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Computerized tomography in subacute necrotizing encephalomyelopathy (Leigh disease).

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since there is no clinical o r laboratory evidence for
such. In addition, a short oral course of vitamin E
raised the plasma level to well above average values.
O n the other hand, low plasma levels may reflect an
increased demand for vitamin E as an antioxidant.
Thus, the low levels may be secondary to primary
oxidative damage involving the spinal neurons in
WHD. A similar hypothesis was postulated to explain
vitamin E deficiency in both thalassemia major [4]
and the syndrome of ceroid lipofuscinosis and seablue histiocytes [81. In our series, the 3 infants who
received pharmacological doses of vitamin E orally
reached high plasma levels without any effect on the
course of the disease. The same was observed in the
other two disorders.
Vitamin E acts as a nonspecific antioxidant that
prevents peroxidation of polyunsaturated fatty acids.
The products of peroxidation can be highly damaging
to the cell. I t is of interest that human infant brain,
which is relatively abundant in highly unsaturated
fatty acids, contains less tocopherol than any other
tissue. It is therefore conceivable that the requirement for vitamin E is higher in infants than in adults.
Although the role of vitamin E deficiency in W H D
is not known, two implications are suggested by our
observations: (1)plasma vitamin E levels may be used
as a marker for early detection of W H D in hypotonic
newborns and ( 2 ) high-dose vitamin E therapy may
be indicated in infants with WHD.
Supported by a grant from the Muscular Dystrophy Association of
America.
We thank Dr Gerald Fenichel for valuable comments and Mr P.
Goldfeder, Ms M. Helfer, and Ms N. Ort for devoted technical assistance.
References
1. Geller A, Gilles F, Schwachman H: Degeneration of the fasciculus gracilis in cystic fibrosis. Neurology (Minneap)
27:185-187, 1977
2. Hashim SA, Schuttringer GR: Rapid determination of tocopherol in macro- and micro quantities of plasma. Am J Clin
Nutr 19:137, 1966
3. Pentschew A, Schwartz K: Systemic axonal dystrophy in vitamin E deficient adult rats. Acta Neuropathol (Berl) 1:313-334,
1962
4. Rachmilewitz EA, Shiffer A, Kahane I: Vitamin E deficiency
in P-thalassemia major: changes in hematological and biochemical parameters after a therapeutic trial with a-tocopherol. Am J Clin Nutr 32:1850-1858, 1979
5. Rosenblum JL, Keating JP, Nelson JS, Prensky AL: A progressive neurological syndrome in six children with chronic liver
disease and alpha-tocopherol deficiency. Pediatr Res 12:555,
1978
6. Sung JH: Neuroaxonal dystrophy in mucoviscidosis. J Neuropathol Exp Neurol23:567-583, 1964
7. Sung JH, Stadlan EM: Neuroaxonal dystrophy in congenital
biliary atresia. J Neuropathol Exp Neurol 25:341-361, 1966
8. Swaiman KF, Garg BP, Lockman LA: Sea-blue histiocyte and
268
posterior column dysfunction: a familial disorder. Neurology
(Minneap) 2 5 : 1084- 1087, 197 5
9. Tomasi LG: Reversibility of human myopathy caused by vitamin E deficiency. Neurology (Minneap) 2 9 1 182-1186, 1979
Computerized
Tomography in
Subacute Necrotizing
Encephalomyelopathy
(Leigh Disease)
William J. Schwartz, MD," Harrol T. Hutchison, MD,"
and Bruce 0. Berg, MD"t
The computerized tomographic brain scans of two patients with subacute necrotizing encephalomyelopathy
contained symmetrical focal lesions that corresponded
to the sites of known anatomical abnormalities in this
disease.
Schwartz WJ, Hutchison HT, Berg BO:
Computerized tomography in subacute necrotizing
encephalomyelopathy (Leigh disease). Ann Neurol
10:268-271, 1981
Subacute necrotizing encephalomyelopathy (SNE) is
a rare familial disorder, usually affecting infants and
children, but with onset at any age [3,4].The disease
is characterized by distinctive pathological abnormalities, with symmetrical and focal lesions in the
brainstem tegmentum, lateral walls of the third ventricle, spinal cord, and basal ganglia. Microscopically, capillary proliferation and myelin and dendritic
destruction are seen with relative preservation of
neuronal perikarya and axons [l, 33. Although the
clinical diagnosis is difficult to establish, abnormal
neurological signs include oculomotor and bulbar
dysfunction, weakness, ataxia, dysphagia, and abnormalities of breathing. Pyruvic and lactic acidemia
has been described [6], and evidence suggests that
SNE may be a disorder of brain pyruvate metabolism
[ I , 51.
From the Departments of *Neurology and +Pediatrics, University
of California, San Francisco, School of Medicine, San Francisco,
CA 94143.
Received Nov 19, 1980, and in revised form Feb 18, 1981. Accepted for publication Feb 21, 1981.
Address reprint requests to Dr Berg, Departments of Neurology
and Pediatrics (Child Neurology), University of California, San
Francisco, School of Medicine, San Francisco, CA 94143.
0364-5134/Sl/090268-04$01.25 @ 198 1 by the American Neurological Association
We have recently cared for t w o patients i n w h o m
the diagnosis of SNE was suspected on clinical a n d
biochemical g r o u n d s . CT brain scans s u p p o r t e d t h e
diagnosis: symmetrical focal lesions were o b s e r v e d
that c o r r e s p o n d e d to the sites of known neuropathological changes i n SNE. The diagnosis was confirmed
at autopsy in Patient 1.
Patient 1
A 6-month-old white girl was transferred to the University
of California, San Francisco, Medical Center for neurological evaluation. She was the 3.75 kg product of an uncomplicated full-term pregnancy, labor, and delivery, and her
early development had been normal until she developed
otitis media at the age of 4 months. Thereafter she was
lethargic, had a poor cry, and showed decreased spontaneous movements. The patient’s father had a hemangioma of
the right face and trunk but no seizures, mental retardation,
o r other neurological signs or symptoms.
General physical examination revealed a wasted infant
with a cafi-au-lait spot on the left knee. H e r breathing was
punctuated by occasional inspiratory gasps. Head circumference was 52.5 cm (50th percentile), and the fontanelle
was closed. She was alert but did not interact with examiners, and she had an infrequent and feeble cry. Cranial
nerve examination was notable for inability to maintain
lateral gaze and occasional paroxysms of dysconjugate
horizontal eye movements. She was restless and showed
proximal ballistic and distal choreoathetotic movements,
F i g 1 . C T brain scans in Patient 1 show bilaterally sjmmetvical low-density area in the medial thalamus (arrows i n A )
and thvozlghout the midbrain (arrows in B).
primarily of the right limbs, as well as adventitial niovements of the mouth and tongue. There was less movement
of the left limbs, and tone was moderately increased in
those limbs. She had an obligate tonic neck reflex to the
right. Deep tendon reflexes were brisk and plantar responses were extensor.
The following laboratory studies were unremarkable:
complete blood count, serum electrolytes, glucose, liver
and renal function tests, chest roentgenogram, electrocardiogram, erythrocyte protoporphyrin, serum ceruloplasmin, urinalysis, urine amino acids, ketoacids, mucopolysaccharides, reducing sugars, vanillylmandelic acid, mercury,
and ferric chloride and nitroprusside tests. Arterial oxygen
tension was 122 torr, carbon dioxide tension 22 torr, and
p H 7.55. Serum lactate levels were elevated at 25 and 40
mgldl (normal, 5 to 18).
A lumbar puncture was traumatic, and the cerebrospinal
fluid (CSF) was grossly bloody with 25,500 red cells and 36
white cells (90% polymorphonuclear leukocytes, 794 lymphocytes, 2% monocytes, and 1% eosinophils). CSF glucose was 58 mg/dl, and protein, 60 mddl. Electromyographic studies and nerve conduction velocities were
normal. Brainstem evoked response monaurally on the
right was normal, but on the left, components could not
be identified. The electroencephalogram showed focal slowing in the right temporal leads, and there was no visual
evoked response over the right cortex. The CT brain scan
is shown in Figure 1.
The patient died one month later. Autopsy was performed
and the gross findings were normal. T h e brain weighed 500
gm; cut sections revealed multiple foci of slightly hemorrhagic granularity and softening in the thalamus, subthalamic nuclei, and substantia nigra. Microscopic sections
from the thalamus, subthalamic nuclei, substantia nigra,
and wall of the third ventricle revealed edematous areas of
Case Report: Schwartz et al: C T Scan in Leigh Disease
269
neuronal degeneration with microglial and astrocytic proliferation and a prominent proliferation of capillaries. Sections taken through the mammillary bodies revealed no
pathological abnormalities.
Fig 2. CT brain scans in Patient 2 show bilateral, symmetrical latencies adjacent to the fourth ventricle (arrows in A) as
well as lucencies adjacent to the third ventricle in the anterior
thalamus (arrows in B).
Patient 2
A 12-year-old white boy had been in good health until one
month prior to admission, when, after a “flu-like’’ illness,
he developed a voracious appetite, hyperpnea, and diplopia. His 15-year-old sister was still hospitalized fifteen
months after the onset of an illness characterized by
ophthalmoparesis, limb weakness, and respiratory embarrassment requiring ventilatory assistance. She was said to
have an elevated CSF protein and abnormal brainstem
evoked responses. A clinical diagnosis of SNE had been
made by the neurologist who referred the patient.
The general physical examination was normal except for
a resting tachycardia of 140 beats per minute and occasional inspiratory gasps, although the patient denied dyspnea. Neurological examination revealed a well-developed
boy of normal intellect and mental status. There was no
dysarthria. A left paralytic pontine exotropia, left ptosis,
and mild facial diplegia were found on cranial nerve examination. There was a mild spastic diplegia with abnormally
brisk stretch reflexes, although the ankle jerks were less
brisk than the quadriceps reflexes. Plantar responses were
extensor bilaterally. Heel-to-shin and tandem gait testing
were both mildly ataxic. The sensory examination revealed
a subjective loss of temperature sensation to the knees
bilaterally.
270 Annals of Neurology
Vol 10 No 3
The following laboratory studies were unremarkable:
complete blood count, erythrocyte sedimentation rate,
VDRL, serum electrolytes, glucose, liver and renal function tests, protein electrophoresis, thyroid function tests,
serum ceruloplasmin, urinalysis, urine amino acids, ketoacids, mucopolysaccharides, reducing sugars, urine ferric
chloride, nitroprusside tests, and toxicology screen. Creatine phosphokinase was mildly elevated at 192 IU per
liter (normal, 4 to 88); serum aldolase and glutamic
oxaloacetic transaminase were normal. Arterial oxygen tension was 124 torr, carbon dioxide tension 18 torr, and p H
7.56. Serum lactate was elevated at 23 mg/dl (normal, 5 to
18).
The CSF was clear and colorless with 7 red cells and 3
white cells (all mononuclear); CSF glucose was 55 mgldl
and protein 50 mg/dl, with a normal electrophoresis. Viral
and bacterial cultures were negative. Electromyography
was normal, but motor nerve conduction velocity in the
right common peroneal nerve was slowed to 28 m/sec
(normal, 35.6 to 63.5 d s e c ) . Brainstem evoked response
monaurally on the right was normal, but there was a prolonged latency of wave V on the left. An electroencephalogram was normal. The C T brain scan is shown in Figure 2.
September 1981
Discussion
The clinical diagnosis in these two patients was SNE,
and the CT brain scan appearance was consistent with
the described neuropathological features of this disease. Although there is no pathological confirmation
of the diagnosis in Patient 2 , the distinctive CT brain
scan, when coupled with the constellation of clinical,
neurophysiological, and biochemical findings and the
positive family history, make the diagnosis of SNE
almost certain. A previous report [21 has described
the presence of symmetrical putaminal lucencies in
the CT scan of four patients with SNE; with improved resolution of present CT scans, we now demonstrate the expected subtentorial lesions in the disease.
The authors thank Dr Richard Wicklund and D r Gary Franklin for
referring these patients to the University of California, San Francisco, for evaluation.
References
1. David RB, Mamunes P, Rosenblum W1: Necrotizing encephalomyelopathy (Leigh). In Vinken PJ, Bruyn G W (eds):
Handbook of Clinical Neurology. Vol 28, Metabolic and Deficiency Diseases of the Nervous System, Part 11. New York,
American Elsevier, 1976, chap 14, pp 349-363
2. Hall K, Gardner-Medwin D: CT scan appearances in Leigh's
disease (subacute necrotizing encephalomyelopathy). Neuroradiology 16:48-50, 1978
3. Montpetit VJA, Andermann F, Carpenter S, et al: Subacute
necrotizing encephalomyelopathy: a review and a study of two
families. Brain 94:l-30, 197 1
4. Pincus JH: Subacute necrotizing encephalomyelitis (Leigh's
disease): a consideration of clinical features and etiology. Dev
Med Child Neurol 14:87-101, 1972
5. Pincus JH, Solitaire GB, Itokawa Y , et al: Thiamine, thiamine
triphosphate and nervous system lesions in subacute necrotizing encephalomyelopathy. Neurology (Minneap) 2 1:444, 197 1
6. Worsley HE, Brookfield RW, Elwood JS, et al: Lactic acidosis
with necrotizing encephalopathy in two sibs. Arch Dis Child
40:492-501, 1965
Mveloma Protein
Sinthesis Within the CNS
by Plasma Cell Tumors
Tali Siegal, MD,"? Joshua Shorr, PhD,"
Isabelle Lubetzki-Korn, MD," Dov Soffer, MDJ
Elizabeth Naparsrek, MD,$ Ron Tur-Kaspa, MD,$
and Oded Abramsky, MD, PhD"
Two patients had central nervous system involvement
from plasma cell tumor, one with leptomeningeal
infiltration and the other with solitary intracranial
plasmacrytoma. In both, cerebrospinal fluid (CSF) electrophoresis revealed IgG monoclonal protein and an
elevated IgG index consistent with local synthesis of
the myeloma protein. The CSF findings were helpful in
the diagnosis and evaluation of tumor recurrence.
Siegal T, Shorr J, Lubetzki-Korn I, Soffer D,
Naparstek E, Tur-Kaspa R, Abramsky 0:
Myeloma protein synthesis within the CNS by
plasma cell tumors. Ann Neurol 10:271-273, 1981
Myeloma protein is the marker for myeloma cells.
Evidence of local synthesis of myeloma monoclonal
protein within the central nervous system (CNS)
would indicate the presence of secreting myeloma
cells in the nervous system even if the cerebrospinal
fluid (CSF) showed no cells. It would also increase
the pathological importance of plasma cells found on
cytological examination of the CSF.
We report two patients with CNS involvement by
plasma cell tumors in whom analysis of CSF monoclonal bands and elevated IgG index (CSFlserum IgG
and CSFlserum albumin ratio) helped to make the
diagnosis of CNS involvement and tumor recurrence.
Patient 1
Multiple myeloma was diagnosed in August, 1978, in a
72-year-old woman with severe left sided-headaches of
eight months' duration. The findings of paraproteinemia
(IgG, K type) and a bone marrow examination revealing a
predominance of plasma cells established the diagnosis.
Her past history was noncontributory.
Neurological examination revealed left twelfth nerve
paralysis. A bone survey (including the skull), bone scan,
electroencephalogram, and CT scan were all normal. Mel-
From the Departments of 'Neurology, tOncology, $Pathology,
and §Hematology, Hadasah-Hebrew University Hospital, PO
Box 12000, Jerusalem 91220, Israel.
Received Dec 2, 1980, and in revised form Feb 19, 1981. Accepted for publication Feb 21, 1981.
Address reprint requests to Dr Siegal.
0364-5134/81/090271-03$01.25 @ 1981 by the American Neurological Association 271
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