Therapeutic efficacy of a case of pyruvate dehydrogenase complex deficiency monitored by localized proton magnetic resonance spectroscopy

Magnetic

Resonance

Imaging, Vol. 14, No. 1, pp. 129-133, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0730-725X/96 $15.00 + .OO

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0 Case Report THERAPEUTIC EFFICACY OF A CASE OF PYRUVATE DEHYDROGENASE COMPLEX DEFICIENCY MONITORED BY LOCALIZED PROTON MAGNETIC RESONANCE SPECTROSCOPY MASAFUMI

HARADA, * MIKI TANOUCHI,* KAEKO ARM,* HIROMU HIROKAZU MIYOSHI, $ AND TOSHIAKI HASHIMOTO~

NISHITANI,”

Departments of *Radiology and tpediatrics, School of Medicine and SDepartment of Radiological Technology, School of Medical Science, University of Tokushima Kuramoto-cho, 3-18-15, Tokushima, Japan We experienced a case of pyruvate dehydrogenase deficiency observed by proton magnetic resonance spectroscopy(‘H MRS). This case was diagnosed as West syndrome by characteristic convulsion and the periodic hypsarrhythmia pattern of EEG. At the age of 11 months, the first examination of ‘H MRS revealed a high peak of lactate, and the high concentration of lactate and pyruvate was confirmed in sampled cerebrospinal fluid (CSF). Deficiency of pyruvate dehydrogenase complex was finally diagnosed by genetic examination. Dichloroacetate was administered to the patient as therapy. Decrease of lactate in the brain was found by ‘H MRS. Lactate and pyruvate in the CSF was also decreased. In accordance with the suspension of dichloroacetate, increase of lactate in the brain was detected and the convulsions reappeared. After readministration of dichloroacetate, the patient was almost symptom free and lactate in the brain and CSF had decreased to the normal extent. We considered that ‘H MRS provides useful information for screening metabolic disorders of infants and assessingthe efficacy of therapy. Keywords: ‘H MRS; West syndrome; Pyruvate; Lactate; Dichloroacetate.

by electroencephalograph (EEG). We diagnosed this patient as West syndrome due to the characteristic generalized myoclonic seizure and EEG pattern. The first examination by ‘H MRS and MRI was conducted on the patient at the age of 11 months when the spasm was suppressed by anticonvulsant for 1 wk. For the measurement of MRI, a short spin-echo sequence (TR = 500 ms, TE = 15 ms, acquisition = 3 times) and a double echo long spin-echo sequence (TR = 2000 ms, TE = 22 and 90 ms, acquisition = 1 time) were used. The sequence for ‘H MRS was PRESS (spin-echo sequence) and the measurement conditions were as follows: TR = 1500 ms, TE = 270 ms, sum of FIDs = 200, total measurement time = 5 min; Chess pulse was used for water suppression. The voxel of 3.4 ml was placed in the rt. parietal lobe. The spin-echo was sampled by 1024 complex data points with a sampling width of 500 Hz using a lowpass filter of 0.5 Hz. The raw FID

INTRODUCTION

West syndrome is an infantile spasm and includes various pathological disorders. Tuberous sclerosis is a frequent disease that occurs in West syndrome. We experienced a case of West syndrome resulting from a deficiency of pyruvate dehydrogenase complex (PDHC). In our case, ‘H MRS played an important role in the diagnosis of PDHC deficiency. Furthermore, the correct diagnosis led to efficacious therapy by administration of dichloroacetate(DCA). ‘H MRS was also used to assess the efficacy of therapy noninvasively. CASE

The gestation of this patient was normal and the Apgar score was 10 at birth. The patient had no history of hypo-oxygenation. Convulsion appeared from the age of 10 months and periodic hypsarrhythmia, which is a characteristic pattern of West syndrome, was found

RECENED

12/19/94;

ACCEPTED

Address correspondence to Masafumi Harada.

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Therapeutic efficacy of pyruvate dehydrogenase deficiency 0 M. HARADA

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Fig. 1. MR images of the brain on this patient before any therapy. (a) T,-weighted image, (b) T2-weighted image. The high intensity in the white matter is shown.

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Fig. 2. (a) ‘H MR spectra of the brain on this patient before any therapy. Abbreviations are the same in the text. The high lactate peak is shown. (b) ‘H MR spectra of the brain during the first DCA therapy. Lactate is decreased. (c) ‘H MR spectra of the brain after the suspension of DCA therapy. The high peak of lactate was found again. (d) ‘H MR spectra of the brain during the second DCA therapy. Lactate is not easily confirmed.

of PDHC deficiency depends on the measurement of PDHC activity in cultured fibroblast cells and genetic examination.* In this case, pyruvate was not detected by ‘H MRS because the concentration of pyruvate was under the limit of sensitivity, but lactate was shown clearly even when the spasm was suppressed by anticonvulsant. It has been shown that repeated seizures cause increase of lactate in the brain,3 and we were not able to completely deny induction of lactate by seizures in our case as well. However, it was reported that the increase in extracellular lactate level is limited to the site of the seizure and depends on the neuron activity.4 We considered that lactate would be gradually washed out from the brain when the seizure was arrested, and the high peak of lactate in our case suggested the possibility of metabolic disorder and suppression of TCA cycles. There are some reports of ‘H MRS examinations that have shown an increase of lactate in the infantile brain,5-s and the reported diseases were hypo-oxygenation? mitochondrial encephalopathy (MELAS, etc.),6

malignant neoplasm,’ and hypoperfusion (infarction, etc.).8 Most cases of mitochondrial encephalopathy were caused by disorder of cytochrome C oxidase.9s10 To our knowledge, there are no reports of PDHC deficiency observed by ‘H MRS. Our first examination of ‘H MRS prompted a pediatrician to measure lactate and pyruvate, which led to a definitive diagnosis of PDHC deficiency. DCA was highly effective as therapy in our case and decrease of lactate was confirmed by assay of the CSF and ‘H MRS. ‘H MRS revealed the changes in lactate noninvasively and repeatedly. CSF sampling by lumbar puncture holds the high risk of nerve injury and infection in addition to incurring a high medical expense. We considered that ‘H MRS is more suitable for the follow-up study than CSF sampling, because of its noninvasive nature, and low risk and low cost (‘H MRS following MRI study requires only the electricity charge and there is no expense for patients in Japan). NAA is considered to be a neuron-specific substance, and the decrease of NAA suggests dysfunction

Therapeuticefficacyof pyruvate dehydrogenasedeficiency0 M. HARADA ET AL.

or delayed neuron development. Because it is difficult to obtain absolute values by ‘H MRS, we calculated the intensity ratios of NAA/Cho for the comparative evaluation of DCA therapy. Some other groups and ourselves have reported that the NAA/Cho ratio showed a change in neuronal development.“-l3 The NAA/Cho ratio increases remarkably until 2 yr of age and increases slowly after 2 yr until adult age. Compared to such a result, the NAA/Cho ratio in this patient was low and growth-dependent development was not found. Only the fourth ‘H MRS measurement after the second DCA therapy showed a slight increase of the NAA/Cho ratio. Although neuron development might have been induced by therapy, further long-term follow-up study will be required. MRI is indispensable for screening the cause of seizure and is usually conducted on all patients of epilepsy. We considered that ‘H MRS offers important information for diagnosis and therapy in the short measurement time following MRI study, and repeated CSF sampling for assessment of the therapeutic efficacy should be replaced by ‘H MRS. The combination of MRI and ‘H MRS study will contribute to clinical management of PDHC deficiency and other hyperlactemia. However, the differential diagnosis between PDHC deficiency and other hyperlactemia, especially mitochondrial encephalopathy, may be difficult. Acknowledgment-This work was supported in part by a Grant-inAid for Scientific Research (1994-1995, #06857059) from the Japanese Ministry of Education, Science, and Culture.

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