Develop. Med. Child Nerrrol. 1975, 17, 621-640

Case Reports

Peripheral Neuropathy in Leigh’s Eiicephalomyelopathy

A. Moosa

Introduction The occurrence of peripheral neuropathy

in patients with progressive central nertous system degeneration usually suggests the diagnosis of either metachromatic or Krabbe’s (globoid cell) leucodystrophy. This report describes the finding of slow motor-nerve conduction velocities in an infant with Leigh’s subacute necrotising encephalomyelopathy.

Case Report A male infant weighing 2864g was born to a

primigravida mother a t full term following a normal pregnancy. The parents reported that his early development was normal, in that he had attained at a normal age such milestones as smiling, focusing, following with the eyes, reach- ing for objects and transferring them. However, he was always considered by his parents to t e ‘floppy’. He never sat, and from six months of age his weight gain began to level off. He was admitted to hospital twice at 11 months because of vomiting and failure to thrive, and at 14 months he again had a bout of severe vomiting. Intellectual develop- ment had proceeded normally until about the age of 14 months but motor development had not proceeded beyond six months of age. His speech had deteriorated from the ability to say single words with meaning to unintelligible sounds only.

On examination, his weight and length were below the third percentile and his head-circuni- ference was on the 25th percentile. The anterior fontanelle was widely patent. He was sociable and followed with his eyes. There was no ophthalmo-

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Department of Paediatrics and Neonatal Medicine, Institute of Child Health, Hammersmith Hospital, London W12.

plegia or fundal changes. abducted at the hips and but with the upper limbs

He ley with his thighs legs flexed at the knees, adducted and internally

rotated at the shoulder, forearms extended at the elbow, and clenched fists. The limbs were hypo- tonic but he was able to lift them against gravity. He was unable to lift up his head from supine or to sit or stand. Tendon reflexes were diminished. There was no sensory loss. Respirations were normal and the liver was not enlarged.

Investigations Blood Chernistry. A persistent ketoacidosis was

present, with a base excess ranging from -4 to -6meq/l; pH 7.35 to 7.47, pC0,25 to 33mmHg and standard bicarbonate 19meq/l. The serum sodium was 140meq$, K + 4.2meqjl and chloride 114meq/l. The blood lactate levels ranged from 19 to 29mg/100ml (normal 9 to 16mg/100ml): blood pyruvate 0 .2 to 1~2mg/100nil (normal 0.36 to 0~59mg/100ml) and the p-OH butyrate 8 to 25mg/100nil (normal 0 .1 to 0.6mg/100ml) and acetoacetate 1.3mg/lOOrnl (normal 0 to 0.4mg/ 100ml). Serum calcium was 5.7meq/l, phosphorus 3.lmeq/l, alkaline phosphatase 9 K.A. units, uric acid 5.4mg/100ml, cholesterol 157mg/100ml and triglycerides 73mg/IOOml (normal 60 to 140mg/100mI). The creatine phosphokinase level was 19iu/I, which is normal. Red cell transketolase was 38iu/l (normal 34 to 9Oiu/I). Thyroid function was normal. During an alanine loading test the blood glucose increased from a fasting level of 37mg/100ml to 50mg/100ml at 15 minutes-a normal response suggesting that gluconeogenesis was intact. A fructose tolerance test was normal.

Urine. pH varied from 5 to 6 and with ammonium chloride loading went down to 4.7. Acetest was intermittently positive. Aminoacid chromato- graphy showed a ninhydrin-positive band, thought to represent an excretory product of ‘Ketovite’. A slight excess of alanine was found on one occa- sion only.

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DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1975, 17

3.1.73

9.4.73 22.5.13*

Bone marrow showed no evidence of vacuolation of cells (Simopoulos et al. 1972).

Cerebrospinal fluid was normal. Nerve conduction and electromyography. The

nerve conduction velocities are given in Table 1. All the velocities were reduced to 50 per cent of normal, suggesting the presence of demyelinating peripheral neuropathy. Needle electromyography of the right deltoid was normal.

R. 25.0 R. 18.5 L. 25.8 R. 26.4 R. 18.4 R. 23.4 R. 17.5

TABLE I Nerve conduction velocities in patient described

stained with H & E and Lux01 fast blue-Cresyl violet. The putamen showed areas of rarefaction, with loss of all parenchymatous elements and marked capillary proliferation. Similar foci of parenchymatous rarefaction and capillary pro- liferation were found in the isthmus of pons (floor of aqueduct) and medulla at mid-olivary level (region of vestibular nuclei). The cerebellar cortex showed Bergmann glial proliferation with obvious Purkinje cell loss. The above changes are characteristic of Leigh’s subacute necrotising encephalomyelopa thy.

Date 1 Velocity mhec

1 UInar Post. tibia1

Normal lyr (Meanf 1 SD) 46.1 5 3.0 38.2 6 3 .3

* 3 weeks after therapy with L-glutamine an thiamine.

Leucocyte enzymes. Normal levels of activity were demonstrated for P-acetylglucosaminase, arylsulphatase A, P-galactosidase and P-acetyl- glucosaminase A and B isoenzymes.

Muscle biopsy (gastrocnemius) was normal, with normal differentiation of the muscle into two fibre types. No ‘ragged red’ fibres were seen with either the Gomori trichrome stain or the oxidative enzyme reactions.

Sural nerve biopsy was normal, with a normal range of fibre sizes (up to 1Oy diameter), though small fibres were preponderant in several areas. No segmental demyelination was seen in longi- tudinal sections. Electronmicroscopy showed evidence of myelin breakdown.

Progress With a probable diagnosis of Leigh’s subacute

necrotising encephalomyelopathy, the boy was treated with L-glutamine (Tang el al. 1972) and thiamine 500mg/day. This had no effect on his clinical condition or his biochemistry. Serial nerve conduction velocities remained unchanged. Six weeks later he died soon after admission to another hospital with a fulminating respiratory infection.

Necropsy 01 Central Nervous System (Dr. P. D. Lewis)

Blocks from the frontal, temporal and occipital regions, basal ganglia, thalamus, mid-brain, pons, medulla and cerebellum were cut at 1Oy and

Discussion This patient had subacute necrotising

encephalopathy confirmed at autopsy. The slow conduction velocities suggested the presence of peripheral neuropathy. The absence of gross pathological change on sural nerve biopsy does not exclude this possibility, since the sural nerve is purely a sensory nerve and the nerves studied electrophysiologically are mixed motor and sensory nerves. Moreover, teased fibre preparations are essential to demonstrate segmental demyelination. This was technically difficult in the small nerve from this patient.

Although hypotonia is a common fitid- ing in patients with subacute necrotising encephalomyelopathy (SNE), peripheral neuropathy has not been well documented. Absent reflexes have been recorded in several cases, and elevated CSF protein in some, but in on11 five reports has involve- ment of peripheral nerves been established by electrophysiology or histology (Reye 1960, Namiki 1965, Clayton et al. 1967, Robinson et LII . 1967, Dunn and Dolman 1969).

Reye (1960) reported on the histology of peripheral nerves in four cases of SNE aged from 18 months to 35 years. In three of these patients, considerable loss of myelin was demonstrated in nerve trunks and posterior nerve-roots, with only 25 to 50 per cent of well myelinated fibres surviving. Anterior nerve roots were spared. Axons were normal. In the fourth

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CASE REPORTS

child, minimal demyelination was found in the vagus nerve only.

Conspicuous axonal changes (ranging from irregular varicose thickening to fragmentation and disappearance) asso- ciated with marked demyelination were demonstrated at autopsy in dorsal roots of the lumbar and sacral segments and the peripheral nerves of the 15-year-old patient described by Namiki (1965). Questionable changes were noted in the anterior roots.

Both patients described by Robinson et al. (1967) showed evidence of denerva- tion on electrophysiological examination. The first case had widespread fibrillation potentials in various muscles on electro- myography, but at autopsy no change was found in the peripheral nerves. The second case had peroneal and ulnar nerve conduc- tion velocities of 28m/sec each, at 15 months of age. These were considered by the authors to be normal but in fact are reduced by about 50 per cent for a child of 15 months. Sural nerve biopsy on this second case showed minimal demyelin- ation, which was also found in other nerves at autopsy.

The patient described by Dunn and Dolman (1969) had a relapsing neuropathy confirmed by electrophysiology which, at seven years of age, showed fibrillation potentials in several muscles and a median nerve conduction velocity of 29- 8m/sec. At eight years, associated with a further relapse, the velocities for the median, ulnar and lateral popliteal nerves were

42m/sec, 45mIsec and 36nilsec respectively, but the threshold of st;.mulation was considerably increased, suggesting involve- ment of peripheral nerves. Necropsy showed considerable loss of myelin, with preservation of axis cylinders.

Involvement of peripheral nerves in SNE is not invariable and its absence there- fore does not exclude the disease. In another patient studied (Moosa and Hughes 1974), no evidence of peripheral neuropathy was found on detailed electro- physiological investigation.

The cause of SNE is unknown but it is probably the end result of several aetiolo- gical factors. Pincus el al. (1969) have found an inhibitor to the thiamine pyrophosphate-adenosine triphosphate phosphoryltransferase enzyme in body fluids of affected patients. Thiamine triphosphate, which is considered to be the neurophysiologically active form of thiamine, is absent from the brain of these patients (Cooper et al. 1969). On the other hand, Hommes et al. (1968), Tang et al. (1972), Grover rt al. (1972) and Brunette et al. (1972) have found a deficiency of liver pyruvate carboxylase in their patients.

Peripheral neuropathy occurs in thia- mine deficiency states, and it remains to be seen if the presence or absence of peripheral neuropathy in patients with SNE can dis- tinguish those associated with thiamine triphosphate deficiency from those due to other causes.

SUMMARY An infant with subacute necrotising encephalopathy is described, in whom slow motor-

nerve conduction velocities suggested the presence of peripheral neuropathy. Peripheral nerves are not invariably involved in patients with this disease, but as they are involved in thiamine-deficiency states it is conjectured that the presence or absence of peripheral neuropathy in patients with subacute necrotising encephalopathy may distinguish those wjth thiamine triphosphate deficiency from those in whom the disease is due to other causes.

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DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1975, 17

RESUME Neuropathie pkriphe‘rique dans l’ence‘phaloniye‘lopathie de Leigh

L‘auteur rapporte le cas d’un nourrisson prksentant une enctphalopathie nkcrosante subaigue chez qui des vitesses de conduction lentes dans les nerfs moteurs suggkraient l’existence d’une neuropathie pkriphtrique. Les nerfs pkriphkriques ne sont pas obligatoire- ment atteints dans l’affection envisagke, mais comme ils le sont dans les etats de dkficience en thiamine, il est supposk que la prksence ou l’absence de neuropathie pkriphkrique chez les malades atteints d’enckphalopathie nkcrosante subaigue peut diffkrencier les cas liks t i une dCficience en thiamine tri-phosphate de ceux diis a une autre cause.

ZUSAMMENFASSUNG Periphere Neuropathie bei der Leigh’schen Enzephalopathie

Es wird iiber einen Saugling mit subakuter nekrotisierender Enzephalopathie berichtet, bei dem eine verlangsamte Nervenleitgeschwindigkeit auf eine periphere Neuropathie hinwies. Die peripheren Nerven sind bei Patienten mit dieser Erkrankung nicht immer betroffen, aber da sie betroffen sind bei Fallen mit Thiamin Mangel wird vermutet, dal3 das Vorliegen bzw. nicht Vorliegen einer peripheren Neuropathie bei Patienten mit subakuter nekrotisierender Enzephalopathie die Falle mit einem Thiarnintriphosphat Mangel gegen solche abgrenzt, bei denen die Erkrankung andere Ursachen hat.

RESUMEN Neuropatia perfkrica en la encefaloniielopatia de Leigh

Se describe un niiio con una encefalopatia necrotizante subaguda, en que la reducci6n en la velocidad de conduccion sugiri6 la presencia de una neuropatia perifkrica. Los nervios perifkricos no est6n invariablernente afectados en pacientes con esta enfermedad, per0 como 10 estan en estados de deficiencia de tiamina, se piensa que la presencia o ausencia de neuropatia perifkrica en pacientes con encefalopatia necrotizante subaguda puede distinguir 10s casos con deficiencia de trifosfato de tiamina de aquellos debidos a otras causas.

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and biochemical study, with special reference to therapy with lipoate.’ Archives of Disease in Childhood, 42,467.

Cooper, J. R., Itokawa, Y., Pincus, J. H. (1969) ‘Thiamine triphosphate deficiency in subacute necrotizing encephalomyelopathy.’ Science, 164, 74.

Dunn, H. G., Dolman, C. L. (1969) ‘Necrotizing encephalomyelopathy. Report of a case with relapsing polyneuropathy and hyperalaninemia and with manifestations resembling Freidreich‘s ataxia.’ Neurology, 19,536.

Grover, W. D., Auerbach, V. H., Patel, M. S. (1972) ‘Biochemical studies and therapy in subacute necrotising encephalomyelopathy (Leigh’s syndrome).’ Journal of Pediatrics, 81, 39.

H o m e s , F. A., Pplman, H. A., Reerink, J. D. (1968) ‘Leigh’s encephalomyelopathy: an inborn error of gluconeogenesis. Archives of Disease in Childhood, 43,423.

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