Cranial Neuropathy,

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Neurological involvement has been reported to occur in 0-37 (Silversides and Richardson 1950) to 26.5 per cent (Pejme 1964) of patients with Epstein-Barr virus infection. In the largest series of hospitalized patients with Epstein-Barr virus infection, neurological abnor- malities were observed in eight of 155 patients ( 5 . 5 per cent) (Silverstein el al. 1972). A broad spectrum of neurological conditions has been reported, including meningo-encephalitis, transverse myelitis, encephalomyelitis, GuiUain-Barre syn- drome, cerebellar ataxia, cranial neuropathy (Grose el al. 1975), peripheral neuropathy (Radin 1967, Liveson and Goodgold 1974, Rademakers el al. 1990), chorea, status epilepticus (Russell el al. I985), acute hemipiegia of childhood and Mollaret’s meningitis (Silversides and Richardson 1950, Pejme 1964, Silverstein el al. 1972, Grose el al. 1975). Neuro- logical recovery is complete in 85 per cent of patients, and occurs usually over several weeks (Silverstein et al. 1972).

Transient, mild thrombocytopenia is common among patients with Epstein- Barr virus infection (Carter 1965), but severe thrombocytopenia is a rare prob- lem (Steeper er al. 1989). Haemorrhagic complications are estimated to occur in less than 0.05 per cent of patients with infectious mononucleosis (Sharp 1969),

Polyneuropathy and T h rom bocytopen ia with Epstein-Barr Virus !nfection

Mary Connolly Anne K . Junker Ka Wah Chan Kevin Farrell

and have rarely been described in association with neurological problems. Case reports of fatal intracranial haemorrhage and median nerve com- pression due to local hacmorrhage have been described (Goldstein and Porter 1969, Silverstein er a/. 1972). Joncas er al. (1974) have described a child with Epstein-Barr virus-related encephalitis and uncomplicated thrombocytopenia.

This paper describes the clinical course and serological studies of a boy who had protracted, life-threatening thrombo- cytopenia, and cranial and sensorimotor peripheral ncuropathies with Epstein- Barr virus infection. We discuss more recent serological methods which may facilitate the diagnosis of active Epstein- Barr virus infection.

Method Haematological, biochemical and im- munological studies were performed in the British Columbia’s Children’s Hospital using established techniques. Serological studies were performed in the Children’s Hospital Virus Diagnostic Laboratory. Antibody to Epstein-Barr virus was detected using well- characterized, commercially available ELISA (Dupont, North Billerica, MA) for virus capsid antigen and Epstein-Barr nuclear antigen 1. Results were inter-

preted according t o t h e manufacturer’s instructions.

Case report The patient was a previously healthy 15-year- old male who presented with a one-month history of bruising easily and bleeding from the gums. H e complained of frontal headaches, weakness and paraesthesia in his upper and lower limbs, and a resting tremor of both hands. The birth history and past medical history were uneventful, and he had received no medications. There was no family history of bleeding disorders or neurological disease.

On initial examination there were petechiae on his skin and palate, ecchymoses, and no lymphadenopathy or hepatosplenomegaly. Examination of mental status was normal. He had bilateral papilloedema; the cranial nerve examination was otherwise normal. There was distal weakness of the arms and legs, postural hand tremor, diminished deep tendon reflexes, and flexor plantar responses. His sense of pain, temperature, joint position and vibration was reduced, in X glove-and-stocking distribution.

NEU ROLOG ICAt COURSE The motor weakness and paraesthesia in the upper and lower limbs increased gradually over a three month period, after which the patient slowly started to improve. However, three months after presentation he developed a right Vlth nerve palsy, followed over a one- week period by a left Vlth nerve palsy, bilateral ptosis. a partial right l l l rd nerve palsy, and dilated pupils which were sluggishly reactive t o light. His visual acuity was 20/50 in the right eye and 20120 in the left. There was bilateral papilloedema. Lumbar puncture at this time demonstrated an opening CSF pressure of 130mmrig. Over the subsequent four months, the cranial neuropathies recovered and the peripheral weakness and paraesthesia con- tinued to improve. 36 months after initial presentation. he has slightly reduced sense of vibration, joint position, pain and temperature in a glove-and-stocking distribution.

H AEMATOI.OG ICAL COURSE The platelet count remained below 20 x 109/1. for five months, despite treatment with prednisone (4mg/kg/day), methylprednisone (30mg/kg/day for three days), intravenous immunoglobulin (400mg/kg/dose for five days) and intravenous Rh(D) immune globulin (2Spg/kg/dose), the recommended treatments for the management of immune thrombo- cytopenia. In addition, interferon ( 4 . 5 ~ ~ on alternate days for 12 days) and danazol (400mg/day for two days) were used without

success. The platelet count initially increased to 71 x 109/~ following splenectomy, which was performed five months after presentation, but then decreased to 5 x IO9/1.. The platelet count returned to normal .seven months following splenectorny and has been normal since then.

I N V FS I’ IG A I’I Oh’s The platelet count was I S x lo9/[. at presen- tation (normal range 150 to 400 x IO’/L). The haemoglobin was 1 3 5 g / ~ , total white cell count was 5.8 x 109/~ , neutrophil count 3 -65 x 109/i , lymphocyte count I -54 x 109/r and monocyte count 0.38 x 109/~ . There were no atypical lymphocytes. The prothrombin time, partial thromboplastin time and fibrinogen level were all normal. Von Willebrand factor was normal. Bone marrow examination demonstrated increased mega- karyocytes, consistent with peripheral platelet consumption. No malignant cells were seen. There was normoblastic erythropoiesis, and normal myeloid maturation. Cytogenetic study showed normal 46XY karyotype. Direct platelet antibody testing was negative.

Culture of blood, urine, stool and CSF were negative for bacteria and viruses. Acute and convalescent sera and CSF specimens for igc; and &pi antibodies to herpes simplex virus, cytomegalovirus, varicella-zoster virus, adenovirus, and enterovirus were non- diagnostic. Hepatitis B surface antigen was negative, as was antibody testing for human immunodeficiency virus. Epstein-Barr virus antibody studies indicated an acute primary Epstein-Barr virus infection (Table I).

Liver enzyme analysis showed elevated alanine transaminase 281~11. (normal 10 to 4 5 ~ 1 ~ ) and aspartate transaminase 118u/1. (normal 15 to 4 0 ~ 1 ~ ) . Serum bilirubin, alkaline phosphatase, albumin, creatinine, blood urea nitrogen, electrolytes, calcium, magnesium and phosphate were all normal. Serum thyroxine. tri-iodothyronine and thyroid stimulating hormone were normal. 24-hour urinary measurements of vanillyl- mandelic acid and homovanillic acid were normal.

Examination of the CSF at presentation demonstrated four nucleated cells (three lymphocytes. one monocyte), two red blood cells, protein 2.76g/~ (normal < 0 * 4 g / ~ ) and glucose 60rng/dr. The CSF albumin was 1 . 3 7 g / ~ (normal 0.05 to 0*5g/L) and IgG was 0*68g/~ (normal 0.05 t o 0*95g/~). The ratio of cSF to serum IgG/albumin (IgG synthesis index) was 0.77 (normal 0.34 to 0.66), suggesting increased IgG synthesis within the nervous system. No oligoclonal bands were detected. Repeat CSF studies four months after

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In - TABLE I B e cz Results of Epstein-Barr virus serological studies

x Dare of test IgM-VCA' IgG-VCA IgM-EBNAl' IgG-ERNAI c (D.M. Y.)

07.10.89 - t N D t - 12.10.89' + t + * 08.1 1.89' - + * 30.01.90' + - 19.02.90 - 11.05.90 t

t -

- i t i - -

'VCA = virus capsid antigen. %BNAI = Epstein-Barr nuclear antigen 1. *On intrarenous gammaglobulin therapy; t N D test.

not cnough sera available to do

presentation demonstrated no nucleated or red blood cells, and an increased protein level of 2*37g/~. The CSF igG level had decreased to O.Zlg/i., and no oligoclonal bands were detected.

The antinuclear antibody was mildly positive (titre 1/80), and the pattern was homogeneous. Smooth muscle, ribonuclear protein and sarcolemmal antibodies were negative. Total serum lgci, IgA, IgM, c3 and c4 were normal. Lymphocyte population studies were essentially normal.

An EEG was normal. Visual evoked responses performed shortly after presentation demonstrated slightly delayed latencies in monocular stimulation in both eyes. Sensory and motor nerve conduction studies were .performed on the median, ulnar, radial, peroneal and posterior tibia1 nerves. The sensory evoked responses were absent in the upper and lower limbs. The conduction velocity of the right, peroneal nerve was 31*6m/s (normal >40m/s) and of the right median nerve was 63m/s (normal >SOm/s). The motor evoked responses were diminished and the distal motor latencies were borderline in the upper and lower limbs. The F wave response was absent in the lower limb. Needle examination of the right quadriceps muscle demonstrated small-amplitude polyphasic potentials.

CT of the head on two occasions was normal. Gallium scan of the liver demonstrated homogeneous hepatomegaly without a focal abnormality. Ultrasono- graphic examination of the abdomen was normal.

Discussion Although neurological and haemato- logical problems are well recognized in

1012 association with Epstein-Barr virus

infection, there are few. reports in the literature in which both systems are involved in the same patient (Goldstein and Porter 1969, Sharp 1969, Silverstein et al. 1972, Joncas et al. 1974). The patient in the present report had a slowly progressive neurological disorder charac- terized by peripheral sensorimotor neuropathy and multiple cranial nerve abnormalities. During this illness he had profound thrombocytopenia, which was not responsive to medical therapy. The patient became gravely i l l , and his unusual clinical features presented a major diagnostic problem for several months.

The diagnosis of Epstein-Barr virus infection was based on the presence of IgM against Epstein-Barr nuclear antigen 1 in the serum obtained shortly after admission, and the seroconversion of IgG against Epstein-Rarr nuclear antigen 1. The IgG to Epstein-Barr nuclear antigen 1 demonstrated on the second and third serum samples was probably related to the intravenous immunoglobulin treatment, and was not detected three months later. Seroconversion by IgG to Epstein-Barr nuclear antigen was demonstrated four and seven months after presentation.

The thrombocytopenia associated with Epstein-Barr virus infection is usually mild and transient (Carter 1965); however, in our patient it was prolonged and life-threatening. It has been postulated that thrombocytopenia is immunologically mediated by a platelet antibody as a result of the combination of the Epstein-Barr virus with the platelet.

Although bone marrow examination did demonstrate increased megakaryocytes consistent with peripheral destruction of platelets, anti-platelet antibodies were not detected in the serum of our patient. Absence of anti-platelet antibodies has been reported previously in Epstein-Barr virus-related thrombocytopenia (Steeper et al. 1989).

The development of neurological signs over a prolonged period of time is not a feature commonly associated with Epstein-Barr virus infection. McKendall et al. (1990) dcscribed a patient with transverse myelitis who had a period of disorientation several months before the onset of clinical signs of myelopathy. Progressive or relapsing neurological manifestations have been described in five other patients (Bray et al. 1992). The present case emphasizes the variable neurological manifestations of Epstein- Barr virus infection, in particular the occurrence of multiple neurological deficits over several months.

The importance of sensitive and specific laboratory tests for the diagnosis of Epstein-Barr virus infection is highlighted by the broad range of neurological manifestations of this virus, and by the occurrence of Epstein-Barr virus-related neurological disorders in the absence of infectious mononucleosis in 15 per cent of patients (Fleisher et al. 1979). It is not possible to culture Epstein-Barr virus in a diagnostic laboratory due to the lack of a permissive cell-culture system. Most reports have related Epstein-Barr virus infection to a neurological condition on the basis of positive heterophile antibody (Silversides and Richardson 1950, Radin 1967, Silverstein et 01. 1972, Liveson and Goodgold 1974) or IgM and IgG antibody titres to virus capsid antigen (Joncas et al. 1974, Grose et af. 1975); few reports have included antibody titres to the Epstein-Barr nuclear antigens (Grose et of. 1975, Russell el af. 1985).

The standard Epstein-Barr virus sero- logical studies have used immuno- fluorescent techniques to identify Epstein-Barr virus-reactive antibodies. Advances in the understanding of

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SUMMARY

Epstein-Barr virus biology has resulted in the identification of individual Epstein-Barr virus proteins, including virus capsid antigen, Epstein-Barr nuclear antigen 1 and Epstein-Barr nuclear antigen 2. This has permitted the development of an ELISA method, which is both cheaper and more time-efficient. Determination of antibody responses to these different proteins permits a ‘staging’ of the infection. As in all infections, IgM- type antibodies precede IgG-type anti- bodies. Early in Epstein-Barr virus infection, antibodies develop to virus capsid antigen and to Epstein-Barr nuclear antigen 2, which is a virus protein involved in growth transform- ation of Epstein-Barr virus-infected cells (Abbott et af. 1990). Epstein-Barr nuclear antigen 1 appears to be critically important in maintaining the Epstein- Barr virus in a latent, non-replicating state (Yates ef al. 1984). Antibodies to Epstein-Barr nuclear antigen 1 appear late in convalescence, up to six months to a year after primary infection (Henle et al. 1987).

A primary infection with Epstein-Barr virus can be confirmed if seroconversion is shown between acute and convalescent sera. However, the long incubation period of Epstein-Barr virus may result in seroconversion before the clinical onset of the disease. Most patients already have antibody to virus capsid antigen when they first become symptomatic, as was the situation in our patient, who had been ill for at least a month before being admitted to hospital. Measurement of antibodies to the other Epstein-Barr virus proteins may facilitate the diagnosis of Epstein- Barr virus infection in these patients. Accepted for publication 2nd March 1994.

Authors’ Appointments Mary Connolly. Department of Neurology; Anne K. Junker, Department of Pediatrics; Ka Wah Chan, Department of Pediatrics; ‘Kevin Farrell, Departments of Pediatrics and Neurology; University of British Columbia, British Columbia’s Children’s Hospital.

*Correspondence to last author at Department of Neurology, B.C.’s Childrens Hospital, 4480 Oak Street. Vancouver, B.C. V6H 3V4, Canada.

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Neurological involvement is an uncommon complication o f Epstein-Barr virus infection, and the long incubation period may complicate the diagnosis. A 15-year-old boy is described with Epstein- 1013

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Barr virus infection complicated by prolonged life-threatening thrombocytopenia, cranial neuropathy and peripheral sensorimotor neuropathy. The abnormal platelet count was unresponsive to multiple- drug therapy and splenectomy, but normalized 13 months after presentation. Neurological recovery was slow; the patient continues to have a mild peripheral sensorimotor neuropathy three years after the onset of the illness. Infection with Epstein-Barr virus should be considered in patients with acute neurological problems associated with thrombocytopenia. Measurement of antibodies to individual Epstein-Barr virus proteins facilitates the diagnosis of Epstein-Barr virus infection.

RGSUMG Neuropathie crbnienne, polyneuropathie el Itirombocytopenie dans utie in fectiotr a virus Epstei- Barr L’implication neurologique est une complication inhabituelle de I’infection a virus Epstein-Barr et la longue periode d’incubation peut compliquer le diagnostic. L’article decrit un garcon de 15 ans avec une infection a virus Epstein-Barr compliquee par une thrombocytopenie menacant la survie. une neuropathie crinienne et une neuropathie peripherique sensori-motrice. 1.e taux anortnal de plaquettes ne repondit pas A de multiples medicament et a une splenomegalie. mais se normalisa spontanement 13 mois apres le premier examen. La recuperation neurologique fut lente; le patient continue a avoir une neuropathie peripherique sensori-motrice rnoderee trois ans apres le debut de la rnaladie. L’infection a virus Epstein-Barr doit Stre envisagee chez les malades avec des problemes neurologiques aigus associes a une thrombocytopenie. La mesure d’anticorps vis a vis des proteines du virus Epstein-Barr facilite le diagnostic d’infection a virus Epstein-Barr.

ZUSAMMENFASSUNG Craniale Neuropathie. Polyneitropathie itnd Thrornbozyiopenie durch eine Epstein-Barr Virus lnfeklion Eine neurologische Beteiligung bei einer Epstein-Barr Virus lnfektion ist eine ungewohnliche Komplikation und durch die lange lnkubationszeit kann die Diagnose erschwert werden. Es wird ein 15-jahriger Junge mi[ einer Epstein-Barr Virus Infektion beschrieben, bei dem als Komplikationen eine prolongierte lebensbedrohliche l‘hrombozytopenie, craniale Neuropathie und periphere sensomotorische Keuropathie beobachtet wurden. Die abnorme Thrombozytenzahl sprach weder auf verschiedene ,Medikamente, noch auf die Splenektomie an, normalisierte sich aber nach I3 Monaten. Die neurologische Befundbesserung verlief langsarn, der Patient hat noch drei Jahre nach Beginn der Erkrankung eine leichte periphere senso-motorische Neuropathie. Bei Patienten mit akuten neurologischen Problemen im %usammenhang mit einer Thrombozytopenie sollte an eine Epstein- Barr Virus lnfektion gedacht werden. Die Antikorperbestimmung zu bestimmten Epstein-Barr Virus Proteinen ermoglicht die Diagnose einer Epstein-Barr Virus Infektion.

RESUMEN h‘europatia craneal, polineuroparia y trombocitopenia en la in feccion por el virus de Epstein-Barr La afectacion neurologica es una complicacion poco corriente en la infeccion por virus de Epstein- Barr y el largo period0 de incubacion puede complicar el diagnostico. Se describe un muchacho de 15 atlos con infeccion por el virus de Epstein-Barr. complicada con una trombocitopenia prolongada que amenazo su vida, neuropatia craneal y neuropatia periferica sensorio-motora. El numero bajo de plaquetas no respondi6 a multiples tratamientos incluyendo la esplenectomia, pero se normalizo a 10s 13 meses del inicio. La recuperacion neurologica fue lenta; el paciente sigue teniendo una neuropatia moderada sensoriomotora periferica tres aaos desputs del inicio de la enfermedad. Hay que tener presente la infeccion por el virus de Epstein-Barr en pacientes con problemas neurolbgicos asociados a una trombocitopenia. La medicion de anticuerpos 10s proteinas del virus de Epatein-Barr facilita el diagnostico de la infeccion.

References Abbott. S. D.. Rowe, M., Cadwallader, K.,

Rickstein. A.. Gordon, J.. Wang, F., Rymo, L., Rickinson, A. B. (1990) ‘Epstein-Barr virus nuclear antigen 2 induces expression of virus- encoded latent membrane protein.’ Journol of Virology, 64, 2126-21 34.

Bray, P. S.. Culp, K. W., McFarlin. D. E., Panitch, H. S.. Torkelson. R. D., Schlight. J. E. (1992) ‘Demyelinating disease after neurologically complicated primary Epstein-Barr virus infection.’ Neurology, 42, 278-282.

Carter, R. L. (1965) ‘Platelet levels in infectious mononucleosis.’ Blood, 25, 817.

Fleisher, G., Lennette. E. T., Henle, G., Henle. W. (1979) ‘Incidence of heterophil antibody responses in children with infectious mononucleosis.’ Journal of Pediatrics. 94, 723-728.

Goldstein, E., Porter, D. Y. (1969) ‘Fatal thrombocyropenia with cerebral hemorrhage in mononucleosis. ’ Archives of Neurology, 20, 533-535.

Grose, C.. Henle. W., Henle, G . , Feorino. P. .H. (1975) ‘Primary Epstein-Barr infections in acute neurologic diseases.’ New England Journal of Medicine. 292, 392-395.

Henle. W., Henle. G . . Anderson, J., Ernberg, I . . Klein, G . . Horwitz. C. A.. hlarklund. G., Rymo. I . . . Wellinder, C., Straus, S. E. (1987) ‘Antibody responses to Epstein-Barr virus determined nuclear antigen (EBNA-I and EBNA-2) in acute and chronic Epstein-Barr virus infection.’ Proceedings of the National Academy Sciences of rhe USA. 84, 570-574.

Joncas. J . H., Chieoine. I... Thivierge, R.. Bertrand, M. (1974) ‘Epstein-Barr virus antibodies in the cerebrospinal fluid.’ American Journal of Diseases of Children, 127, 282-285.

Liveson. J. A., Goodgold, J . (1974) ‘Mononeuritis multiplex associated with infectious mono- nucleosis.’ Canadian Journal of the Neurological Sciences, 203-205.

Mc.Kendal1. R. R.. Sadiq, S. A.. Calverley. J . R. (1990) ‘Unusual manifestations of Epstein-Barr

virus-encephalomvelitis.' In/ecrion, 18, 3 3 - ? 5 . Pejnie. J . (1964) 'Infectious mononucleosis.' Acra

Medrcu Scandinavica. 413, 1-98. Rademakers, R. P., Verkijk, A.. van Hoogenhuijze.

J . de Graaf, P . (1990) 'Polyradiculoneuritis and inappropriate ADli secretion in infectious mononucleosis.' Netherlands Journal o j .Medicine, 36, 252-254.

Radin, E. I-, (1967) 'Peripheral neuriris as 3 complication of infectious mononucleosis.'

Joiirnal of Bone and Jornr Surgery. 49A,

Russell, J . , Fischer. M., Zivin. J . A,. Sullivan, J . , Drachman, I). A. (1985) 'Status epilepticub and Epstein-Barr virus encephalopathy: diagnosis by modern serologic techniques.' Archives of .Yeiuolog.v. 42, 789-792.

Sharp, A. A . (1969) 'Platelets. bleeding and hemostasis in infectious mononucleosis,' In Carter, R. L., Penman, H. G. (Eds.) Infecrious Mononiicleosis. Oxford/Edinburgh: Blackwell

535-538.

AVariant Form of Hypobetalipo- proteinaemia Associated with Ataxia, Hearing Loss and Retinitis Pi gmentosa

Muneaki Matsuo Setsuko Nomura Toshiro Hara Makoto Kinoshita Kyosuke Yamamoto Tateo Kuno Y a w fumi Maeda Sumio Miyazaki

Abetalipoproteinaemia, which is caused by a complete absence of apolipoprotein B, is characterized by fat malabsorption, spinocerebellar degeneration and retinitis pigmentosa. The inheritance pattern is autosomal recessive (Kane and Have1 1989).

Familial hypobetalipoproteinaemia is a

Scientific, pp. 99-1 10. Silversides, J . I.., Richardson, J . C. (1950)

'Neurological complications of infectious mononucleosis.' Journal of the Canadian Medical Association. 63, 138-143.

Silverstein. A., Steinberg, G.. Nathanson, M. (1972) 'Ncrvous system involvement in infectious mononucleosis.' Archives r?f Neurolo,gy, 26,

Steeper, T. A., fIorwitz, C. A.. Moore. S. B., Henle. W.. Henle. G.. Ellis. R. , Flynn. P. J . (1989) 'Severe thrombocytopenia in Epstein-Barr virus-induced mononucleosis.' Wexiern Journal 01 Medicine, 150, 170-173.

Yates. J . , Warren, N.. Reisman, D., Sugden, B. (1984) 'A cis-acting element from the Epstein- Barr viral genome that permits stable replication of recombinant plasmids in latently infected cells.' Proceedings of rhe h'arional Academy of Sciences offhe USA. 81, 3806-3810.

353-358.

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disorder distinct from abetalipoprotein- aemia, and is inherited in an autosomal dominant pattern. In heterozygous hypobetalipoproteinaemia, levels of apolippprotein B are reduced to about half of normal, and other apolipoproteins are slightly reduced or unaffected (Granot and Deckelbaum 1989, Lontie et al. 1990). Although most heterozygote patients with hypobetalipoproteinaemia are asymptomatic, a few cases show neurological signs and symptoms (Scott et al. 1979, Granot and Deckelbaum 1989).

We report an unusual apolipoprotein disorder with ataxia, retinitis pigmentosa and hearing loss.

Case report A six-year-old Japanese boy visited our hospital because of unsteady gait. His parents were second cousins. His mother had a history of a spontaneous abortion, but this pregnancy and labour were both normal. His birthweight was 3 160g. Development during infancy was normal. He could walk alone but unsteadily from the age of 17 months, and he was not able to run. He could not speak until the age of two years, when hearing loss was noticed. Growth was within normal limits. He had no history of persistent diarrhoea or loose stool suggesting fat malabsorption. On examination, the boy's height was

112.5cm (-0-7 SD) and his weight was 18.5kg (-0.7 SD). Physical examination of his chest and abdomen reveakd no ZOl.5