Thymoma, CMFAS, and peripheral neuropathy may be related through altered immune mechanisms, and the thymoma might be responsible for the development of CMFAS, together with or through peripheral nerve damage. We suggest that the possibility of thymoma should be considered in CMFAS, even though thymectomy does not seem to correct the syndrome.

We thank Dr C . Jimenez for sending us the second patient, Ur I. Illa for determination of anti-acetylcholine receptor antibodies, and Martha Messman for her expert technical assistance.

References 1. lsaacs H. A syndrome of continuous muscle-fibre activitv. . "1 Neurol Neurosurg Psychiatry 1961;24:319-325 2. Coers C , Telermann-Toppet N, Durdu J. Neurogenic benign fasciculations, pseudomyoronia and pseudotetany. A disease in search of a name. Arch.Neuro1 1981;38:282-287 3. Wallis WE, Poznak AV, Plum F. Generalized muscular stiffness, fasciculations, and myokymia of peripheral nerve origin. Arch Neurol 1970;22:430-439 4. Welch LK, Appenzeller 0,Ricknell JM. Peripheral neuropathy with myokymia, sustained muscular contraction, and continuous motor unit activity. Neurology 1972;22:161-168 5. Vilchez JJ, Cabello A, Benedito J, et al. Hyperkalemia paralysis, neuropathy arid persistent motor neuron discharges at rest in Addison's disease. J Neurol Neurosurg Psychiatry 1980;43: 818-822 6. Black JT, Garcia-Mullin R, Good E, et al. Muscle rigidity in a newborn due to continuous peripheral nerve hyperactivity. Arch New01 1972;27:413-42 5 7. Isaacs H , Frere G. Syndrome of continuous muscle fiber activity: histochemical, nerve terminal and end-plate study of two cases. S Afr Med J 1974;48:1601-1607 8. Lublin FD, Tsairis P, Strelecz LY, et al. Myokymia and impaired muscular relaxation with continuous motor unit activity.J Neurol Neuroscrg Psychiatry 1979;42:557-562 9. Oda K, Fukushima N, Shibasaki H, et al. Hypoxia-sensitive hyperexcitability of the intramuscular nerve axons in Isaacs' syndrome. Ann Neurol 1989;25:140-145 10. Bourouresques G, Delpuech F, Giudicelli R, et al. PolyradiculonPvrite au cours d'une myasthknie avec thymome bknin. Nouv Press Med 1981;10:25 3-2 54 11. Bogousslavsky J, Re& F, Doret AM, et al. Encephalopathy, peripheral neuropathy, dysautonomia, myasthenia gravis, malignant thymoma and antiacetylcholine receptor antibodies in the CSF. Eur Neurol 1983;22:301-306 12. Stoll DB, Lublin F, Brodovsky H, et al. Association of subacute motor neuronopathy with thymoma. Cancer 1984;54:770-772 13. Witt NJ, Bolton CF. Neuromuscular disorders and thymoma. Muscle Nerve 1988;11:398-405 14. McComas AJ. Neuromuscular function and disorders. London: Butterworths, 1977:315-317 15. Walsh JC. Neuromyotonia: an unusual presentation of intrathoracic malignancy. J Neurol Neurosurg Psychiatry 1976;39: 1086-1091

Regronal Variation in Brain Lactate in Leigh Syndrome by Localized IH Magnetic Resonance Spectroscopy John A. Detre, MD,+§ Zhiyue Wang, PhD,*P Andrew R. Bogdan, PhD,I( Debra A. Gusnard, MD," Carolyn A. Bay, MD,? Peter M. Bingham, MD,P and Robert A. Zimmerman, MD*

Localized water-suppressed 'H magnetic resonance spectroscopy was performed in an 11-month-old infant with Leigh syndrome. Spectra obtained from the basal ganglia, occipital cortex, and brainstem showed elevations in lactate, which were most pronounced in regions where abnormalities were seen with routine T2weighted magnetic resonance imaging. This approach has allowed us to examine metabolism in brain tissue directly and noninvasively, and may provide a sensitive means for evaluating metabolic disease and the response to therapy in the brain. Detre JA, Wang Z , Bogdan AR, Gusnard DA, Bay CA, Bingham PM, Zimmerman RA. Regional variation in brain lactate in Leigh syndrome by localized 'H magnetic resonance spectroscopy. Ann Neurol 1991;29:218-221

Subacute necrotizing encephalomyelopathy (Leigh syndrome) is an autosomal recessive disorder of infancy and early childhood associated with a multifactorial regional disorder of respiratory metabolism [l-51 and symmetrical spongionecrotic lesions in the basal ganglia, tectum, mesencephalopontine tegmentum, periaqueductal gray matter, and the gracilis fascicles [ 3 , 4, 61. The syndrome is clinically associated with abnormalities of muscle tone, developmental delay, seizures, emesis, intermittent tachypnea, and blindness. The diagnosis of Leigh syndrome is based largely on clinical and neuroradiological observations. Cerebrospinal fluid lactate and pyruvate levels are elevated, and blood levels are usually elevated as well. Due to the inaccessibility of brain tissue for biochemical analysis, muscle biopsy specimens E2-51, liver biopsy specimens E2, 51, and cultured fibroblasts El, 2, 4, 71, as well as other tissues, have recently been used to further characterize

From the Departments of "Radiology, +Genetics and Metabolism, and $Neurology, Children's Hospital of Philadelphia, the §Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, and IlSiemens Medical Systems, Aston, PA.

Received Jun 27, 1990. Accepted for publication Aug 15, 1990. Address correspondence to Dr Detre, Department of Neurology, Hospital of the University of Pennsylvania, 3 W Gates Building, 3400 Spruce Street, Philadelphia, PA 19104.

2 18 Copyright 0 1991 by the American Neurological Association

N AA

I I

cho

A

B

Fig 1. T2-weighted axial magnetic resonance imaging scan through the basal ganglia showing hyperintensity characteristic of high syndrome ( T R = 3.000 msec; TE = 120 mseci. The locdtions in this pbne of 2j-mm3 regions of interest chosen for spectro.rropj1 from the basal ganglia and from a normal appearing region in the occz$itaI lobe are shown.

the biochemical deficits. Here, we report the use of image-localized, water-suppressed 'H magnetic resonance spectroscopy (MRS) to measure regional brain lactate concentrations in a patient with clinical and neuroradiological findings consistent with Leigh syndrome. This approach has enabled us to examine the brain tissue directly and noninvasively, and to correlate regional metabolic changes with lesions observed by magnetic resonance imaging (MRI).

Methods An 1I-month-old female infant with symptoms of hypotonia, lack of visual tracking, and developmental regression suggestive of Leigh syndrome was routinely sedated with Nembutal 6 mdkg (Abbott Laboratories, N. Chicago, IL) i.v. and studied by using MRI and 'H MRS on a Siemens Magnetom SP 1.5 T system (Siemens, Inc, Iselin, NJ). The Siemens circularly polarized adult head coil was used for both MRI and MRS studies. Pulse rate and oxygen saturation were monitored continuously throughout the study by using a Biochem pulse oximeter (Biochem International, Inc, Waukesha, WI). Oxygen saturation exceeded 96%. Routine T1-weighted sagittal and T2-weighted axial images were obtained. Several 25 x 25 X 25-mm3 regions of interest (ROIs) were then chosen from the images for spectroscopy. Localized watersuppressed 'H MRS was then performed by using STEAM [S] with TR = 1,500 msec and TE = 270 msec. Localization of each ROI was confirmed by imaging the selected ROI in orthogonal planes IS}. Spectra were processed by using 4-Hz

I

4.0 C

I

I

3.5

3.0

2.5

2.0

1.5

I

1.0

I

0.5

Chemical Shiftippm

Fig 2. Water-suppressed ' H magnetic resonance spectra obtained from normal covtex (A), occipitd lobe in a patient with Leigh syndrome (B)$and right basal ganglia in a patient with Leigh syndrome (Ci. Spectra are plotted on eqaal signal intensity scaleJ. Singlet resonances from cbolzne (cho, 3.2 ppm), creatine (we, 3.0 ppm), N-acetylaspartate (NAA,2.0 ppm), and the lactate doublet (lac, 1 ..3 ppm) are clear4 resolved. Levels of lactate are elevated in both B and C, whereas N-acetylaspartate is most markedh decreased in C. exponential line broadening, a second order spline baseline correction to selected zero points, and a time-dependent phase correction to compensate for residual eddy currents from the magnetic field gradients [9].Quantification was performed by using peak areas with correction for relaxation using published values for T1 and T2 of metabolites in human brain [lo]. Absolute quantitation was estimated by using a pubhshed value for brain creatine ill].

Results and Discussion T2-weighted MRI (Fig 1) showed hyperintensity symmetrically in the basal ganglia, in periaqueductal gray matter, and in patches of cerebral cortex, characteristic of Leigh syndrome 1121. ROIs were chosen from the abnormal regions in the basal ganglia and brainstem, as well as from a normal appearing region of the occipital

Brief Communication: Detre et al: Brain Lactate in Leigh Syndrome

219

Regional Concentration of Metabolites

Region

Choline (mM)

Creatine (mM)"

NAA (mM)

Lactate (mM)

Normal cortex

1.9

Occipital cortex Basal ganglia

1.7

8.0 8.0 8.0

9.6 6.6 5.4

0.7 1.7

8.0

6.1

1.9

Brainstem

1.8 3.6

3.6

"All spectral intensities were normalized to a creatine concentracion of 8 mM. NAA

=

N-acetylaspartate.

lobe. The locations of two of these ROIs in the axial plane are outlined in Figure 1. 'H MRS from these ROIs are shown in Figure 2. Singlet resonances from creatine, choline, N-acetylaspartate (NAA), and the lactate doublet are well resolved. Resonances from glutamate and glutamine are poorly observed in these spectra due to zero quantum and other effects for these highly coupled species at the echo time used [13]. A spectrum of normal cortex obtained from a 27-month-old child is also shown. Spectra are plotted on equal intensity scales. In the patient's spectra, elevations in brain lactate are observed throughout the brain but are most pronounced in the basal ganglia and brainstem, regions with an abnormal MRI appearance. The increase in lactate is consistent with a deficiency in oxidative substrate utilization, and the regional variation in lactate concentration is indicative of a regional variation in respiratory deficiency. In these regions, a decrease in the NAA resonance is also seen. The role of NAA in brain is unknown, but it is believed to be of neuronal rather than glial origin [ 147. The decrease in NAA is suggestive of neuronal loss. Although MRS is a quantitative technique, absolute quantitation requires an internal or external standard and a knowledge of the relaxation times T 1 and T2 for each metabolite [S, 151. We have estimated the absolute regional concentration of metabolites by assuming a fixed brain concentration for creatine of approximately 8 mM [ll] and by using published values of T1 and T2 for the metabolites in normal brain. The regional concentrations of choline, NAA, and lactate are shown in the Table. Some error in these estimations would be expected if T1, T2, or the creatine concentration were markedly different in the brain sample studied. A recent study using human brain extracts, however, has shown that the creatine concentration is relatively uniform 1111, and in the present study, the creatine resonance produced comparable absolute intensities in all spectra obtained. These results show that regional variations in brain metabolism can be demonstrated by using 'H MRS. Specifically, we have shown abnormally high levels of lactate throughout the brain, with regional variations, in a patient with clinical evidence of Leigh syndrome. 220 Annals of Neurology Vol 29 No 2 February 1991

The measurement of brain lactate is particularly significant in instances where blood lactate levels may not always be elevated C57. The spectroscopically determined brain lactate concentration may also prove to be a sensitive indicator of response to therapy in metabolic disease. Through the use of shorter echo times, a number of other metabolites such as glutamate, glutamine, gamma-aminobutyric acid, and aspartate can be observed reliably by using 'H MRS [13]. An increase in these Krebs cycle-dependent intermediates in addition to lactate might suggest an enzymatic deficiency in the electron transport chain, and would therefore predict a poor response to therapies aimed at increasing pyruvate metabolism, such as thiamine. This would further enhance the usefulness of 'H MRS for diagnosis and evaluation of metabolic disorders of the central nervous system. J.A.D. is a recipient of National Institutes of Health (NIH) Grant HL-07614 and was supported, in part, by NIH Grant RR-02305 and a grant from the McDonnell Foundation.

References 1. Robinson BH, De Meirleir L, Glerum M, et al. Clinical presentation of mitochondrial respiratory chain defects in NADHcoenzyme Q reductase and cytochrome oxidase: clues to pathogenesis of Leigh's disease. J Pediatr 1987;110:216-222 2. Dimauro S, Servidei S, Zeviani M, et al. Cytochrome c oxidase deficiency in Leigh syndrome. Ann Neurol 1987;22:498-506 3. Fujii T, It0 M, Okuno T, et al. Complex I (reduced nicotinamide-adenine dinucleotide-coenzyme Q reductase) deficiency in two patients with probable Leigh syndrome. J Pediatr 1990;116:84-87 4. Martin JJ, Van de Vyver FL, Scholte HR, et al. Defect in succinate oxidation by isolated muscle mitochondria in a patient with symmetrical lesions in the basal ganglia. J Neurol Sci 1988; 84:189-200 5. Van Erven PPM, Gabreels FJM, Ruitenbeek W, et al. Subacute necrotizing encephalomyelopathy (Leigh syndrome) associated with disturbed oxidation of pyruvate, malate and 2-oxoglutarate in muscle and liver. Acta Neurol Scand 1985;72:36-42 6. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 1951;14:216-221 7. Hansen TL, Christensen E, Brant NJ. Studies on pyruvate decarboxylase and lipoamide dehydrogenase in subacute necrotizing encephalomyelopathy. Acta Pediatr Scand 1982;71:263267 8. Frahm J, Bruhn H , Gyngell ML, et al. Localized hgh-resolution proton NMR spectroscopy using stimulated echoes: initial applications to human brain in vivo. Magn Reson Med 1989;$:79-93

9. Klose U. In vivo proton spectroscopy in presence of eddy cur10.

11.

12.

13.

14.

15.

rents. Magn Resun Med 1990;14:26-30 Frahm J, Bruhn H, Gyngell ML, et al. Localized proton NMR spectroscopy in different regions of the human brain in vivo. Relaxation times and concentrations of cerebral metabolites. Magn Reson Med 1989;11:47-63 Petroff OA, Spencer DD, Alger JR, Pritchard JW. High-field proton magnetic resonance spectroscopy of human cerebrum obtained during surgery for epilepsy. Neurology 1989;39: 1197-2202 Medina L, Chi TL, DeVivo DC, Hilal SK. MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): Correlation with biochemical deficit. AJNR 1990; 11:379-384 Frahm J, Michaelis T, Merboldt K-D, et al. Localized NMR spectroscopy in vivo. NMR Biomed 1989;2:188-195 Birken DL, Oldendorf WH. N-acetyl-L-aspartic acid: a literature review of a compound prominent in ‘H-NMR spectroscopic studies of brain. Neurosci Biobehav Rev 1989;13:23-31 Tofts PS, Wray S. A critical asessment of methods of measuring metabolite concentrations by NMR spectroscopy. NMR Biomed 1988;l:l-10

Cerebrospinal Fluid Dynamics in the Tardive Cauda Equina Syndrome of Ankylosing Spondylitis Christian Confavreux, MD,” Jean-Paul Iarbre, MD, 1 Edouard Lejeune, MD,t Marc Sindou, MD,$ and Gilbert Aimard*

Typical cauda equina syndrome secondary to longstanding ankylosing spondylitis is reported in a 63-yearold man. Radionuclide cisternography demonstrated a resorption defect of cerebrospinal fluid in the enlarged lumbosacral dural sac. After transient symptomatic improvement with acetazolamide, a lumboperitoneal shunt was placed. T h e rate of cerebrospinal fluid, isotope resorption became normal. In the 5 years of follow-up, partial remission has been observed. Confavreux C, Larbre J-P, Lejeune E, Sindou M, Aimard G. Cerebrospinal fluid dynamics in the tardive cauda equina syndrome of ankylosing spondylitis. Ann Neurol 1991;29:221-223

Tardive cauda equina syndrome in ankylosing spondylitis (CES-AS) is a rare but well-known entity since From the Tlinique de Neurologie, HBpital Neurologique, and $Service de Neurochirurgie, HBpital Neurologique, Lyon, and +Service de Rhumatologie, HBpitd des Charpennes, Villeurbanne, France. Received Apr 10, 1990, and in revised form Jun 20 and Aug 8, 1990. Accepted for publication Aug 10, 1990. Address correspondence to Dr Confavreux, Clinique de Neurologie, HBpital Neurologique, 59 Boulevard Pinel, 69003 Lyon, France.

Babinski’s pioneer work [l}. To date, 69 cases have been reported 12-7}. Inflammation and fibrosis predominating o n dura matter and epidural space associated with enlargement of the caudal sac, narrowing of epidural space, adherence of dura matter to adjacent bony and ligamentous structures, and bony erosions of laminae and spinous processes are the basic radiological [Z, 81, surgical 13-5, 7, 9-11], and pathological C6, 121 features. The long interval separating the onset of ankylosing spondylitis (AS) and cauda equina syndrome (CES) and the common finding that AS has been burned out for several years when CES begins suggests that active inflammation is not directly involved in its pathogenesis. Alternatively, retractile fibrosis in the epidural space could lead t o a “between-trunk-andbark” variety of entrapment syndrome. We report a patient, with study of the cerebrospinal fluid (CSF) dynamics by isotopic techniques. A resorption defect of the isotope from the caudal sac was observed. Correction by lumboperitoneal shunting resulted in partial improvement of radicular pain.

Patient Report A 63-year-old, HLA-B27 positive, graduate engineer suffered from a relapsing form of AS since the age of 23 years. Sacroiliac joints and spine became fused with pronounced kyphosis. In 1956, vertebral osteotomy with posterior osseous graft was performed at the T12-L1 level for correction of the spinal deformation. During the subsequent years, inflammationand pain in the joints subsided and analgesics and anti-inflammatory drugs could be stopped. The patient never received radiation therapy to the spinal column for AS. A new pain in the L-5, S-1, and S-2 distributions began in 1968, at age 51 years, predominantly on the left side, with severe exacerbations due to mechanical factors. In 1974, water-soluble contrast medium myelography showed an enlarged and lobulated lumbosacral dural sac with no evident radicular compression (Fig 1A). Pain worsened progressively and became chronic and severe. At admission in May 1980, loss of cutaneous sensation on left perianal region, heel, and sole, slight weakness on the left in L-5 innervated muscles, and bilateral ankle areflexia were present. Erythrocyte sedimentation rate was normal. Total protein level was 280 mg/ L, and white cell count was 2 per cubic millimeter in CSF. Lumbosacral mega cul-de-sac was more apparent on metrizamide myelography as well as erosion of posterior walls of the vertebral bodies (scalloping) and a posterior lobulated meningocele predominantly at the L-4 level (Fig 1B). Computed tomographic (CT) scan confirmed erosion of the laminae and posterior spinous processes on their axial side in the lumbosacral region (Fig 2). Electromyography with needle electrode examination showed fibrillations and decreased numbers of motor unit potentials bilaterally in the L-4, L-5, and S-1 root distribution, consistent with neurogenic abnormalities. F waves were delayed or abolished. Nerve motor and sensory conductions were slowed in the lower limbs (30-36 misec). Noramidopyrine had a partial analgesic effect, but transcutaneous electrical stimulation, carbamazepine, steroids, isaxo-

Copyright 0 1991 by the American Neurological Association

221