Subacute Necrotizing Encephalomyelopathy (Leigh's Disease): a Consideration of Clinical Features and Etiology

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  • Develop. Med. Child Neurol. 1912, 14, 81-101

    Subacute Necrotizing Encephalomyelopathy (Leighs Disease): a Consideration of

    Clinical Features and Etiology Jonathan H . Pincus

    Introduction Subacute necrotizing encephalomyelop-

    athy (SNE), or Leighs disease, is a degener- ative nervous system affliction; in the large majority it starts before two years, and the great variability in the clinical picture often makes ante-mortem diagnosis very difficult. Feeding problems, weakness, external ophthalmoplegia, loss of vision, swallowing difficulties, ataxia, convulsions and peri- pheral neuropathy have all been described in different combinations. Essentially, the diagnosis has rested upon autopsy findings of necrotizing lesions, with a characteristic distribution within the ner- vous system. The changes which are considered typical include cell loss, demyel- ination and reactive microgliosis, with a relative sparing of neurons in affected regions. There is always a marked increase in the number of capillaries with plump endothelial cells. These lesions, which usually vary in age, are seen mainly in the midbrain and lower brain-stem regions, the spinal cord, thalamus, basal ganglia, dentate nucleus of the cerebellum and, often, the optic nerve and tracts. Involve- ment of peripheral nerves, cerebellar and cerebral cortex and white matter have also been recorded, but less commonly. The

    mammillary bodies are usually spared, otherwise the nature and distribution of the lesions most closely resemble those of Wernickes encephalopathy : for this reason, it has long been supposed that SNE might in some way reflect a disturbance in thiamine metabolism.

    Although the use of thiamine in doses which would be appropriate for dietary thiamine deficiency states has not in any way altered the clinical status of patients with SNE, several children have seemed to benefit from the use of very large amounts of thiamine and thiamine derivatives such as thiamine propyldisulfide (TPD) (Pincus et al. 1971a, Sheremata et al. 1971, Weil et al. 1971). Evaluating the results of therapy in any rare condition is difficult, particu- larly so in conditions such as this where spontaneous remissions have been known to occur. It is therefore of great importance to establish as accurately as possible the natural course of the disease, and the frequency, length and completeness of spontaneous remissions; these seem to vary not only from case to case but also within a single family in which more than one child is affected.

    It seemed also to be worthwhile to review the clinical material available in the

    Associate Professor of Neurology, Department of Neurology, Yale University School of Medicine,

    87 333 Cedar St., New Haven, Connecticut 06510.


    literature to discover clues which might be helpful in diagnosis. Most of the cases reported have been substantiated by autopsy, which immediately prejudices the results and makes the disease appear to be almost uniformly fatal. Even so, the disease is marked by extraordinary varia- bility in age of onset, rapidity of onset and course, as well as by the actual symptoms and signs of disturbance. I t is possible that more benign forms of the disease might be discovered if a reliable chemical test for its presence could be developed and a diagnosis sustained without autopsy. Such a test has been devised and is under evaluation as a clinical diagnostic tool (Cooper et al. 1970).

    In this review we have included 86 cases reported in the literature. We have not included 12 more with whom we have had contact through the urinary test we have developed, and who are as yet unreported.

    Age at Onset As can be seen in Table I, the onset of

    illness occurred before one year of age in more than half the reported cases, and before two years in the large majority of cases. Nonetheless considerable variability exists, and two children were in their second decade at the onset of symptoms (Garcin et al. 1956, Tuthill and Henn 1964). More recently, two cases with onset in adult life have been described (Feigin and Goebel 1969), but exceptional features in these cases have led us not to include them in our Tables.

    The development of the symptoms that lead parents to seek medical attention tends to be insidious in most cases, but it is occasionally subacute with symptoms developing over the course of a week to ten days. More than a dozen cases have occurred with an acute presentation, usually in association with seizures (Poser and Van Bogaert 1960, Tuthill 1960, Tom and Rewcastle 1962, Aronson and Okazaki

    TABLE I Clinical features of SNE

    Age at onset of symptoms < 12 months 52/86 -= 24 months 78/86 > 24 months 8/86

    Rhythm of onset Insidious Subacute Acute

    Course length < 12 months < 24 months > 24 months

    61/86 12/86 13/86

    43/83 55/83 27/83

    Course rhythm Chronic unremitting 46/83 Chronic remitting 23/83 Subacute unremi t ting 12/83 Acute unremitting 2/83

    Respiratory 61 Cranial nerves 3-12 57 Hypotonia 51 Movement disorder (cerebellar or extra-pyramidal) 34 Blindness 31 Babinski sign(s) 30 Seizures 21 Absent tendon reflexes 21 Spasticity 13 M icroencephal y 5

    Incidence of symptoms and signs

    1963, Worsley et al. 1965, Anderson 1966, Bignami et al, 1966, Guazzi et al. 1968, Kamoshita et al. 1968, Crome 1970, Montpetit et al. 1971). As can be seen in Table 11, seizures are characteristic of cases with acute presentations, but other- wise are unusual in this disease. It should be noted, however, that two of these cases were microcephalic. Microcephaly has been reported in a total of six cases (Feigin and Wolf 1954, Guazzi et al. 1968, Crome 1970, de Villard 1970), and its presence suggests that the nervous system has been affected in the fetal, perinatal or postnatal period, even in children whose presenting symptoms are acute and whose early de- velopment is said to be unremarkable. The significance of the mode of presentation for the prognosis is suggested by the short course of the illness in those with an acute presentation, as compared with the longer course in those with an insidious present-



    TABLE I1 Comparison of courses between those with acute and insidious onset

    Age at onset of symptoms: < 12 months < 24 months

    Course length: < 12 months < 24 months > 24 months

    Course rhythm: chronic unremitting chronic remitting subacute unremitting acute unremitting


    Acute onset

    Range: 3 to 36 months

    Range: I day to 36 months

    10113 12/13

    8/12 I I j12 1/12

    4/13 4/13 3/13 2/13


    Insidious onset

    Range: birth to 7 years 36/61 51/61

    21/61 31/61 30161

    45/60 13/60 2/60

    15/61 *

    Range: I month to 15 years


    *Five of these lived for longer than 24 months after onset and five for less than 12 months.

    ation. Seizures themselves did not seem to influence the course of the illness.

    Presenting Complaints The presenting complaints tended to be

    fairly uniform when patients became ill in the first year of life (Table 111). In 45 out of the 52 cases reported, weight loss, weak- ness and some degree of psychomotor retardation were prominent features, either alone or in combination. Anorexia and vomiting were very frequent. Eight cases had periodic unexplained fevers, often associated with the acute development of

    TABLE 111 Most common presenting complaints

    Psychomotor retardation

    Vomiting Weight loss Weakness Seizures

    ( 73 64 60 48 48 29

    ( %) 25 12

    12 20


    Fevers I 15 I - I Movement disorder 2 Coma Hemiplegia Blindness

    38 12 12 6

    I - l l 2 1 Nystagmus

    neurological symptoms such as seizures, which were present in 15 of the 52 cases.

    The presenting complaints were much more variable in those who became ill after 18 months of age. Six of the 14 in this age- group had some form of movement prob- lem which included clumsiness, falling, loss of ability to walk or ataxia. Four of the 15 had some form of mental retardation such as loss of speech, progressive apathy, lethargy or frank dementia. Seizures occurred in three, vomiting in only two and hemiplegia in two cases.

    Remissions In most cases the disease is chronic and

    progresses inexorably over more than six months, but occasionally its tempo is subacute, or even acute with death occurring within two weeks of onset. About 25 per cent of the cases have spontaneous remissions (Table IV), but these are seldom complete and often consist merely of a brighter mood or the resolution of an episode of hyperventila- tion. Remissions are usually brief, lasting only for several weeks, but prolonged periods of improvement have been re- ported which lasted for months or even years. In most cases, remissions have been single, though repeated alternation be-



    TABLE IV Remissions in SNE (23 cases reported)*


    Status during remission Normal

    5 Abnormal


    Clearing of acute exacerbation

    Nature of remission 9

    Reversal of chronic trend


    Less than 6 months Length of partial remission 16

    3 I Length of complete remission I More than 6 months 4 1 Early in course Mid-course Late in course

    Timing of remission 8 13

    *Data concerning remissions were often incomplete.

    tween exacerbation and remission have characterized a few cases (Christensen et al. 1956, Worsley et al. 1965, Dunn and Dolman 1969). While remissions may occur early or late in the course of the disease, they are exceedingly rare once respiratory failure develops, particularly when it lasts more than a day. Only two such cases have been reported: in one, remission was in- complete and lasted for 24 weeks (Thieffry et al. 1965); in the other, remission was virtually complete, lasted for several months and was associated with thiamine and TPD therapy (Pincus et al. 1971).

    While more than half the cases lived for less than a year after the onset of symp- toms, 30 per cent of the reported cases have lived for more than two years. The longest reported survivals of 15 years (Namiki 1965), 12 years (Hardman et al. 1968) and 9 years (Peterson and Alvord 1964, Montpetit et al. 1971) suggest that the disease is not wholly incompatible with a prolonged life. It is conceivable, too, that the milder forms of this disease are even more common than the fatal ones which thus far have been the only ones described.

    Exacerbations The disease progresses in a step-wise

    fashion, with exacerbations often associa-

    ted with fever (Christensen et al. 1956, Anderson 1966, Ford 1966, Procopis et al. 1967, Guazzi et al. 1968, Kamoshita et al. 1968, Richter 1968, Dunn and Dolman 1969, de Villard 1970, Montpetit et al. 1971). These may be followed by a period of stabilization, during which no further deterioration and occasionally some im- provement occurs. Death often occurs during an episode of exacerbation and is often associated with fever. It is not easy to determine whether fevers are a mani- festation of the primary central nervous system problem or whether viral illnesses or other exogenous problems cause neuro- logic deterioration. Sudden exacerbations have been noted in 47 cases, most of which were associated with fever. Crome (1970) noted deterioration after a DPT inocula- tion. In case 2 of Ebels t t al. (1969, a pneu- moencephalogram was followed by apnea and death; in the first case of Robinson et al. (1967), sudden deterioration followed an operation; in case 1 of Peterson et al. (1964) upper respiratory infections led to worsen- ing, and in Case 4 of Reye (1969), sudden worsening followed an attack of rubeola. Seizures have preceded episodes of pro- longed apnea (Lewis 1965). Thus, acute exacerbations in a child with a progressive central nervous system problem must suggest the possibility of SNE.



    Variations Within a Family There is less variability of the age of

    onset within families with more than one child involved. In only three of 23 such fam- ilies has the age of onset varied by more than six months. In the cases of Worsely et nl. (1965) and Montpetit et al. (1971) the span was 14 months, and in the case of Peteison and Alvord (1964) it was 23 years. This is important in establishing the generally good prognosis of normal siblings of affected children who have remained in good health for six months beyond the age at which their affected siblings first manifested symptoms.

    The same has not been true of the course of the disease, which has varied by more than 23 years in five of the 23 families reported. The differences in course among siblings have been 23 years (de Villard 1970), 3 years (Feigin and Wolf 1954), 5 years (Peterson and Alvord 1964), 6 years (Montpetit et al. 1971) and 12 years (Namiki 1965). Thus any evaluation of therapeutic measures in which the length of illness in a sibling is used as a control must be regarded with extreme caution.

    Unfortunately, the onset and course has also varied significantly in a single family. Ebels et al. (1965) reported two siblings, of whom one had an unremitting course and the other had partial remissions following acute exacerbations. Feigin and Wolf (1954) reported a similar family in which the boy died during an acute exacerbation at 17 months after an in- sidious illness of five months duration; his sisters illness also began insidiously at the end of her first year, but she enjoyed a six-month period of weight-gain and in- creased strength before relapsing. More dramatic improvement in siblings has seemed to result from certain therapeutic measures such as the use of lipoic acid (Clayton et nl. 1967). The use of thiamine and TPD has more often been associated with marked improvement in patients


    compared with their untreated siblings (Pincus et a/. 1 9 7 1 ~ ; Sheramata et a / . 1971, Weil et al. 1971), but against the general background of variability in this disease, these reports fall short of proof.

    Heredity Data concerning siblings have been in-

    cluded in reports of 48 autopsy-proven cases of SNE. Eighty-six of the siblings have been normal, 15 have had autopsy-proven SNE and in 20 more the diagnosis was almost certain on clinical grounds. Serious medical problems existed in ten other siblings, but a diagnosis of SNE did not seem justified: these consisted of five neonatal deaths, one child who died of pertussis, two children with schizophrenia, one with cerebral palsy and mental retardation and one with a cerebrovascular accident at one year of age. If these ten are included in the group which was unaffected by SNE, the incidence of SNE in siblings of affected children is 26 .8 per cent. This is close to the theoreti- cal 25 per cent expected in an autosomal recessive disorder. That this is indeed the mode of inheritance is further suggested by the high rate of consanguinity in the parents: in five of the 28 families, con- sanguinity was reported in the parents (Feigin and Wolf 1954, Ebels et a / . 1965, Namiki 1965, Robinson et a/. 1967, Guazzi er a]. 1968). Also, the diseas...


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