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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.47.11.1211 on 1 November 1984. Downloaded from

Journal of , Neurosurgery, and Psychiatry 1984;47:1211-1215

Adult form of Leigh's disease: a clinico pathological case with CT scan examination

F GRAY,* F LOUARN,t R GHERARDI,* JF EIZENBAUM,t C MARSAULTt From Departement de Pathologie, * Service de Neurologie, t and Service de Neuroradiologie, t H6pital Henri Mondor, Creteil, France

SUMMARY The clinical and pathological findings of a 31-year-old woman, in whom the diagnosis of Leigh's disease was made, are reported. CT scan examination with contrast enhancement showed symmetrical areas of low density, in both thalami, anterior limbs of internal capsules and corpus callosum. Longstanding chronic involved the optic chiasma and the cerebral peduncles and consisted of loss, status spongiosus, astrocytic and marked proliferation. The neurons were spared. In the , internal capsules and corpus cal- losum, these lesions were more recent and consisted of focal , perivascular oedema and few lymphocytic perivascular cuffings. guest. Protected by copyright.

Subacute necrotising encephalomyelopathy (Leigh's of the left upper lid, bilateral paresis of the 6th nerve, a disease) rarely occurs in adults: to our knowledge right facial palsy and a right extensor plantar response. The only 16 pathologically studied cases have been general examination was unremarkable. The patient reported'-9 and only one of these had computed seemed well nourished and showed no signs of chronic alcoholism. BP was 120/80 mmHg. CSF was normal on tomography.' This paper reports the clinical and two occasions; two days before death, it contained 68 mg/ pathological findings of an adult case in which the 100 ml protein, 18% y globulin. EEG showed non specific diagnosis of Leigh's disease was made. generalised slow waves. The CT scan revealed bilateral, ill defined areas of low density in both thalami and anterior Case report limbs of internal capsules (fig la, b). Parts of these lesions showed diffuse enhancement after contrast injection. Such A 31-year-old Chilean woman was admitted to hospital a contrast enhancement was also seen in the splenium of because of visual impairment and increasing stupor. The the corpus callosum (fig lc, d). family history was difficult to obtain because the patient The following investigations gave normal results: lived alone, did not speak French well and was stuporous. cell count, FSR, urea nitrogen, serum , Na, K, P, She only could say that her mother was epileptic. The Ca, ceruloplasmin, antinuclear antibodies, viral antibodies, patient was not alcoholic. At the age of 21 years, she had parasite antibodies. suffered from an episode of confusion which lasted one From the first day of hospitalisation, intravenous 5% week and resolved spontaneously. Two months before then 10%, glucose infusion was administered with a vita- death, she developed intellectual slowing, behavioural min supplement containing 50 mg/day of . Four http://jnnp.bmj.com/ abnormalities and impairment of recent memory. One days before death, she received an additional intravenous month later, she experienced transient fever, and injection of 1 g/day thiamine hydrochloride. She deterior- nausea and over the following weeks, her mental state ated rapidly becoming increasingly drowsy. Chewing worsened; she had visual hallucinations, became stuporous movements became more marked. Neurological examina- and was admitted to the hospital. The patient could answer tion revealed bilateral pinpoint non-reactive pupils, com- when questioned; she frequently yawned and made chew- plex and variable disorders of movements, bilateral ing movements. Neurological examination revealed ptosis facial palsy, generalised rigidity, brisk deep tendon reflexes and bilateral extensor plantar responses. One day before

her rose to on September 25, 2021 by Address for reprint requests: Dr F Gray, D6partment de death, temperature 42°C without evidence of Pathologie, H6pital Henri Mondor, 51 av du Mal de Lattre de infection and she became deeply comatose. In spite of Tassigny, 94010 Creteil Cedex, France. attempt to resuscitate her, she died of acute 10 days after admission. Received 6 March 1984 and in revised form 3 May 1984. Accepted Post-mortem examination, 27 hours after death, revealed 5 May 1984. mild bronchopneumonia. The liver was normal. 1211 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.47.11.1211 on 1 November 1984. Downloaded from

1212 Gray, Louarn, Gherardi, Eizenbaum, Marsault guest. Protected by copyright.

Fig 1 CT scan examination. (a, b) plain scan: ill defined low dense areas in both thalami and anterior limbs ofinternal capsules. (c, d) same levels after contrast injection: enhancement in both thalami and in the splenium ofthe corpus callosum.

Neuropathological examination was performed after 20 Lesions clearly seen in sections stained for myelin, http://jnnp.bmj.com/ days of 10% formalin fixation. Blocks from many regions looked ill defined; they did not correspond to a vascular of both cerebral hemispheres, , and territory and involved the upper part of the optic chiasma, were embedded in paraplast or in cellofdin and the head of both caudate nuclei, the septum pellucidum, stained with haematoxylin and eosin, Loyez stain for the anterior limbs of both internal capsules, the anterior myelin, Bodian silver impregnation for combined parts of both thalami (fig 2a), the splenium of the corpus with Luxol fast blue and by the Gordon and Sweet method callosum, the superior and inferior colliculi and the peri- for reticulin. The brain weighed 1300 g. Gross examina- aqueductal region (fig 2b). A small focus of myelin loss was tion showed bilateral pale granular fresh necrotic lesions observed in the inferior part of the corpus callosum in its involving symmetrically the heads of the caudate nuclei, middle third. The cerebral cortex, centrum semi-ovale, the on September 25, 2021 by the internal capsules, the walls of the third ventricle and mammillary bodies, the anterior parts of the cerebral the thalami. Older greyish lesions were observed in the peduncles, pons, medulla, cerebellum and spinal cord were posterior parts of the cerebral peduncles. The optic unaffected. chiasma looked atrophic and greyish. The mammillary Microscopical examination showed two types of . The bodies were normal macroscopically. first consisted of longstanding chronic changes involving J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.47.11.1211 on 1 November 1984. Downloaded from

Adult form of Leigh's disease: a clinico pathological case 1213

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4 Fig 2 (a) Coronal section ofthe basal ganglia through the mammilary bodies. Loyez stain x 1: Necrotic, ill defined Fig 3 (a) Tegmentum ofthe cerebral peduncle at the level area involving both and internals capsules. Myelin ofthe third cranial nerve, nucleus. Haematoxylin and eosin loss is also present in the fornix and the inferior aspect ofthe x 16: spongiosis, gliosis and vascular proliferation. The corpus callosum. The mammillary bodies are spared. (b) neurons are spared or demonstrate central chromatolysis. Horizontal section ofthe cerebral peduncles. Loyez stain x (b) Thalamus haematoxylin and eosin x 16: necrosis with 1: myelin loss in the inferior colliculi and periaqueductal numerous lipid phagocytes, capillary proliferation with grey matter. perivascular lymphocytes. Absence ofhaemorrhages.

the optic chiasm and the cerebral peduncles. They con- Discussion http://jnnp.bmj.com/ sisted of ill-defined areas of myelin loss, status spongiosus, astrocytic gliosis and marked capillary proliferation with Since the initial description by Leigh,'° more than a endothelial hyperplasia. The neurons when present, for hundred cases of subacute necrotising encephalo- example in the third nerve nuclei and in the periaqueductal have been reported (for review, see grey matter, (fig 3a) were generally preserved but many David et Since the clinical and showed the changes of central chromatolysis. Axons were al"). picture relatively spared. The other type of lesion was more recent biochemical findings may vary, the diagnosis is and involved the basal ganglia, internal capsules, walls of based on the neuropathology. Biochemical studies of the third ventricle and the corpus callosum. These lesions have shown an abnormality of the metabolism on September 25, 2021 by consisted of focal necrosis associated with perivascular thiamine, though this is not linked to a single inher- oedema; many lipid phagocytes were present and few ves- ited molecular deficit. Four different metabolic dis- sels were cuffed by lymphocytes. However, the neurons turbances have been proposed as the cause of this were relatively spared. Capillary proliferation was marked. disease: (1) pyruvate carboxylase deficiency, (2) the No haemorrhages were seen (fig 3b). presence of a factor which inhibits thiamine J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.47.11.1211 on 1 November 1984. Downloaded from

1214 Gray, Louarn, Gherardi, Eizenbaum, Marsault pyrophosphate ATP phosphotransferase, (3) pyru- seem to be a criterion for separating the adult form vate decarboxylase deficiency and (4) cytochrome of subacute necrotising encephalomyelopathy oxidase deficiency (see Ohtake et al'2). (" Leigh's syndrome") from the infantile form The lesions observed in the brain of this 31-year- ("Leigh's disease") as proposed by Sipe.4 old woman are very similar to those described in Since so few cases have been reported, the clinical Leigh' s infantile subacute necrotising encephalo- picture of adult subacute necrotising encephalo- myelopathy'3 (bilateral and symmetrical necrotising myelopathy is not yet well established. It seems or demyelinating alterations with microvascular and therefore difficult to make the diagnosis of Leigh's glial proliferation and relative preservation of the disease in adults on clinical grounds only. Some neurons, involving the optic nerves, basal ganglia symptoms however are more frequently observed: and brainstem. The histopathological appearance of visual impairment which may be the only sign for these alterations also resemble that of Wernicke's several years, psychiatric symptoms, autonomic and . This had led Feigin and Wolf'4 first sleep disturbances and epileptic . The course to suggest that the lesions of subacute necrotising of the illness is often characterised by an insidious encephalomyelopathy were related to a defect in onset followed by a quiescent period and a subacute thiamine utilisation. However, in Leigh's disease, or acute termination; a remitting or relapsing course the mamillary bodies are spared while their mimicking is not rare.69 involvement is almost constant in Wernicke's A femoral arteriogram performed in one case7 encephalopathy. In addition, basal ganglia, optic showed hyperaemia of the pons and medulla with- nerves, pons, medulla and spinal cord are frequently out mass effect. affected in subacute necrotising encephalomyelo- CT scan in infantile subacute necrotising pathy but rarely in Wernicke's encephalopathy. In encephalomyelopathy'7-20 has shown bilateral contrast, thalamic lesions are more common in hypodense areas in the middle of the putamen. In Wernicke's encephalopathy.'5 Microscopically, one adult case7 computed tomograms were inter- guest. Protected by copyright. haemorrhages, which are a characteristic feature of preted as showing oedema of the midbrain. In our Wernicke' s encephalopathy are absent in Leigh' s case, bilateral and symmetrical hypodensities with disease. In the present case, Wernicke's contrast enhancement were seen in both thalami, encephalopathy can be reasonably excluded since adjacent internal capsules and corpus callosum. there was no history of alcoholism or malnutrition Such a contrast enhancement has never been previ- and the mamillary bodies were normal. ously reported in Leigh's disease. it probably cor- Subacute necrotising encephalomyelopathy responds to the alteration of the blood-brain barrier mainly occurs in infants and children. Some juvenile and/or to the capillary proliferation which was also forms have been reported.2 Adult cases have been found microscopically in the thalamus. seldom described.9 Some of them have been ques- In contrast to what is observed in Wernicke's tioned4 6I7 because of a history of chronic alcoholism encephalopathy, thalamic lesions are said to be rare or nutritional deficiency in some case or because of in Leigh's disease. Nevertheless, they were observed an involvement of the mamillary bodies. in six out of 10 cases of adult subacute necrotising Among the cases in which subacute necrotising encephalomyelopathy,2 3 67 and in the present case encephalomyelopathy was a reasonably certain the thalamus was severely involved. In addition, the diagnosis who survived to adulthood, five demons- thalamic lesions were somewhat different from trated initial neurological symptoms in childhood those observed in the optic pathways and midbrain. which antedated the terminal illness by 15 to 33 They looked more acute and showed marked nec- years. These should be considered as juvenile forms. rosis, oedema and lymphocytic perivascular cuffs. Only four cases, like ours, had an adult onset. http://jnnp.bmj.com/ When questioning the inherited character of the We thank Professor LW Duchen for useful com- disease in the 10 cases of subacute necrotising ments and criticism. encephalomyelopathy with an age at death over 20 years, it appears that three belong to the same fam- ily eight: in one case, increased levels of inhibitor References in members of the family;7 factor were found other Feigin I, Goebel HH. "Infantile" subacute necrotizing in two cases, the patients mothers were epileptic (ref encephalopathy in the adult. Neurology (Minneap) on September 25, 2021 by 2, present case). The family history was clearly nega- 1969; 19:749-59. tive in three cases34 6 and in one case,9 family history 2 Solheid C, Stoupel N, Martin JJ. La forme adulte a was not available. This familial occurrence is evolution chronique de 1'encephalopathie necrosante roughly similar to that found in 50% of the infantile de Leigh. Sa situation vis a vis des formes infanto- cases.'6 Thus, the lack of familial history does not juveniles. Acta Neurol Belg 1971;71:282-95. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.47.11.1211 on 1 November 1984. Downloaded from

Adult form of Leigh's disease: a clinico pathological case 1215 Martin JJ. Sur la delimitation clinicopathologique de tem. Part II. Amsterdam: North Holland Publishing l'encephalopathie de Gayet-Wernicke et de la forme Co 1976;349-63. adulte de 1'encephalopathie de Leigh. Acta Neurol 12 Ohtake M, Takada G, Miyaba-Yashi S, Arai N, Tada K, Belg 1972;72: 347-54. Morignaga S. Pyruvate decarboxylase deficiency in a Sipe JC. Leigh's syndrome: the adult form of subacute patient with Leigh's encephalomyelopathy. Tohoku J necrotizing encephalomyelopathy with predilection Exp Med 1982;137:379-86. for the brainstem. Neurology (Minneap) 1973; 13 Montpetit VJA, Andermann F, Carpenter S et al. sub- 23:1030-8. acute necrotizing encephalomyelopathy. A review and Feigin I, Budzilovich GN. Further observations on sub- a study of two families. Brain 1971;94: 1-30. acute necrotizing encephalomyelopathy in adults. J 14 Feigin I, Wolf A. A disease in infants resembling Wer- Neuropathol Ex Neurol 1977;36: 128-39. nicke's encephalopathy. J Pediatr 1954;45: 243-63. 6 Ulrich J, Fankhauser-Mauri C. Subacute necrotizing '5 Victor M, Adams RD, Collins GH. The Wernicke. Kor- encephalopathy (Leigh) in an adult. Eur Neurol sakoff syndrome. In: Contemporary Neurology Series 1978; 17:241-6. (Philadelphia, Davies) 1971. 7 Whetsell WO Jr, Plaitakis A. Leigh's disease in an adult 16 Jellinger K, Seitelberger F. Subacute necrotizing with evidence of "inhibitor factor" in family members. encephalomyelopathy (Leigh). Ergeb Inn Med Kin- Ann Neurol 1978;3:519-24. derheilk 1970;29:155-219. 8 Kalimo H, Lundberg PO, Olsson Y. Familial subacute 7 Hall K, Gardner-Medwin D. CT scan appearances in necrotizing encephalomyelopathy of the adult form Leigh's disease. Neuroradiology 1978; 16:48-50. (adult ). Ann Neurol 1979;6:200-6. 18 Ollivier A, Diebler C. Tomodensitometrie cranienne Kepes JJ. Oncocytic transformation of Choroid Plexus dans la maladie de Leigh. Une observation. Nouv Epithelium. Acta Neuropathol 1983;62: 145-8. Press Med 1980;9:2355. '° Leigh D. Subacute necrotizing encephalomyelopathy in '9 Schwartz WJ, Hutchison HT, Berg BO. Computerized an infant. J Neurol Neurosurg Psychiatry tomography in subacute necrotizing 1951; 14:216-21. encephalomyelopathy (Leigh Disease). Ann Neurol "David RB, Gomez MR, Okasaki H. Necrotizing 1981; 10:268-71. guest. Protected by copyright. encephalomyelopathy (Leigh). In: Vinken PJ, Bruyn 20 Giroud M, Dumas R. La maladie de Leigh. Ses aspects GW. Handbook of Clinical Neurology Volume 28. cliniques, biochimiques, histologiques et tomoden- Metabolic and Deficiency Diseases of The Nervous Sys- sitometriques. Rev Pediat 1982;28: 395-8. http://jnnp.bmj.com/ on September 25, 2021 by