A clinical study on the interval form of carbon monoxide intoxication

Takeshi MATSUISHI*, Tatsuro NAGASAKI** Nobuo KIRIIKE***, Anne MILLAR*

*Yokohama National University, Faculty of Education and Humain Sciences, Department of Disability Studies
**Municipal Hospital of Fujisawa City, Department of Psychiatry
***Osaka City University, School of Medicine, Department of Psychiatry

Abstract
Longitudinal study of 4 cases of the interval form of carbon monoxide (CO) intoxication is presented along with the results of computerized tomography (CT) and magnetic resonance imaging (MRI). The lucid interval, which describes the interval between the acute phase of intoxication and the emergence of the delayed neurological sequelae, varied from 17 to 32 days. In all four cases the most characteristic symptoms were mental deterioration, urinary and fecal incontinence, gait disturbance and mutism. In two of the cases other neuropsychological symptoms , such as spacial agnosia, finger agnosia , and dressing apraxia were experienced.
CT scans in 3 of the 4 cases showed low density in the white matter of the frontal lobe as the neuropathological substrate involved. The one case whose CT scan showed no abnormal signs in the white matter was investigated with MRI and an area of abnormality was identified in the periventricular region of the frontal lobe.

Introduction.
In 1906, Sibelius C. first described the interval form of carbon monoxide intoxication as a series of neurological symptoms which appear following a lucid interval of variable duration after the acute phase of intoxication. Clinically it is characterised by various neurological and psychological symptoms, the most common being gait disturbance, mental deterioration, urinary and fecal incontinence and mutisim .
In the interval form of carbon monoxide poisoning the white matter of the frontal lobe is involved . Some believe hypoxia to be the main pathological factor but this alone cannot explain the changes leading to demyelination (Brierley and Graham, 1984). It has been suggested that CO has a specific cytotoxic effect and causes a condition known as Grinkers myellinopathy along with a reduction in blood flow (Ginsberg et al.,1974) .
In the literature the interval form of CO intoxication has received little attention. To highlight this severe form of CO poisoning , the authors present 4 cases in detail. CT and MRI were used to investigate the degenerative changes induced in the brain in an attempt to shed some light on the pathogenesis of this form of CO intoxication.
Furthermore the authors explore the therapeutic effect of oxygen at high pressure (OHP) or hyperbaric oxygen treatment (HBO)which have in the past been confined to the treatment of the acute form of CO intoxication, but show promising signs in the treatment of the interval form.

CASE REPORTS
CASE 1.
B.J., a 57 year old man, had been depressed for over one year due to business failures. On June 5th, 1984 he attempted suicide by asphyxiating himself with car exhaust fumes. During the act he had a change of mind and in a drowsy state, beckoned to a passerby for help. He was immediately taken to hospital. On admission neurological examination was normal and he remained in a conscious state except for occasional lapses into delirium The patient was discharged after 5 days.
The patient remained in this lucid state for 31 days before the appearance of neurological symptoms characteristic of the interval form of CO poisoning. Initially the patient experienced urinary and fecal incontinence, mutisim, and gait disturbance. The patients condition steadily deteriorated and within a week he had fallen into an almost complete apallic state (Kretschmer 1940). It was at this point he was readmitted to hospital. On neurological examination he was unresponsive to stimuli and was unable to vocalize. Prominent bilateral Gegenhalten was present in the upper limbs and primitive reflexes such as the grasp and sucking reflex were elicited. Deep tendon reflexes were present and exaggerated and the patient had a positive Babinski sign. No disturbance to the swallow mechanism was noticed and the patients sleep cycle was undisturbed. Pulmonary and cardiovascular systems were unaffected and laboratory tests revealed no visceral complications other than a lower U.T.I..
The patient remained hospitalized for two months where his condition remained unchanged. Occasionally he vocalised simple words such as "Yes" or "Good morning". He regained some control over his extremities yet he had difficulty holding an upright posture and inclined to extend his spine. An increase in the patients sexual libido was evident and he continuously touched his genital organs. On admission a CT scan revealed a diffuse area of low density extending broadly within the white matter of the cerebrum. These findings remained unchanged after two months. An EEG revealed low voltage delta and theta waves. Alpha waves were not detected. After a year the CT scan showed that the diffuse atrophy of the brain and the low density area had become exclusively confined to the frontal lobe .
CASE 2
.M.C., a healthy 51 year old company executive, was admitted to hospital on March 23rd, 1984 after being discovered in a comatose state. On the night of the 22nd, after consuming copious amounts of alcohol, M.C. passed out in his car which was parked in a garage with the engine running. The following morning he was discovered and rushed to hospital.
On admission a CT scan showed areas of low density in the globus pallidius and the internal capsule. An EEG recorded diffuse theta waves of moderate amplitude with a frequency of 6Hz. Alpha waves were rarely recorded. The patient immediately underwent OHP therapy but due to the development of pulmonary oedema it had to be discontinued after the first treatment. The patient gradually became more alert and after one week it appeared he had made a full recovery. A CT scan at this time showed similar signs of recovery with a decrease in the size of the low density area of the globus pallidus and the internal capsule. An EEG recorded alpha waves of 9Hz which were occipitally dominant and of moderate amplitude (40 - 80 mmvol.). Hyperventilation caused a moderate increase in theta waves.
The patient remained in this lucid state for 17 days before the appearance of neurological complications. He became mutistic and experienced urinary incontinence. Dementia rapidly progressed and by April 12th could only respond to his name. With the aid of others he was capable of walking but had a strong tendency to extend his spine and is likely to lean backward. Inertia was prominent and the patient adopted abnormall postures for long periods of time. His IQ was found to be below 33 by the cubic test of Korse.
In the early weeks of the interval form of CO poisoning the patient underwent OHP therapy. He was treated daily for 10 sessions after which treatment was discontinued as it was judged ineffective. On May 4th he was transferred to a hospital for long term rehabilitation. Urinary incontinence disappeared and his gait became more stable yet Parkinson's disease prevailed. A few months later certain neuropsychological symptoms appeared the most obvious being dressing apraxia, spacial agnosia, finger agnosia, discalculia, and constructional apraxia.
On August 14th his IQ was estimated to be 59 by the WAIS test. On August 9th an EEG recorded slow alpha waves with a basic rhythm which were occipitally dominant. By November 9th his EEG was normal. A CT scan showed the low density areas of the globus pallidius and the internal capsule to be reduced in size and more clearly demarcated. While the CT scan revealed no abnormalities in the white matter an MRI scan clearly identified an area of abnormality in the periventricular region of the frontal lobe suggestive of demyelination of the white matter. Furthermore it revealed diffuse atrophy of the brain resulting largely from atrophy of the white matter . After a further 8 months the patient remained in a state of dementia and scored 71 on an IQ test. On December 26th he was discharged from hospital. Presently he resides with his wife, he remains in a euphoric state and there is little hope that he will return to his former job.
CASE 3.
S.M., a 47 year old male was in a state of depression due to marital problems. On August 21st, 1978 he attempted suicide by asphyxiating himself with car exhaust fumes. He was discovered 4 hours later in a comatose state. The patient remained unconscious for 72 hours until gradually he regained consciousness . After a 17 day lucid interval he became restless and started wandering aimlessly. A week later he experienced difficulty walking, his movements were retarded and mutistic. He then fell into an apallic state and was hospitalized.
On admission neurological examination revealed bilateral, exaggerated, deep tendon reflexes and muscle rigidity in all limbs. Urinary and fecal incontinence were also recognised. The patient immediately underwent OHP therapy and after 9 sessions he was capable of conversing. At this stage the patient exhibited Korsakov syndrome along with certain neuropsychological symptoms. An increase in the patients sexual libido was also noticed. After 20 sessions of OHP therapy the patients incontinence disappeared but due to financial restrictions the treatment had to be discontinued . S.M. was discharged and transferred to a mental hospital.
The pattern of the patients EEG and CT findings are as follows. At the onset of the delayed neurological complications the EEG recorded delta and theta waves of moderate amplitude in the frontal region. CT scan revealed a low density area in the white matter of the frontal lobe. On October 3rd , EEG recorded a lower amplitude, faster wave pattern and by October 23rd alpha waves of moderate amplitude with a frequency of 10Hz were recorded. Subsequent CT scans showed the low density area in the frontal lobe to markedly increase in size. At no time were low density areas in the gray matter observed.
CASE 4.
D.S., a 44 year old male, was heavily in debt and on January 25th, 1982 he attempted suicide by asphyxiation with car exhaust fumes. Six hours later he was discovered in a comatose state which lasted for 2 hours. Following a symptom free period of 32 days urinary incontinence and gait disturbance ensued. The patient began to fall into an apallic state and on March 10th was admitted to hospital for OHP therapy.
On admission neurological evaluation revealed he was mutistic. Primitive reflexes were elicited and Gegenhalten was evident. The patient also had a positive bilateral pyramidal sign. OHP therapy commenced and after several sessions D.S. could respond to his name and eat with assistance. Gradually he became more independent and capable of moving his limbs. While sitting he had a strong tendency to extend his spine and his body became very rigid. Korsakov syndrome was present and lasted for 2 weeks. By March 20th he had completed 8 sessions of OHP treatment and was able to converse simply. After 11 sessions he could walk slowly despite the presence of Parkinson's disease. Various neuropsychological symptoms , including visuospacial agnosia, dressing apraxia, and constructional apraxia, were experienced which disappeared after a month. The patient progressed to a complete recovery and returned to his former job. The EEG sequence was as follows: On admission, high voltage delta waves in the frontal region were recorded but by April 30th a normal EEG was obtained. Similarly the CT findings reflected the patients recovery. On admission a prominent low density area in the frontal lobe was observed which gradually disappeared and by June 20th almost no abnormalities were recognized except for a slight dilatation of the 4th ventricle.

DISCUSSION

The neuropathological substrate in the acute form of CO poisoning is diffusely distributed in the CNS. Garland and Pearce(1967), studying victims at necropsy, found a preponderance of low density areas in certain areas of the gray matter, in particular the globi pallidi, the basal ganglia, the hippocampus and the Purkinje cell layer of the cerebellum. Demyelination and necrotic lesions were also identified in the white matter of the cerebrum. . Furthermore they observed that no combination of neurological and psychiatric symptoms could be regarded as specific for CO intoxication as all may be encountered in other hypoxic states.
In this discussion we will focus on the relationship between clinical presentation and CT scan findings. Sawada et al. claim that the patients whose CT scans demonstrated marked low density area in the globusi palliddus showed poor long-term prognosis. Sawada et al, however, failed to refer to the interval form of CO poisoning and its associated neuropathological changes. From the findings of our 4 cases,the interval form of CO poisoning presents a different clinical scenario. In essence the neuropathological substrate appears to be confined to the white matter of the cerebrum, in particular the frontal lobe. Carbon monoxide is thought to have a specific cytotoxic effect resulting in the neuropathological condition known as Grinkers myellinopathy (Grinker, 1925, Lapresle and Fardeau, 1966). However, the degenerative changes induced during the acute phase may prevail into the interval form accounting for the presence of low density areas in the gray matter.
Of the four cases of the interval form of CO intoxication presented here 3 clearly demonstrate the main site of pathology to be the white matter of the cerebrum,in particular the frontal lobe. This is consistent with the findings of Yoshii et al. (1980 )  who studied the interval form of CO poisoning and described similar CT findings. In the cases presented here the findings of the CT scans reflected the pattern or signs and symptoms. Case 3, S.M., after a lucid interval of 17 days began to exhibit the clinical features of the interval form of CO poisoning. A CT scan revealed a low density area in the white matter of the frontal lobe which progressively increased in size. Correspondingly the patients symptoms became more severe and was subsequently admitted to a mental hospital. Case 1 presented with a similar pattern. Case 4, D.S., had a 32 day symptom free period before falling into an apallic state. At this point a CT scan revealed a prominent low density area in the white matter of the frontal lobe. This patient was unique as he immediately underwent OHP therapy which was continued until the patient made a full recovery. A CT scan mirrored the patients recovery with almost no abnormalities identifiable except for a slight dilation of the 4th ventricle. The use of OHP therapy has, in the past, been confined to patients suffering from acute CO poisoning, however the results here indicate a possible role for it in the treatment of the interval from of CO intoxication. Case 2 presented with a somewhat different CT profile. During the acute phase the patient exhibited a characteristic CT scan with low density areas in the globus pallidus and the internal capsule. These low density areas decreased in size as the patient recovered from the acute phase. After a 17 day lucid interval, the delayed neurological symptoms characteristic to the interval form of CO poisoning appeared. Although no abnormalities in the white matter were visible on CT scan an MRI scan clearly identified an area of abnormality in the periventricular region of the frontal lobe suggestive of demyelination of the white matter. Choi (1983) also reported the results of CT scans on patients with the interval form of CO poisoning. Of the 17 cases examined 5 showed bilateral areas of low density in the basal ganglia, 2 showed areas of decreased density in the white matter and the remaining 10 showed no abnormalities. Choi, however , failed to make any correlation between the symptoms experienced and the degenerative changes in the nervous tissue, it is therefore difficult to make any remarks regarding their findings. Unfortunately, the number of reported cases correlating the degenerative changes with the clinical signs are few. From a clinicopathological point of view, the results obtained here suggest the white matter lesion is responsible for the clinical symptoms experienced in the interval form of CO poisoning.
The role of OHPor HBO therapy in the treatment of the carbon monoxide poisoning cannot be ignored (Hyperbaric Oxigen Therapy:A Committee Report)and requires immediate investigation. Many authors have demonstrated that increased partial pressures of O₂ hasten COHb dissociation in humans (Britten and Myers,1985; Pace et al.,1950) . Similarly restoration of mitocondrial function (Brown and Piantadosi,1989)may be related to the therapeutic effect of OHP. Recently it has been claimed that the effect of OHP pertains to the involvement of polymorphonuclear leukocytes in CO-mediated neurological injury (Thom,1993a) . From clinical experience, OHP therapy is regarded as an effective treatment of acute CO poisoning however its effectivity has not yet been scientifically established. Thom et al. (1995), in a randomly controlled trial, investigated the effect of OHP therapy in cases of acute CO intoxication and found the treated group to have a lower incidence of neurological sequelae.
In Japan OHP therapy is also been used in the treatment of the interval form of CO intoxication. From the results presented in this paper and from other studies ( Kawasaki et al.,1982) it would appear that treatment with OHP is most effective when commenced at the onset of the interval form. Hence, early diagnosis is essential. During the initial anoxic insult or the latent period, however, no clinical signs distinguish the patients destined to suffer relapses from those who will have an uncomplicated recovery. However, it appears that the interval form is associated with a decreased density in the white matter of the frontal lobe.
The need for extensive research is highlighted in an attempt to understand the degenerative changes and the mechanisms involved in this severe form of CO poisoning. Magnetic Resonance Imaging (MRI) is an extremely sensitive means of detecting degenerative changes in the brain and may be a prognostic guide to the outcome of carbon monoxide intoxication.

Reference

Brierley J.B.,and Graham D.I..,Hypoxia and vascular disorders of the central nervous system, Chap 4 in Greenfield's Neuropathology, 4th ed. Ed. Hume Adams,J., Corsellis J.A.N. and Duchen L., W., Edward Arnold ,London,1984.
Britten,J.S. and Myers, R.A.M., Effects of hyperbararic treatment on carbon monoxide elimination in human, Undersea biomed. Res., 12,431-438,1985.
Brown, S.D., and Piantadosi, C.A., Reversal of carbon monoxide-cytochrome C oxidase binding by hyperbaric oxygen in vivo, Adv.Exp.Biol.Med.,248,747-754,1989.
Choi,I.S., Delayed neurologic sequelae in carbon monoxide intoxication, Arch,Neurol., 40,433-435, 1983.
Garland ,H., and Pearce,J., Neurological complications of carbon monoxide poisoning, quarterly J.of med.,36,445-455,1967.
Ginsberg,M.D.,Myers,R.E.and McDonagh,B.F. , Experimental carbon monoxide encephalopathy in the primate. II. Clinical aspectst, Arch. Neurol.,30,209-216,1974.
Grinker,R.R.,, Über einen Fall von Leuchtgasvergiftung mit doppelseitiger, Pallidumerweichung und schwerer degeneration des tieferen Großhirnmarklagers,Z.ges.Neurol.Psychiat., 98,433-456,1925.
Hyperbaric Oxigen Therapy: A Committee Report, Undersea and Hyperbaric Medical Society,Bethesda, MD,1992.
Kawasaki,T.,Konishi, H.,Uema, T.,Shimizu, A.,and Nishimura T., A case of complete recovery from the interval form of carbon monoxide poisoning with apallic syndrome treated with oxygen under high pressure and its EEG findings, Psychiat. Neurol. Jap.(in Japanese), 84,77-84, 1982.
Kretschmer,E., Das apallische Syndrom, Ztschr.Neurol.Psychiat, 169,576-579.1940.
Lapresle, J., and Fardeau, M., Les leuco-encéphalopathies de l'intoxication oxycarbonée, Acta Neuropathol, 6,327348,1966.
Lehmann,H.J., Apallic syndrome in diseases of cerebral white matter, Chap 10 In: The apallic Syndrome. Chap 10, 57-58, Ed. Dalle Ore,G.,.Gerstenbrand, F.,Lücking,C.H., Peters,G.,Peters,U.H.,  Springer-Verlag,1977.
Pace , N.,Strajman, E.,Walker,E.L., Acceleration of carbon monoxide elimination in man by high pressure oxygen, Science, 111.652, 1950.
Sawada,Y., Sakamoto,T., Nishide,K., Sadamitsu,D., Fusamoto H., Yoshioka,T.,and Sugimoto,T., Correlation of pathological findings with computed tomographic findings after acute carbon monoxide poisoning, N.Engl.J.Med. 30.1296, 1983.
Sibelius,C., Die psychischen Störungen nach akuter Kohlenoxydvergiftung, Mschr.Psychiat. 18,39-178,1906.
Thom,S.R. , Leukocytes in carbon monoxide-medicated brain oxidative injury, Toxicol.Appl.Pharmacol., 123,234-247,1993a.
Thom,S.R.,Taber,R.L.,Mendiguren,I.I.,Clark,J.M.,Hardy,K.R.,and Fisher,A.B., Delayed neuropsychological sequelae following carbon monoxide poisoning and its prophylaxis by treatment with hyperbaric oxigen, Ann.Emerg.Med.,25,474-480,1995.
Yoshii,F.and Sinohara,Y., Carbon monoxide poisoning and serial computerized tomography, Clin.Nerol.(in Japanese),13,286-288,1980.

(Journal of the Faculty of Education and Human Sciences,Yokohama National University, No2. 97-104, December, 1999)