Devclop. Mcd. Child Ncrrrol. 1974, 16, 64-18

Case Reports

Subacute Necrotising Encephalomyelopathy in Three Siblings

Neil Gordon H.B. Marsden D.M. Lewis

Introduction There are a number of metabolic dis-

orders which appear to be ‘vitamin de- pendant’. There are certain children with homocystinuria who respond to large doses of pyridoxine, as do some with cystathianinuria. Methylmalonic aciduria occurs in vitamin B1, deficiency. Recently. babies have been described who presented with severe metabolic aciduria. There was marked developmental retardation and methylmalonic aciduria without any evi- dence of vitamin B1, deficiency. A child with this condition has been treated with large doses of the vitamin, with improve- ment in the metabolic abnormalities (Rosenberg et ul. 1968). Vitamin B1 has been used in the treatment of maple- syrup-urine disease and resulted in a fall in the plasma concentrations of leucine. isoleucine and valine (Scriver et al. 1971).

Subacute necrotising encephalomyelo- pathy of Leigh (SNE) is a condition which may be of varied aetiology but sometimes seems to be vitamin-dependant. There is evidence that it is a syndrome related to the oxidation of pyruvate, which involves a multi-enzyme complex consisting of at least three enzymes and a number of CO-

enzymes (Clayton et ul. 1967). SNE has a high familial incidence, suggesting an autosomal recessive mode of inheritance. II

Royal Manchester Children’s Hospital, Pendlebury, Manchester.

The clinical findings and the metabolic manifestations are so variable that unless there is a family history it may be im- possible to be certain of the diagnosis during life.

Case Histories We report a family with three children;

all the children were affected and illustrate well the problems presented by this disease. There was no other family history of significance.

CASE 1 (A. W., d.0.b. 6.10.62)

First child of nonconsanguineous parents. Born in India. Maternal age 33 years. Mother vomited throughout pregnancy and contracted dysentery during the first trimester. Gestation 36 weeks. Delivery normal. Birthweight 2.5kg. She was a difficult feeder and screamed a lot. Vomiting was forceful and persisted as a regular feature until 18 months of age. She smiled at seven weeks, sat at seven months and stood with support at eight months. By 18 months she was talking. using sentences.

When first seen at 2; years she was able to walk, although unsteadily, she could dress herself to a large extent and was able to feed herself. She exhibited fine hair over the limbs, upper lip and back. She was hypotonic and had a slight tremor of the arms and legs. Reflexes were unremarkable. The findings suggested a cerebellar or brain- stem disorder. Her signs deteriorated at times of intercurrent respiratory infections.

A year later, at 36, she had regressed. She was not walking as well as previously and her tremor was more marked. Her weight was only 9kg. At about this time she developed a series of

64

CASE REPORTS

respiratory infections, not serious in themselves, which led to a profound lowering of her mood and level of activity, and further weight loss to 6.3kg. After three or four months she seemed to improve again.

She died suddenly, shortly before her 4th birthday. Investigations, including full blood- count, urine analysis, urea, and electrolytes, were non-contributary, apart from a persistent de- pressed plasma bicarbonate. Permission for post- mortem was refused.

CASE 2 (S.W., d.0.b. 6.7.67)

A normal pregnancy and delivery. Birthweight 3,4kg. Development was entirely normal until the age of one year, when she weighed 8'5kg. Over the next 12 months she had several vomiting episodes lasting up to three weeks, associated with mild respiratory infections. Her appetite declined and she lost 2kg in weight.

She was admitted to hospital at two years. Her height and weight were both well below the third centile. She was irritable. Her trunk and limbs were covered with a downy hair. She had normal eye movements, generalised muscular hypotonia and extensor plantar responses.

From then on her general health fluctuated. Her parents remarked that just as she seemed to be doing well and beginning to progress, a further episode of respiratory infection and vomiting would set her back even further. She reached the point of almost walking unaided but then became progressively more ataxic. Examination showed a strabismus, vertical nystagmus, and a tremor of the hands. It was felt at this time that she had a degenerative, possibly demyelinating, condition affecting the brain stem, although the fact that her sister had died after a similar condition strongly suggested an inherited neuro-metabolic disorder.

In February 1971, aged 3: years, the blood pyruvic acid was found to be raised and the lactic acid was at the upper limit of normal. When repeated later both were markedly raised. Intra- venous glucose had no effect on pyruvate levels. Exercise lead to a sharp increase in pyruvic acid (0.9mg to 2.14mg) and lactic acid (25mg to 41mg). Intramuscular thiamine hydrochloride 50mg had no appreciable effect on these levels. In November 1971 she was started on oral thiamine hydro- chloride 200mg t.d.s. At this time she was vomiting daily, anorexic, and barely able to sit unsupported. She had become withdrawn and incontinent. The thiamine hydrochloride had no effect on her clinical condition; in fact soon afterwards she had to be admitted to hospital to be rehydrated

and have the acidosis corrected with intravenous fluids and bicarbonate. She continued to vomit intermittently, but the degree of acidosis and levels of pyruvic and lactic acids did not appear to relate to her clinical state.

In January 1972, at 43 years, she was started on twice-weekly intramuscular injections of 5mg lipoic acid. After this there was a steady improve- ment in her condition. Her appetite recovered and she put on weight. She fed herself and sitting balance improved. She became more outgoing and even joked. Her father repeatedly stated he could always tell when she had had her lipoic acid, as her speech for the next day or two was much clearer. Oral thiamine hydrochloride was stopped, without any change in the child's condition.

In addition to pyruvic and lactic acid estimations, tests were carried out on plasma urea and electro- lytes, glucose, serum proteins, calcium, phosphate and alkaline phosphatase, on liver function and lipoproteins. The results were all normal, as were results of electrocardiography and electroen- cephalography. She showed a persistent acidosis (estimated on arterialised capillary blood), apart from the occasions when this was compensated for by oral and intravenous bicarbonate. Serum alanine levels were greatly increased on one occasion but normal on two further estimations. Blood ammonia levels of 0.097 and 0~054umol/ml (normal range 0~013-0~034umol/ml) have been recorded. An inhibitor substance of thiamine pyrophosphate-adenosine triphosphate phospho- transferease was found in the urine.

The child died at home after a brief period of hyperventilation, but no exact details are known of the child's condition at that time. At post- mortem examination the brain weighed 13278

Fig. 1. Coronal section through the cerebral hemi- spheres, showing symmetrical lesions at inferior aspect of the thalami.

65

DEVELOPMENTAL MEDICINE AKD CHILD NEUROLOGY. 1974. 16

Fig. 2. Transverse section through the pons and medulla.

(normal I237g) and uas hyperaemic. Bilateral symmetrical lesicns ucre present at the infero- lateral margins of the thalamus (Fig.1). They Here dark pink to red in colour and showed softening of tissue. Smaller. rather paler pink arcas were present in the midbrain. Similar lesions Mere present in the upper pons, symmetr:callydistributcd in the floor of the fourth ventricle, and larger cerebellar foci Mere seen more posteriorly in the roof of the ventricle. In the upper medulla the lesions Here small and scattered with a central area of involvement in the lower medulla (Fig. 2). There was bilateral symmetrical distribution of lesions in the posterior and lateral columns of the cervical spinal cord only (Fig. 3).

On microscopic examination, demyelination was noted and was more extensive and symmetrical than the lesions in the brain stem seen with the naked eye. Capillary proliferation was prominent in many areas and there was neuronal loss with shrinkage and pyknosis or central chromatolysis of remaining cells (Figs. 4 and 5) . Cavitation was a feature in some places, with proliferation of phagocytic microglia. In the older lesions cavita- tion was more marked with collection of peri- vacular microglia and reactive gliosis, which was hypocellular. fibrillary, and prominently iso- morphic.

CASE 3 (S.W.. d.0.b. 25.1.69)

Born at 42 weeks gestation, birthueight 3 '8kg. Normal neonatal period. She received triple immunization and poliomyelitis vaccination. Milestones in the first year were normal. but she uas not walking unaided until 18 months.

She b a s admitted to hospital at the age of two years with a history of vague ill-health and loss of appetite. Shortly before admission she developed headache and loss of balance. She had an upper respiratory tract infection and fever. Weight was well below the third centile. Her trunk and limbs were covered with fine douny hair and she was hypotonic and ataxic, with normal deep tendon reflexes and flexor plantar responses. Full blood- count, niantoux test, urea and electrolytes, muscle enzymes and plasma amino acids were normal, with the exception of plasma bicarbonate which was slightly depressed at ZOmEq/l.

By 23 years she had developed an internal strabismus, and four months later (November

Fig. 3. Coronal section through the cerebral hemispheres and transverse section through the midbrain, pons, medulla and cervical spinal cord, showing distribution of lesions.

66

CASE REPORTS

Figs. 4 and 5. Low and high power photomicrographs of lesions in the brain stem, showing capillary pro- liferation and neuronal degeneration. ( H & E x 100 and x 300.)

1971) pyruvic and lactic acid levels were measured and found to be slightly raised. Exercise lead to a trebling of the pyruvate level. Blood alanine tremor and her speech became indistinct. levels were normal. Following a 24-hour adrnis- sion to hospital for biochemical assessment, she

vomited and developed dyspnoea. She became anorexic, lethargic and floppy. She developed a

On re-admission to hospital she was not clinically dehydrated. Her respiratory rate was 56 per minute,

67

i) t \ .€LOP\IF\TAL VEDICINE AYD CHILD UEUROLOGY. 1974. 16

but there \+as no cyanosis or intercostal recession. There was no sign of infection. The eyes sho\\ed dancing oscillating nio\ements on fixation. Muscle tone \4as reduced but the tendon reflexes \\ere normal. She exhibited a partially compensated inetabolic acidosis w i t h a pH of 7.37. standard bicarbonate IlniEq I. p C 0 , 13mmHg and base deficit of 15. At the time of this acute deteriora- t ion her p!rtivic acid and lactic acid le\els \\ere 2 '14 and 50.5nig IOOml respectively. but on the day of onset of her acute deterioration, whilst she \vas still apparentl!. sell and behaving normall>. her ketoacids \\ere e\en more niarkedl! r a i d .

She improved \\ith parenteral fluids and bi- i ; i r hona te.

I r i March I Y72. thiamine hydrochloride XOmg t.d.s. M;IS added to the treatment nith twice- ireeiily injections oflipoic acid. She did not shou the striking improvement exhihited by her older sister (('aze 2 ) and continued to hyperventilate. She remained anorexic. shaky and floppy and \+as >itting badly (see Table).

I n May 1972 she was started on thiamine tetra- i'urfuryl disulphide (TTFD) 30nig;kg daily in divided doses. She was unable to swallow the small sugar-coated tablets and chewing them caused her breath and the Mhole house to smell of burning rubber. This objectionable smell did not arise if the tablets mere swallowed whole. For the short time she was on this treatment there was no detectable clinical improvement.

In September 1972 treatment was stopped and, if anything, the child's clinical condition improved. Hohever, since then there has been a gradual deterioration. punctuated by relapses and re- missions. A course of nicotinamide 50mg t.d.s. was given. combined with pyridoxine 25nig q.d.s. and glutamine 150mg five times a day (Tang et a / . 1Y72); there was no definite response. It was de-

decided. therefore. to give courses of intensive treatment for periods of a week. alternating with three meek5 off treatment.

The child has been given lipoic acid (5mg i m . each day for a neck) and biotin (vitamin H) l0mg orally each day for a Meek, as pyruvate carboxy- lase is biotin-dependant (Brunette et L I I . 1972). During this period the child has remained in relatively good health and there have been no relapses. The biochemical studies are not yet complete and it is hoped to report these findings at a later date. We do know, however, that prior to both these courses of treatment the patient's urine had repeatedly shown large amounts of /3-hydroxybutyric acid and now rarely shows any excess. If the child remains in better health these intensive courses of treatment will be repeated.

Discussion The onset of subacute necrotising ence-

phalomyelopathy (SNE) occurs usually in the first two years of life and the child's development may be normal for the first year. The duration of the disease is usually four years or less. but it can be more pro- longed. The diagnosis is to be thought of when there are recurrent episodes of ataxia, choreo-athetosis, hypotonia and vomiting. The child may present with feeding diffi- culties, vomiting, difficulties in swallowing or sucking, hypotonia and weakness, and with developmental retardation and some- times regression. Among the less common presenting symptoms are epileptic seizures. dystonic movements and abnormalities of gait (Montpetit et a/. 1971).

TABLE Results of pyruvic and lactic acid estimations (Case 3)

Pyruvic Lactic

(mg 11 OOml) (mgi 100ml)

1 S.11.71 0.79 16.5 Well 19. 1.72 0.49 16.0 Resting 19. 1.72 1 .46 29.0 After exercise 17. 2.72 2 . 4 68 .O Well, but sudden deterioration

withjn two hours of taking specimen

23. 3.72 2 .13 50.5 Acute deterioration with hyper- ventilation, anorexia, hypotonia

2. 5.7' 1.01 21.6 Incomplete recovery 19. 9.72 1.44 28.5 Incomplete recovery

Date acid acid Remarks

~ __ - ~ -

68

CASE REPORTS

As the disease progresses, the weakness and hypotonia become more marked and repiratory abnormalities such as ‘air hunger’ are often a particular feature. The neurological abnormalities are many, but the suggestive combination is ocular ab- normalities and long-tract signs: these include nystagmus, bizarre rolling eve movements, ptosis, strabismus, pupil ab- normalities, optic atrophy, and pyramidal, extrapyramidal and cerebellar signs. Vomiting, seizures, and developmental regression can become an increasing prob- lem. Death often seems to be related to the respiratory complications.

Laboratory tests may not be of much help. There can be raised blood levels of lactate and pyruvate, but there is consider- able controversy about whether this is characteristic of the disease or secondary to such factors as dehydration, hypoxia or hyperventilation. Raised alanine levels have been found in the blood and urine, possibly as a result of excess pyruvate combining with glutamate to form a- ketoglutarate and alanine (Lonsdale et al. 1969).

The pathological findings show many similarities with Wernicke’s encephalo- pathy. The brain lesions are usually symmetrical, mainly affecting the basal ganglia and the brain stem. Lesions also occur in the periaqueductal tissues, the cerebellum, spinal cord, posterior nerve roots and peripheral nerves. The substantia nigra is more often affected than the mamil- lary bodies ; and the widespread demyelina- tion sometimes found in subacute necrotis- ing encephalomyelopathy is another of the differences between the two conditions. The characteristic lesion is a ‘status spongiosus’ with marked proliferation of capillaries and a relative preservation of neurones (Dayan et al. 1970).

The typical episodic nature of the history may be due to the overloading of impaired enzyme systems. The relapses, which may

last for days, often seem to be precipitated by such factors as fever, excitement, or a high-carbohydrate meal. If there is a partial inability to oxidise pyruvate, a multi- enzyme complex is involved and a defici- ency or abnormal function of any part of this system may give rise to features similar to those of thiamine deficiency (Clayton et al. 1966). There is, therefore, a distinct possibility that this is a group of diseases of varying aetiology.

The excess alanine that has been found in some instances (Londsdale et al. 1969) is presumably formed from pyruvate, and appears in the urine when the plasma con- centration overwhelms the renal clearance mechanism. This finding does not appear to be of aetiological significance and is not always present. However, when it is, it is suggested that if excess pyruvate combines withglutamate to form a-ketoglutarate and alanine, the former may be syphoned away from its essential role in brain metabolism.

When there is a high intake of carbo- hydrate, the limited thiamine reserves of the brain may be inadequate. Then the thiamine may be used mostly to meta- bolise carbohydrate and be withdrawn from its membrane function, which is crucial to the integrity of the nervous system. This may explain, for example, the absence of similar neurological syndromes in complete starvation with a very low carbohydrate intake, as opposed to starva- tion with a diet almost entirely composed of carbohydrate (Pincus et al. 1971).

In one child suffering from Leigh’s encephalopathy, a liver biopsy showed a virtual absence of the enzyme pyruvate carboxylase, which is responsible for the conversion of pyruvic acid into oxalo- acetic acid (De Groot et al. 1969). The normal result of the glucose tolerance test and the normal response to glucagon and epinephrine, with low fasting blood-sugar levels and high levels for pyruvate and

69

DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1974. 16

lactate, suggest a diminished gluconeo- genesis: for the process of gluconeogenesis the conversion of pyruvate into oxalo- acetic acid is the most important route. A deficiency of pyruvate carboxylase in the liver has also been reported in a patient with SNE by Tang and his colleagues (1972).

I t is difficult to differentiate clinically Leigh’s subacute necrotising encephalo- myelopathy from the heterogenous group, congenital lactic acidosis (Scharer 1972). There have been a number of re- ports of acidosis due to an error in lactate and pyruvate metabolism (e .g . Haworth ei al. (1967). The metabolic acidosis is often transient, as may be the clinical symptoms, and the most likely aetiology seems to be a block in the oxidation of pyruvate. A defect in pyruvate decarboxylase has been re- ported in a child with an intermittent neurological disorder (Blass et al. 1970). There was a history of repeated episodes of ataxia and choreo-athetoid movements, and there were raised levels of pyruvic acid in the blood and of alanine in the urine. Blood alanine and lactate levels were also slightly increased.

I t ha5 already been suggested that the metabolic disorder underlying the SNE syn- drome may not be the same in all cases. One or other of the relevant enzymes may be absent, or the structure of the apoen- zyme may be defective so that it cannot combine normally with its co-enzyme. It is this possibility that has led to the treat- ment of the disease with massive doses of thiamine or one of its derivatives, in the hope that swamping the body with the co- enzyme may enable at least some of it to combine. Another possible effect of this treatment may be that, if there is a sub- stance that can inhibit the co-enzyme, an exce\h of the latter may well overwhelm the effect of the inhibitor.

An inhibitor of thiamine pyrophosphate- adenosine triphosphate phosphoryl-trans- ferase ha5 been found in the urine and

blood of patients with SNE (Cooper et al. 1970). and our thanks are due to Professor J. R. Cooper and Dr. J. H. Pincus for identifying this inhibitor substance in the urine of the second child in this family. The enzyme is responsible for the synthesis of thiamine triphosphate, and the absence of this substance has been reported in the brain of a child who died with SNE (Cooper et a/. 1969). This finding may not only help to explain the metabolic disorder in some of these patients, but also provide a diagnostic test. The co-enzyme form of thi- amine is thiamine pyrophosphate, and al- though little is known about the function of thiamine triphosphate, there is certainly evidence to suggest that it is the neuro- physiological form of thiamine (Pincus 1972). If thiamine does have a co-enzyme independent r61e in nervous tissue it may be involved in ion movement.

A number of other forms of treatment have been tried for SNE. Thiamine propyl disulphide and thiamine tetrafurfuryl-di- sulphide have been given, as they enter the cell by diffusion and are then converted to thiamine, while the latter is dependent on active transport and intracellular levels are not proportional to dosage (Pincus et al. 1971) Thiamine pyrophosphate itself has been used, and lipoic acid which is also involved in the oxidation of pyruvate (Clayton et al. 1967). Other therapy has included biotin, vitamin B,,, D-penicilla- mine and decadron (Blass et al. 1971). In the present state of knowledge it seems reasonable to try all of these substances in the hope of affecting the course of the disease. Some may affect the biochemical abnormalities, but it remains to be proven that they benefit the clinical course of this disease.

AcX-tio,~,le[igements: The authors wish to thank Miss E. M. Hammond and Mr. Christopher Chard for the biochemical investigations. and Professor J. R. Cooper and Dr. J. H. Pincus of Yale University for their help in the investigation of the second child in this family.

70

CASE REPORTS

SUMMARY A number of metabolic disorders are vitamin-dependent, and among these may be

subacute necrotising encephalomyelopathy (SNE). A description is given of three children in one family suffering from this disorder.

The symptomatology is reviewed and it is stressed that laboratory tests are of limited value in diagnosis. Pathological findings are characteristic, and similar to Wernicke’s encephalopathy. SNE appears to be related to the oxidation of pyruvate ; as this is dependent on a multi-enzyme complex, it is likely that SNE is the result of a number of apo-enzyme and co-enzyme deficiencies. Theories in support of this are discussed, together with the rationale for treatment of the disorder with a variety of co-enzymes.

RGSUMG Encephalomyelopathie necrosante subaigue

Nombre de conditions sont sous la dkpendance de vitamines et parmi celles-ci il est possible qu’il y ait une enckphalopathie nkcrosante subaigue (SNE). Trois enfants d’une famille souffrant de ce trouble font l’objet d’une description.

La symptomatologie est analysie et il est soulignk que les examens de laboratoire ont peu de valeur diagnostique. Les signes pathologiques sont caractkristiques et semblables ii ceux de l’enckphalopathie de Wernicke. La SNE apparait like A l’oxydation des pyruvates; comme celle-ci depend d’un complexe multi-enzymatique, il est vraisemblable que la SNE est le rksultat d’un certain nombre de dkficiences d’apo-enzymes et de co-enzymes. Les thkories en faveur de cette hypothese sont discuttes, ainsi que les raisons d’un traitement du trouble par differentes variktts de co-enzymes.

ZUSAMMENFASSUNG Subakute nekrotisierende Enzephalomyelopathie

Es gibt eine Anzahl von Erkrankungen, die vitaminabhangig sind, und zu diesen ist moglicherweise auch die subakute nekrotisierende Enzephalomyelopathie (SNE) zu rechnen. Die pathologischen Befunde sind chrakteristisch und ahnlich denen der Wernicke- Enzephalopathie. Die SNE scheint mit der Pyruvatoxidation in Verbindung zu stehen : da dies von einem Multi-Enzymkomplex abhangt, ist es wahrscheinlich, dalj die SNE auf dem Fehlen mehrerer Apo- und Coenzyme beruht. Theorien, die dies unterstiitzen, werden diskutiert, zusammen mit der wissenschaftlichen Begrundung der Behandlung dieser Erkrankung mit einer Vielfalt von Coenzymen.

RESUMEN Encefalomielopatia necrotizante subaguda

Un nsmero de alteraciones son vitamino-dependientes y entre ellas puede contarse la encefalomielopatia necrotizante subaguda (ENS). Se describen tres niiios en una familia que padecian esta alteraci6n.

Se revisa la sintomatologia y se subraya que 10s tests de laboratorio son de un valor limitado para el diagn6stico. Los hallazgos anatomo-patol6gicos son caracteristicos y similares a la encefalopatia de Wernicke. ENS parece estar en relaci6n con la oxidaci6n del piruvato. Como kste esth en dependencia con un complejo multi-enzimhtico, es plausible

71

DtVFLOPMV1EYTAL VEDICIhE AND CHILD hEUROLOGY. 1974, 16

que la ENS sea el resuitado de un grupo de deficiencias en apo y co-enzimas. Se discuten tenrias que apoyan esta hipbtesis y se razona a1 tratamiento de la alteracibn con una variedad de co-enzimas.

REFERENCES Blass. J . P.. Avigan. J., Uhlendorf, B. W. (1970) 'A defect in pyruvate decarboxylase in a child with an inter-

mittent movement disorder.' Joiwtrul o / Clitiiral Itrvesrigoriotr, 49, 423. Kark. R . A. P.. Engel. W. K. (1971) 'Clinical studies o f a patient with pyruwte decarboxylase deficiency'.

.+ircliirr.s 11f ,Nrur~iIiig,v. 25. 449. Brunette. M. G., Delvin. E.. Hazel. B.. Scriver. C. R. (1972) 'Thiamine responsive lactic acidosis in a patient

uith low-KM pyrubate carboxSlase activity in liver.' Pediufrirs. 50, 702. Clayton. 8. E.. Dobbs. R . H.. Patrick. A. D. (1967) 'Leigh's subacute necroiizing encephalopathy: clinical

and biochemical s tudy M ith special reference to therapy nith lipoate.' ..lr.c/rive.s o f Diseuse in Clddliood. 12. 467.

C'OO~CT. J . K.. Itokaxa. Y.. Pincus. J . H. (1969) 'Thiamine triphosphate deficiency in subacute necrotizing l.ncephaloin~elopatli

Pincus. J . H.. Ito . ( 1970) 'Experience uith phosphoryl transferase inhibition in subacute necrotizing t.ncephaloniyelopath)..' .C'en, EnglutrdJoio.tru/ i f Medicitre. 283, 793.

Dayan. ,4. D.. Ockenden. B. G.. Cronie. L. ( 1970) 'Necrotizing encephalornyelopathy of Leigh. Neuro- pathological tindings in 8 cases.' .4rc/rires oi/ Diseme in Clrild/rood. 45, 39.

De Groat% C . J.. Honimes. F. A.. Jonxis. J. H. P. (19691 'The enzyme defect in Leigh's encephalopathy.' in .Allan. J . 11.. Holt, K . S.. Ireland. J. T.. Pollitt, R. J. (Eds.) €trz.vt?ropenir Atzaeniins, L>~.sosomes ntrdorher

-

Pupi~r. t . Edinburgh : Livingst one. Haxorth, J . C., Ford, J. D.. Younoszai. M, K. (1967) 'Familial chronic acidosis due to an error in lactate

and pyuvate nietabolism.' Cuircrdiatr .tledical As.iociutiotr Jourtrul, 97, 773.

hyperpyruvic acideniia, hyperalanineniia and hyperalaninuria.' Perliritrirs, 43, 1025. Lonsdale, D.. Faulkner. W. R., Price, J.. Snieby, R. R. ( 1969) 'Intermittent cerebellar ataxia associated with

Montpetit. V. J. A., Andermann, F., Carpenter, S. Fawcett, J . S., Zborowski-Sluis. D., Giberson. H. R.

Pincus. J . H. (1972) 'Subacute necrotizing encephalornyelopathy (Leigh's disease): a consideration of clinical

Cooper, J. R.. Itokaua, Y . . Gumbinas, M. ( 1971 ) 'Subacute necrotizing encephalornyelopathy.'

Rosenberg. L. E.. Lilljeqvist. A, . Hsia, Y . E. (1968) 'Methylmalonic aciduria.' New England Jourtzul of

Scharer. K . ( 1972) 'Congenital lactic acidosis.' itr Stern, J.. Toothill. C . (Eds.) Orgutrir Aridurias. Edinburgh:

Scriver. C. R.. MacKenzie. S.. Clow. C. L. . Delvin. E. (1971) 'Thiamine responsive maple-syrup-urine

Tang. T. T., Good, T. A,, Dyken. P. R., Johnson, S. D., McCreadie, S. R.. Sy, S. I., Lardy, H. A., Randolph.

1971 1 'Subacute necrotising encephalomyelopathy.' Brain. 94, 1 .

features and etiology.' Devekiptiienral iMedicitre atid Child Neurolog>,, 14, 87.

,4rrhivr.\ of I"eurolog>.. 24, 51 1 .

Merlicirre, 278, 13 19.

Churchill Livingstone.

disease.' Lunrer. i. 310.

F. B. ( 1 972) 'Pathogenesis of Leigh's encephalornyelopathy.' Journal of Pediatrics. 81, 189.

Pleural Fluid Effusion and Eosinophilia Following Ventriculo-pleural Shunting

Joan L. Venes

introduction Drainage of cerebrospinal fluid (CSI.)

into the pleural or peritoneal cavity is an accepted method of treatment for hydro- cephalus (Ransohoff 1954, Sulavik and Katz 1963, Ames 1967. Weiss and Raskind 1969). Shunt obstruction by, for example. fibrinous exudate or omentum is a common cause of shunt malfunction in hydro-

Section of Neurosurgery, Department of Surgery and Pediatrics, Yale University School of Medi- cine. Neu Haven. Connecticut 065 10.

12

cephalic children, but malfunction caused by malabsorption of CSF is less frequent (Ames 1967, Dean and Keller 1972).

The following is a report of three child- ren in whom malfunction of a ventriculo- pleural shunt was related to malabsorption and was accompanied by pleural effusion and eosinophilia.

Case Reports CASE I

This 15-month-old girl had a ventriculo-pleural shunt inserted at three months of age for hydro-