic brain damage, especially pallidal

lesions, in heroin addicts
a,b ,
Solveig Norheim Andersen *, Kari Skullerud a
a
Institute of Pathology, Neuropathological Section, The National Hospital, University of Oslo,
N-0027 Oslo, Norway
b
Institute of Forensic Medicine, The National Hospital, University of Oslo, N-0027 Oslo, Norway

Received 7 September 1998; received in revised form 17 March 1999; accepted 14 April 1999

Abstract

The occurrence of pallidal lesions with or without other hypoxic / ischaemic brain injuries was
evaluated in 100 intravenous (i.v.) heroin addicts. The brains were collected consecutively from
forensic autopsies during the period from January 1995 to June 1996. The autopsies were required
by the police and performed at The Institute of Forensic Medicine, The National Hospital, Oslo.
There were 21 women and 79 men, median age 32 (range 21–47) and 34 (19–60) years,
respectively. Of 38 brains with abnormalities, twenty-five cases showed isolated or combined
lesions of hypoxic / ischaemic origin. Pallidal lesions were found in nine brains; six lesions were
old, one was subacute (a couple of weeks), and two were part of recent, generalized hypoxia /
ischaemia. Six persons had old infarcts in the hippocampal formation, and one of them in
combination with old pallidal infarcts. In seven brains small and old infarcts were found in
watershed areas in the cerebellum. Between five and ten percent of i.v. heroin addicts might have
pallidal infarcts, either as the sole lesion, or combined with other manifestations of hypoxic /
ischaemic brain injury. This might give severe mental disturbances in the affected persons.
 1999 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Hypoxic / ischaemic brain damage; Pallidal lesions; Transient global ischaemia; Drug addiction;
Heroin

*Corresponding author. Tel.: 147-22-868-676; fax: 147-22-209-583.

E-mail address: try-and@online.no (S.N. Andersen)
0379-0738 / 99 / $ – see front matter  1999 Elsevier Science Ireland Ltd. All rights reserved.
PII: S0379-0738( 99 )00040-7
52 S.N. Andersen, K. Skullerud / Forensic Science International 102 (1999) 51 – 59

1. Introduction

Bilateral, symmetrical lesions in the globus pallidus, presumably being the result of
acute heroin intoxication, were described in 1969 [1]. In addition to cases with bilateral
cystic lesions in the globi pallidi, Richter et al. saw cases of dementia following
overdose, and concluded that the chronic brain-damage syndrome was probably caused
by anoxia in connection with the overdose, although none of the patients had a history of
cardiac arrest [2].
Recently, Oehmichen et al. [3] investigated 180 brains from intravenous (i.v.) drug
addicts, all human immunodeficiency virus negative. Eighteen cases of acute heroin
intoxication whose survival time was from hours to days, showed ischaemic nerve cell
damage, resembling that seen in systemic hypoxia. Among 162 chronic abusers, only
26% revealed nerve cell loss in the hippocampal formation and / or Purkinje cell layer.
However, immunohistochemical studies of the hippocampal formation in 46 cases
revealed enhanced expression of glial fibrillary acid protein (GFAP) by astrocytes
and / or proliferation of microglia (CD68 expression) in 89% of the cases examined. Only
three cases showed pallidal necroses. The authors concluded that chronic intravenous
drug abuse may result in hypoxic / ischaemic brain damage.
Brains from the medico-legal autopsies performed at the Institute of Forensic
Medicine, University of Oslo, are examined at the Neuropathological Laboratory at the
same hospital. Among them are many drug addicts, the majority of whom die from a
lethal dose of heroin. After a casual finding of bilateral pallidum infarcts in the brain of a
heroin addict, we started systematically to take sections from the pallidal area in all
persons who had a history of i.v. drug abuse, to get an estimate of the frequency of
pallidal lesions and their relationship to other hypoxic / ischaemic injuries, Fig. 1.

2. Materials and methods

During the period from January 1, 1995 to June 1, 1996 we consecutively collected
106 brains from persons with a history of i.v. drug abuse, confirmed by the police. Six
cases were excluded because of autolytic changes. The brains were fixed for at least 3
weeks in 8% unbuffered formalin after which they were sectioned at 0.5–1.0 cm
intervals. Standard blocks from the water-shed area in the left frontal cortex and white
matter, from the left thalamus, hippocampus (both sides), globus pallidum (both sides),
cerebellum including the dentate nucleus, pons (2 sections), medulla oblongata (2
sections), and sections of all gross lesions were taken for microscopic examination. The
blocks were embedded in paraffin and the slides were subsequently stained with H&E.
In all cases peripheral blood was taken for analysis of alcohol and screening of drugs, as
well as testing for HIV.
Twenty-one cases were female and 79 male, and the median age was 32 (range
21–47) years and 34 (range 19–60) years, respectively.
As controls for pallidal lesions, we used brains from chronic alcoholics where — in
addition to the previously mentioned blocks — sections from the globus pallidus are
always taken to evaluate the presence or absence of hepatic encephalopathy.
 S.N. Andersen, K. Skullerud / Forensic Science International 102 (1999) 51 – 59 53

Fig. 1. (a) Coronal section through the brain with bilateral, old and cystic infarcts in the globus pallidus
(arrows). Midline lesion in corpus callosum is a post-mortem artifact. (b) Whole-mount section of globus
pallidus with an old infarct in the medial segment.
54 S.N. Andersen, K. Skullerud / Forensic Science International 102 (1999) 51 – 59

Table 1
Registered cause of death in 100 i.v. drug addicts
Heroin alone 84
Heroin and alcohol 6
Hypoxic cerebral lesion 3
Exsanguination from stab wounds 2
Drowning 1
Burns 1
Intoxication from Isopropanol 1
Undetermined cause of death 2

3. Results

The forensic pathologists classified the causes of death as shown in Table 1. Among
the cases registered as death due to heroin alone were also persons with traces of other
substances in the blood, but these were evaluated to be of minor importance. The two
cases of ‘undetermined cause of death’ were supposed to be heroin intoxication; despite
relatively low blood morphine levels, urine analysis disclosed 6-monoacetyl morphine
and revealed that heroin had been taken in shortly before death.
Neuropathological findings are listed in Table 2. Altogether 38 brains presented some
kind of cerebral pathology, often more than one in the same brain. Twenty-five of them
had signs of circulatory disturbance in any form.
Five brains showed acute hypoxic / ischaemic injury with nerve cell damage or loss,
dependant on the survival time. Three of them survived a lethal overdose after
resuscitative measures for 1.5, 1.5, and 13 days, respectively, and the cerebral injury was
suggested to be the immediate cause of death. The fourth person was found dead in an
old bus probably 2 days after an intoxication, while the last was found dead outdoors.
The brains showed hypoxic / ischaemic cell damage in the cerebral cortex, hippocampi,
thalamus, and in the Purkinje cell layer of the cerebellum. As the blood morphine levels

Table 2
Neuropathological findings No of cases
Acute hypoxic-ischaemic damage 5
Bilateral hippocampal sclerosis 6
Pallidal lesions .2 weeks 6 9
|2 weeks 1
,2 weeks 2
Other vascular lesions (infarcts) 2
Cerebellar watershed infarct 7
Inflammatory disorders of significance 3
Old contusions 5
Alcoholic cerebellar atrophy 2
Inflammatory changes in nucl. tr. spin. n. V a 5
Insignificant congenital malformations 4
Microscopic astrocytoma over the aqueduct 1
a
Nucleus of the fifth cranial nerve in the brain stem.
 S.N. Andersen, K. Skullerud / Forensic Science International 102 (1999) 51 – 59 55

Table 3
Additional cerebral lesions in patients with pallidal infarcts and other hypoxic / ischaemic damage
Patient no Pallidal infarcts Other hypoxic / ischaemic injuries Additional findings
1 .2 weeks – –
2 .2 weeks – Alcoholic cerebellar atrophy
3 .2 weeks Small, old, cerebellar infarcts Many old, cerebral contusions
4 .2 weeks Bilat. hippocampal sclerosis –
5 .2 weeks – –
6 .2 weeks – –
7 |2 weeks Acute hypox. / ischaemic damage –
8 ,2 weeks – –
9 ,2 weeks Acute hypox. / ischaemic damage –
10 – Acute hypox. / ischaemic damage Old, cerebral contusions
11 – Acute hypox. / ischaemic damage –
12 – Acute hypox. / ischaemic damage –

were rather high, the cerebral injury might have been a contributory cause of death only.
In two of the five brains, the diffuse neuronal necrosis was combined with acute pallidal
infarcts (Cases 7 and 9, Table 3).
Another six brains showed the residual state of an old hypoxic / ischaemic injury with
bilateral nerve cell loss and gliosis in the Sommer sector of the hippocampal formation,
with nerve cell loss and gliosis. All died from acute heroin intoxication. In one of the six
brains hippocampal damage was combined with old pallidal infarcts (Case 4, Table 3).
Pallidal infarcts were found in 9 of the 100 brains (Table 3). In addition to the three
cases mentioned above with additional findings consistent with an acute or old hypoxic /
ischaemic injury, a fourth case showed an old watershed infarct in the cerebellum which
could have been of hypotensive origin. Five of the brains with pallidal lesions did not
show any other hypoxic / ischaemic injuries.
Three brains contained inflammatory disorders of significance (Table 2). Two had
extensive meningeal infiltration of lymphocytes, as well as several vessels with rather
dense perivascular cuffs of lymphomonocytic infiltration (Fig. 2a). These two cases
turned out to be the only HIV sero-positive cases in the study, but without having
developed AIDS. The third case displayed brain stem encephalitis with lots of microglial
nodules in both grey and white matter in serial blocks of the brain stem exclusively (Fig.
2b), but heroin overdose was the definite cause of death.
Seven cases had old watershed infarcts in the cerebellum; one of them combined with
old, bilateral infarcts in the globus pallidus (Table 3). The contusions in five brains were
old and rather extensive, but the police reports did not tell much about the past histories
of the deceased. Two of the other cases had unquestionable cerebellar atrophy of
alcoholic type, and were among the persons who died from a combination of heroin and
alcohol.
Five cases showed inflammatory changes in the nucleus of the fifth cranial nerve
(nucl. tract. spin. n. V) within the brain stem, but we do not know if they had felt pain,
numbness or other symptoms from the sensory nerve of the face. The four ‘insignificant
congenital malformations’ comprised heterotopic glial tissue in the meninges, malforma-
56 S.N. Andersen, K. Skullerud / Forensic Science International 102 (1999) 51 – 59

Fig. 2. (a) Perivascular inflammation with cuffs of chronic inflammatory cells around vessel wall in the brain
of a HIV-positive case. (b) Microglial nodule in a case with brain stem encephalitis with multiple microglial
nodules combined with perivascular lymphocytes in serial blocks from the brain stem.

tion of frontal gyrus unilaterally, a small vascular cerebellar malformation, mild

aqueduct stenosis with hydrocephalus, and a fifth case showed a microscopic as-
trocytoma over the aqueduct.
None of the brains from several hundred alcoholics, used as controls, showed any sign
of pallidal infarcts.

4. Discussion

One hundred years ago the Bayer Company of Germany created a semi-synthetic
derivate of morphine which they named Heroisch or heroin. It is the diacetyl derivative
 S.N. Andersen, K. Skullerud / Forensic Science International 102 (1999) 51 – 59 57

of morphine, is 2–3 times more potent than morphine, and gives a greater euphoria and
stimulation [4,5]. Heroin overdose leads to coma with depressed respirations, increased
pulse rate and contracted pupils [2]. Upon recovery from coma a variety of neurological
complications have been observed, including cerebrovascular infarctions, post-anoxic
encephalopathy, unilateral parkinsonism, ballistic- and hemiballistic movements
[2,4,6,7]. A case of acute progressive ventral pontine disease has also been described [8].
The present investigation confirmed our previous impression that brains from heroin
addicts often show pathological lesions. As many as 38 of the 100 brains examined had
some kind of pathology found by routine examination, and eight of them had several
types of lesions. We were most interested in the pallidal infarcts, with or without relation
to other kinds of hypoxic / ischaemic brain injury and / or additional cerebral lesions
(Table 3). Nine brains demonstrated bilateral infarcts in the globus pallidus region — six
were old, from weeks to years; one brain showed subacute, symmetrical infarcts a
couple of weeks old, while the last two brains had acute, bilateral lesions as part of
transient global ischaemia.
Carbon monoxide is well known to cause lesions in the globus pallidus, and was for a
long time thought to be pathognomonic for elective symmetrical necrosis in this region
[9]. The symptoms may be delayed several weeks after exposure. In addition several
other causes have been described, such as cyanide [10].
The cause of infarcts in relation to i.v. injections in drug addicts is in the literature
still said to be obscure. Different reasons have been proposed; from generalizes hypoxia,
emboli from bacterial or fungal endocarditis, to hypersensitivity reaction or angiitis
[7,11–14]. Now it is well known among ambulance personnel giving first aid to drug
addicts suffering from an overdose, that the first problem is respiratory arrest. This may
even lead to cardiac arrest. As a consequence the drug addicts often take their doses
together with friends who can resuscitate them if necessary.
The globus pallidus is divided into an external and an internal part, and plays an
important role as a coordinator for voluntary and involuntary movements, as well as
cognitive and behavioural function [15]. The pallidal lesions may cause symptoms
depending upon their exact location. Bucher et al. [16] described a study of pathophysio-
logical characteristics of the globus pallidus external and internal divisions. Seven
patients with pallidal lesions possibly caused by hypoxia or poisoning by cyanide or
carbon monoxide were investigated, using high-resolution magnetic resonance imaging.
Patients with dystonic syndromes had isolated lesions in the internal globus pallidus,
resulting from loss of inhibitory pallidal projections to the thalamus, giving hyperkinetic
signs. Patients with signs of akinetic-rigid syndromes showed abnormalities in the
external globus pallidus or in the central parts, resulting from increased inhibition of the
thalamus, and explaining the hypokinetic signs. Patients with lesions in both parts of the
globus pallidus had akinetic-rigid or dystonic syndromes.
Dubois et al. wrote about ‘Cognitive and Behavioral Changes in Patients with Focal
Lesions of the Basal Ganglia’ in 1995 [17]. They describe that patients suffering from
bilateral lesions of the basal ganglia, and especially the globus pallidus, can appear
apathetic and unconcerned, in the absence of any motor disorder or akinesia. According
to Laplane et al. [15] this behavioural inertia is characterized by a marked reduction of
spontaneous activity that can be temporarily reversed by external stimulation. And
58 S.N. Andersen, K. Skullerud / Forensic Science International 102 (1999) 51 – 59

despite obvious malfunction in everyday life, neuropsychological testing of the patients

may show normal results. The reason is that the testing activates the patient, who needs
external stimulation to start. The patients showed a lack of concern regarding both their
own problems and those of their relatives. Some had depressive thoughts and anxiety.
The neuropsychological findings were similar to those observed following frontal lobe
damage. Patients with focal lesions of the striatopallidal complex usually preserve their
intellectual efficiency [15]. In contrast, patients with hippocampal lesions in their
dominant hemisphere suffer damage of recent memory [18]. Six of our heroin addicts
had old hippocampal lesions. Altogether 15 persons among the 100 had either pallidal
and / or hippocampal lesions with possible serious cerebral dysfunction. This might raise
questions about how to handle or take care of the heroin abusers, because some of them
are apparently not able to do so themselves.
We conclude that 5–10% of the heroin addicts have pallidal lesions, either as the only
manifestation, or combined with other manifestations of hypoxic / ischaemic damage.
The lesions may cause mental and motor dysfunction of clinical significance.

Acknowledgements

¨
The authors wish to thank Ms. Hjordis Risberget for excellent technical assistance.

References

¨
[1] G. Strassmann, W. Sturner, M. Helpern, Gehirnschadigungen, insbesondere Linsenkernerweichungen bei
¨
Heroinsuchtigen, ¨
nach Barbituratvergiftung, Spattod ¨
nach Erhangen und Herzstillstand in der Narkose,
Beitr. Gerichtl. Med. 25 (1969) 236–242.
[2] R.W. Richter, J. Pearson, B. Bruun, Y.B. Challenor, J.C.M. Brust, M.M. Baden, Neurological complica-
tions of addiction to heroin, Bull. NY Acad. Med. 49 (1973) 3–21.
[3] M. Oehmichen, C. Meißner, A. Reiter, M. Birkholz, Neuropathology in non-human immunodeficiency
virus-infected drug addicts: hypoxic brain damage after chronic intravenous drug abuse, Acta Neuro-
pathol. 91 (1996) 642–646.
[4] J.W. Langston, E.B. Langston, Neurological consequences of drug abuse, in: A.K. Asbury, G.M.
McKhann, W.I. McDonald (Eds.), Diseases of the Nervous System, Vol. 2, W.B. Saunders Company,
Philadelphia, 1986, pp. 1333–1340.
[5] R. Ashley, Heroin, St. Martins Press, New York, 1972.
[6] L.M. Protass, Delayed postanoxic encephalopathy after heroin use, Ann. Intern. Med. 74 (1971)
738–739.
[7] N. Vila, A. Chamorro, Ballistic movements due to ischemic infarcts after intra-venous heroin overdose:
report of two cases, Clin. Neurol. Neorosurg. 99 (1997) 259–262.
[8] J.H. Hall III, H.R. Karp, Acute progressive ventral pontine disease in heroin abuse, Neurology 23 (1973)
6–7.
[9] J. Lapresle, M. Fardeau, The central nervous system and carbon monoxide poisoning. II. Anatomical
study of brain lesions following intoxication with carbon monoxide (22 cases), Progr. Brain Res. 24
(1967) 31–74.
[10] R.N. Auer, H. Benveniste, Hypoxia and related conditions, in: D.I. Graham, P.L. Lantos (Eds.),
Greenfield’s Neuropathology, 6th ed, Arnold, London, 1997, pp. 274–275.
[11] J.C.M. Brust, R.A. Richter, Stroke associated with addiction to heroin, J. Neurol. Neurosurg. Psych. 39
(1976) 194–199.
 S.N. Andersen, K. Skullerud / Forensic Science International 102 (1999) 51 – 59 59

[12] L.R. Caplan, D.B. Hier, G. Banks, Current concepts of cerebrovascular disease – Stroke: stroke and
drugs, current concepts of cerebrovascular disease, Stroke 13 (1982) 869–872.
[13] M. Riße, G. Weiler, Heroinsucht als seltene Ursache einer symmetrischen Palli- dumnekrose, Z.
Rechtsmed. 93 (1984) 227–235.
[14] R. Jensen, T.S. Olsen, B.B. Winther, Severe non-occlusive ischemic stroke in young heroin addicts, Acta
Neurol. Scand. 81 (1990) 354–357.
[15] D. Laplane, M. Levasseur, B. Pillon, B. Dubois, M. Baulac, B. Mazoyer, S. TranDinh, G. Sette, F. Danze,
J.C. Baron, Obsessive-compulsive and other behavioural changes with bilateral basal ganglia lesions,
Brain 112 (1989) 699–725.
[16] S.F. Bucher, K.C. Seelos, R.C. Dodel, W. Paulus, M. Reiser, W.H. Oertel, Pallidal lesions, Structral and
functional magnetic resonance imaging, Arch. Neurol. 53 (1996) 682–686.
[17] B. Dubois, B. Defontaines, B. Deweer, C. Malapani, B. Pillon, Cognitive and behavioural changes in
patients with focal lesions of the basal ganglia, Adv. Neurol. 65 (1995) 29–41.
[18] W.B. Scoville, B. Milner, Loss of recent memory after bilateral hippocampal lesions, J. Neurol.
Neurosurg. Psychiat. 20 (1957) 11–21.