- Email: [email protected]
18Fluoro-2-deoxyglucose (18FDG) PET scan of the brain in propionic acidemia: clinical and MRI correlations
Brain & Development 21 (1999) 312±317
Original article 18
Fluoro-2-deoxyglucose ( 18FDG) PET scan of the brain in propionic acidemia: clinical and MRI correlations
M. Al-Essa a, S. Bakheet b, Z. Patay b, L. Al-Shamsan a, A. Al-Sonbul a, J. Al-Watban b, J. Powe b, P.T. Ozand a, c,* a
Department of Pediatrics,King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Department of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia c Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia b
Received 10 June 1998; received in revised form 21 January 1999; accepted 25 March 1999
Abstract The clinical data and the imaging ®ndings of the positron emission tomography (PET) and the magnetic resonance imaging (MRI) studies in ®ve patients, previously diagnosed to have propionic acidemia, were retrospectively reviewed. The patients were all normal at birth. The ®rst clinical signs, typically hypotonia and failure to thrive, appeared during the ®rst 2 years of life. With progression of the disease, the neurological ®ndings consisted of variable degrees of dementia and extrapyramidal symptoms, notably dystonia, choreoathetosis and rigidity of variable degrees. Initial cerebral PET and MRI studies were normal. Follow-up MRI examinations showed progressive basal ganglia degeneration, with evidence of atrophy and signal abnormalities within the caudate nuclei and the putamina. The thalamic structures were normal. The PET studies demonstrated increased uptake in the basal ganglia and thalami, followed by decreased uptake in the basal ganglia at a later stage of the disease. The structural (MRI) and the functional (PET) studies of the brain were found to be complementary in the evaluation of propionic acidemia, and were in good correlation with the clinical ®ndings. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Propionic acidemia; 18FDG PET, and MRI brain scans; Neurological ®ndings
1. Introduction Propionic acidemia is an autosomal recessive metabolic disorder. It is caused by the de®ciency of propionyl carboxylase, an enzyme involved in the metabolism of l-isoleucine [1,2]. The disease often presents with precipitous neonatal metabolic decompensation of such severity that most neonates probably die before a diagnosis is reached. In other patients, the disease is characterised by progressive encephalopathy with central hypotonia of varying severity [3], and in severe cases, by symptoms of basal ganglia disease [4,5]. A more indolent form may manifest later in infancy, with either extrapyramidal symptoms or with seizure disorders. Propionic acidemia is a rare disorder in Western countries. Its incidence is reported between 1:50 000 [6] and 1:500 000 births [7]. Conversely, the disease is encountered
* Corresponding author. Department of Pediatrics, MBC #58, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211 Saudi Arabia, Tel.: 1 966-1-442-7762; fax: 966-1-442-7858/7784. E-mail address: [email protected] (P.T. Ozand)
as a relatively common organic acidemia in Saudi Arabia, occurring in 1:2000±5000 births depending on the region [8,9]. This may be due to the high consanguinity among the population and to a high identi®cation rate through the nation-wide neonatal metabolic screening program. We present our experience based on the brain 18¯uoro-2-deoxyglucose PET and the MRI studies of ®ve paediatric patients and correlate the results with the clinical ®ndings. 2. Materials and methods The Inborn Errors of Metabolism Unit at King Faisal Specialist Hospital and Research Centre is a referral Centre in Saudi Arabia for the management of patients with diverse metabolic disorders. Our ®les contain the data on approximately 2000 patients with various con®rmed congenital metabolic disorders, including 50 patients with propionic acidemia. The diagnosis of propionic acidemia is made using a standard technique of blood tandem mass spectrometry (MS/MS) and urine gas chromatography/mass spectrometry (GC/MS), as described previously [10]. Five patients (age range: 2±5 years) had both cerebral
0387-7604/99/$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S03 87-7604(99)0003 0-3
M. Al-Essa et al. / Brain & Development 21 (1999) 312±317
313
Table 1 Presentation of patients with propionic acidemia and their current clinical status a Current Age at onset Age Patient #1 5 years Patient #2 3 1/2 years Patient #3 4 1/2 years Patient #4 2 years Patient #5 2 years
Age at diagnosis
Consanguinity (Neonatal deaths)
Sex Lethargy, poor Seizure Mental feeding, retardation acidosis
Extrapyramidal Hypotonia Failure to signs thrive
Birth Birth
15 Days 24 Days
Yes (2) Yes (2)
F M
1 111
Yes Yes
Moderate Moderate
Moderate Moderate
Severe Moderate
Moderate Moderate
6 Days
17 Days
Yes (±)
F
1
No
Mild
Mild
Mild
2 Days Discovered by screening program
13 Days 1 Day
Yes (±) Yes (3)
F M
11 2
No No
No No
Mild to Moderate Mild Mild
Mild Mild
Mild Mild
a Extrapyramidal signs (involuntary movements and alterations in muscle tone); mild: barely noticeable, moderate: clinically obvious and affecting posture, standing and walking, severe: present at sleep. Mental retardation as determined by intelligence quotient (I.Q.): mild, I.Q. 52-67; moderate, I.Q. 36-51; severe, I.Q. 20-35.
18
¯uoro-2-deoxyglucose PET and MRI examinations of the brain. The imaging studies were performed within a onemonth interval; therefore, they were felt to be comparable. The patients were sedated if necessary for the examinations by 75 mg/kg orally administered chloral hydrate. All brain MRI studies were performed on 1.5 Tesla superconductive magnets. Typical imaging protocols included conventional non-enhanced sagittal and transverse T1weighted spin echo, axial proton density, and T2-weighted spin echo or fast echo sequences, using circularly polarised head coils [4]. The 18¯uorine was produced in-house, using a 30 MeV cyclotron and 18¯uoro-2-deoxyglucose ( 18FDG) was produced using a commercial automated synthesis technique (CTI, Knoxville, TN.) All patients were studied after fasting for at least 4 hours. Normoglycemia was con®rmed by plasma glucose determination prior to injection. The patients were injected while comfortably resting in a quiet, dimly lit room. Each patient was injected with 100 to 370 MBq of 18FDG (adjusted according to patient's weight), given as a bolus intravenously. Imaging began 45 to 60 min later. Data was acquired for 30 min, using Siemens Exact 47 PET scanner (Siemens Medical System, Hoffman Estates IL) and reconstruction was performed, using Shepp 0.34 ®lter and the manufacturer's autoattenuation software. Images reconstructed at a slice thickness of 0.3375 cm were then analysed directly on the computer monitor [11]. When necessary, images were compared with available CT and/or MRI studies in order to accurately localise relevant structures on the PET images. A consensus reading to arrive at the ®nal interpretation of all individually interpreted PET scans combined the interpretations of twoexperienced nuclear medicine physicians. Only visual analysis was performed and the metabolic activity of the different cerebral structures was graded as increased, normal, absent, mildly reduced, moderately reduced, or severely reduced.
3. Results 3.1. Clinical data All ®ve patients were born in consanguineous families. They presented with vomiting, lethargy and acidosis early in life, typically during the ®rst month of life. In three subjects, there was a positive family history of early neonatal deaths. Ages varied between 2 and 5 years. Failure to thrive was evident in all subjects. This was felt to be due to poor nutrition and repeated acidotic crisis with vomiting. Neurologically, three patients had mild hypotonia and extrapyramidal signs; however, their mental status remained normal. Two patients had moderate to severe hypotonia, extrapyramidal signs, and mental retardation with frequent tonic-clonic seizures. Table 1 summarises the initial clinical presentation, family history, and current neurological status of the ®ve patients. 3.2. PET ®ndings The cerebral PET scans performed in two patients at 1 month of age were found to be normal in one (Fig. 1A), and in the other who exhibited a secondarily generalised seizure disorder (electroencephalogram showed left temporal lobe spike discharges), the PET images (done within 3 days of the seizures) were also normal; however, a focal area of increased uptake in the medial portion of the left temporal lobe was detected, this was believed to correspond to the seizure focus (Fig. 1B). With further progress of the disease and the appearance of mild extrapyramidal symptoms as described above, the PET studies performed in two patients, showed increased 18FDG uptake in the thalami and basal ganglia bilaterally (Fig. 1C). At a later stage, approximately 2 years of age, follow-up PET scan in two patients with moderate to severe extrapyramidal symptoms, revealed a generalised decreased uptake of 18FDG in the basal ganglia (Fig. 1D).
314
M. Al-Essa et al. / Brain & Development 21 (1999) 312±317
Fig. 1. 18FDG PET images of the brain in propionic acidemia. (A) At 1 month of age: the PET scan is normal (patient # 4). (B) In this patient (who had a seizure disorder at one month of age) a striking focal area of increased uptake in the medial portion of left temporal lobe is conspicuous (patient # 1). (C) Initially there is diffuse uptake of the tracer in the thalami and basal ganglia (involving the putamen and the caudate nuclei). There is a relatively decreased cortical uptake (patient # 5 at 2 months of age). (D) Finally, parallel to the disease progress, signi®cant decreased uptake in the head of the caudate nuclei and moderate reduced metabolic activity in the putamina become apparent. The thalamic activity normalises (patient # 2 at 2 years of age).
3.3. MRI ®ndings The MR images were evaluated for morphological and signal abnormalities of the brain and in particular, the basal ganglia. The results showed good correlation with those of the PET studies. The MR images performed in two patients at 1 month of age were normal (Fig. 2A,B). Parallel to the clinical progression of the disease, symmetrical involvement of the basal ganglia became apparent, consisting of abnormal faintly increased signal intensity on the T2-weighted fast spin echo images (Fig. 2D), at the level of the putamina, globi pallidi and the heads of the caudate nuclei in conjunction with a suggestion of swelling. Signal abnormalities are not conspicuous on the T1weighted image. Typically, the thalamic structures remained essentially normal (Fig. 2C).
In the advanced stage of the disease, atrophy (Fig. 2E), and abnormal hypersignal of the heads of the caudate nuclei, the anterior parts of the putamina, and the globi pallidi become evident (Fig. 2F). Also, diffuse white matter signal abnormalities, consistent with delayed mylination and/or dysmylination and brain atrophy were seen. The degree of central nervous system involvement as imaged by these two techniques may vary from one patient to another; however, the observed abnormalities showed the same pattern of progression. 4. Discussion Propionic acidemia is an autosomally inherited inborn
M. Al-Essa et al. / Brain & Development 21 (1999) 312±317
315
Fig. 2. Brain MR imaging ®ndings in propionic acidemia (T1- and T2-weighted images). Initial MRI in a 1-month-old child shows normal morphology with no abnormal signal intensity of the basal ganglia (A, B) (patient #1). Parallel to the progression of the disease, the T2-weighted image (D) shows an abnormal, faintly increased signal intensity appearance of the putamina, the heads of the caudate nuclei and the globi pallidi in conjunction with a suggestion of swelling. Signal abnormalities are not conspicuous on the T1-weighted image (C). The thalamic structures are normal (patient # 4 at 1 year of age). In the advanced stage of the disease, atrophy (E), and abnormal hypersignal of the heads of the caudate nuclei, the anterior parts of the putamina, and the globi pallidi, and diffuse cerebral atrophy are evident (F) (patient # 2 at 3 years of age).
error of L-isoleucine metabolism. It may present both as an acute or chronic metabolic disorder of the organic acidemia type. In the neonatal period, it is characterised by a prodrome of feeding dif®culty, lethargy and vomiting, commonly confused with pyloric stenosis [12,13]. If not diagnosed and treated promptly, the disease progresses rapidly leading to frank metabolic acidosis and coma. Eventually, severe thrombocytopenia develops and it is not uncommon for infants to expire due to intracranial bleeding [8,14]. If the patient survives the initial metabolic crisis, the early manifestation of the disease is central hypotonia
[8,15], and in severe cases, extrapyramidal symptoms (rigidity, dystonia and choreoathetosis) appear due to basal ganglia degeneration [4,5]. The disease may be asymptomatic [16] or present in adulthood as chorea and dementia [17]. In our series, there was no apparent correlation between the severity of the disease (Table 1) and the biochemical parameters tested (plasma propionylcarnitine level and propionylcarnitine/acetylcarnitine ratio as assessed by MS/ MS, and urinary 3-hydroxypropionic acid and propionylglycine levels as assessed by GC/MS). To our knowledge, at
316
M. Al-Essa et al. / Brain & Development 21 (1999) 312±317
present there are no markers that can be used reliably to monitor the clinical progression of the disease. Despite the unequivocal laboratory evidence of propionyl-CoA carboxylase de®ciency, the neurological symptoms may not develop at all in some individuals, including adults [16]. The explanation for this is poorly understood. The pathogenesis of the disease is not clear and may be related to the toxicity of the propionic acid itself [18]. A patient with propionic acidemia presents a management challenge. The recent availability of carnitine [19,20], particularly the intravenous form, has facilitated both the acute and chronic care. Unfortunately, repeated episodes of infections, vomiting and anorexia [21] create a vicious circle ultimately resulting in chronic malnutrition and the patients fail to thrive. Our experience suggests that during an episode of acute metabolic decompensation, the patient should be treated vigorously with IV carnitine, with 10% dextrose or total parenteral nutrition, and in severe cases with insulin [22]. Recently, aminoacid mixture, restricted to the appropriate amino acids has become available for this purpose [23]. It is advisable to give these patients metronidazole to decrease the production of propionic acid by intestinal bacteria [24,25]. All patients should receive biotin [26]. Despite of the intensive treatment with these therapeutic modalities, some of our patients advanced to the terminal stage of the disease, which may re¯ect the natural progression of the severe phenotypic variety. 18 Fluoro-2-deoxyglucose PET scanning has been found to be a sensitive indicator of the altered brain metabolism in diverse pathologies of the central nervous system [11]. However, we are unaware of any report of PET ®ndings in propionic acidemia. Our data suggests that in the initial stages of propionic acidemia both the MRI and PET studies of the brain indicate normal ®ndings (Figs.1A and 2A). With progression of the disease, an increased uptake of 18FDG in the striatum is followed by the absence of glucose metabolism. This is demonstrated by PET and ®ndings correlated at a latter stage with the morphological changes visualised by MRI. These neuroimaging ®ndings indicate the particular vulnerability of these structures. As expected, the basal ganglia disease invariably presented with extrapyramidal symptoms in the form of rigidity, choreoathetosis and dystonia. We speculate that the degeneration of the fronto-striatal system, which plays an important role in cognitive and motor functions, may be a determinant in the pathophysiology of neurological abnormalities in propionic acidemia. The global developmental delay as observed in some patients is partly explained by repeated acidotic attacks, vomiting, poor feeding, recurrent infections, and chronic propionate toxicity leading to poor nutrition, failure to thrive, and inertia. This is manifested as a progressive encephalopathy and re¯ected by generalised brain atrophy (Fig. 2E) and decreased 18FDG cortical uptake (Fig. 1C). In our experience, the cerebral PET and MRI ®ndings generally show good correlation with the clinical severity
of the disease. PET scan studies showed decreased 18FDG uptake in the basal ganglia, notably at the level of the heads of the caudate nuclei and putamina in an advanced stage of the disease, which preceded the MRI morphological changes. This is not surprising, since this patient had frank extrapyramidal symptoms at the time of the imaging work-up. It is interesting that one patient (Fig. 1B) had a seizure detected by PET scan as a striking focal area of increased uptake in the medial portion of the left temporal lobe. His MRI and PET examinations were otherwise normal. The degree of the central nervous system involvement, as assessed by these two techniques, may vary from one patient to another, however the pattern and the progression of the imaging abnormalities are similar. The thalami in all patients were normal by MRI. PET scan revealed initial increased uptake followed by normalisation of glucose metabolism in these structures. However, PET could not identify the white matter abnormalities that are readily detected by MRI. 5. Conclusion 18
Fluoro-2-deoxyglucose PET of the brain is a highly sensitive technique for detecting early metabolic abnormalities (i.e. decreased glucose uptake) in the basal ganglia and the cerebral cortex in propionic acidemia patients. Magnetic resonance imaging was found to be more accurate in the detection of morphological changes, such as brain atrophy and necrosis of the basal ganglia, and white matter abnormalities. The functional changes indicated by 18FDG PET and the structural abnormalities shown on MRI were found to be complementary in the imaging evaluation of propionic acidemia. Acknowledgements The authors would like to thank Dr. Sultan Al-Sedairy, the Executive Director of the Research Centre, King Faisal Specialist Hospital and Research Centre, for his kind and continuous support. Part of this work was done under funds provided by Sheikh Ra®q Al-Hariri (Research Centre Grant #85-0030). References [1] Barnes ND, Hull D, Balgobin L, Gompertz D. Biotin-responsive propionic acidemia. Lancet 1970;2:244±245. [2] Brandt IK, Hsia YE, Clement DH, Provence SA. Propionic acidemia (ketotic hyperglycinemia): dietary treatment resulting in normal growth and development. Pediatrics 1974;53:391±395. [3] Surtees RA, Matthews EE, Leonard JV. Neurologic outcome of propionic acidemia. Pediatr Neurol 1992;8:333±337. [4] Brismar J, Ozand PT. CT and MR of the brain in disorders of the propionate and methylmalonate metabolism. Am J Neuroradiol 1994;15:1459±1473.
M. Al-Essa et al. / Brain & Development 21 (1999) 312±317 [5] Hamilton RL, Haas RH, Nyhan WL, Powell HC, Grafe MR. Neuropathology of propionic acidemia: a report of two patients with basal ganglia lesions. J Child Neurol 1995;10:25±30. [6] Lehnert W, Sperl W, Suormola T, Baumgartner ER. Propionic acidemia: clinical, biochemical and therapeutic aspects. Experience in 30 patients. Eur J Pediatr 1994;1(Suppl.):S68±S80. [7] Lemieux B, Auray-Blais C, Giguere R, Shapcott D, Scriver CR. Newborn urine screening experience with over one million infants in the Quebec network of genetic medicine. J Inherited Metab Dis 1988;11:45±55. [8] Ozand PT, Rashed M, Gascon GG, et al. Unusual presentations of propionic acidemia. Brain Dev 1994;16:46±57. [9] Rashed M, Ozand PT, al Aqeel A, Gascon GG. Experience of King Faisal Specialist Hospital and Research Center with Saudi organic acid disorders. Brain Dev 1994;16:1±6. [10] Rashed MS, Ozand PT, Bucknall MP, Little D. Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids pro®ling using automated electrospray tandem mass spectrometry. Pediatr Res 1995;38:324±331. [11] Assessment: positron emission tomography. report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology, Neurology 1991;41:163-167. [12] Katzman PJ, Arnold G. Propionic acidemia presenting as pyloric stenosis. Clin Pediatr 1995;34:613±615. [13] Lehnert W, Junker A, Wehinger H, Zoberlein HG, Baumgartner R, Ropers HH. Propionic acidemia associated with hypertrophic pyloric stenosis and bouts of severe hyperglycemia. Montasschr Kinderheilkd 1980;128:720±723. [14] Stork LC, Ambruso DR, Wallner SF, et al. Pancytopenia in propionic acidemia: hematologic evaluation and studies of hematopoiesis in vitro. Pediatr Res 1986;20:783±788.
317
[15] Al Essa M, Rahbeeni Z, Jumaah S, et al. Infectious complications of propionic acidemia in Saudi Arabia. Clin Genet 1998;54:90±94. [16] Wolf B, Paulsen EP, Hsia YE. Asymptomatic propionyl CoA carboxylase de®ciency in a 13-year-old girl. J Pediatr 1979;95:563±565. [17] Sethi KD, Ray R, Roesel RA, et al. Adult-onset chorea and dementia with propionic acidemia. Neurology 1989;39:1343±1345. [18] Steinman L, Clancy RR, Cann H, Urich H. The neuropathology of propionic acidemia. Dev Med Child Neurol 1983;25:87±94. [19] Roe CR, Millington DS, Maltby DA, Bohan TP, Hoppel CL. L-Carnitine enhances excretion of propionyl coenzyme A as propionylcarnitine in a propionic acidemia. J Clin Invest 1984;73:1785±1788. [20] Wolff JA, Carroll JE, Le PhucThuy, Prodanos C, Haas R, Nyhan WL. Carnitine reduced fasting ketogenesis in patients with disorders of propionate metabolism. Lancet 1986;1:289±291. [21] Hyman SL, Porter CA, Page TJ, Iwata BA, Kissel R, Batshaw ML. Behaviour management of feeding disturbances in urea cycle and organic acid disorders. J Pediatr 1987;111:558±562. [22] Kalloghlian A, Gleispach H, Ozand PT. A patient with propionic acidemia managed with continuous insulin infusion and total parenteral nutrition. J Child Neurol 1992;7:S88±S91. [23] Kahler SG, Millington DS, Cederbaum SD, et al. Parenteral nutrition in propionic and methylmalonic acidemia. J Pediatr 1989;115:235± 241. [24] Koletzko B, Bachmann C, Wendel U. Antibiotic therapy for improvement of metabolic control in methylmalonic aciduria. J Pediatr 1990;117:99±101. [25] Thompson GN, Chalmers RA, Walter JH, et al. The use of metronidazole in management of methylmalonic and propionic acidemias. Eur J Pediatr 1990;149:792±796. [26] Wolf B, Feldman GL. The biotin-dependent carboxylase de®ciencies. Am J Hum Genet 1982;34:699±716.
Original article 18
Fluoro-2-deoxyglucose ( 18FDG) PET scan of the brain in propionic acidemia: clinical and MRI correlations
M. Al-Essa a, S. Bakheet b, Z. Patay b, L. Al-Shamsan a, A. Al-Sonbul a, J. Al-Watban b, J. Powe b, P.T. Ozand a, c,* a
Department of Pediatrics,King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Department of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia c Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia b
Received 10 June 1998; received in revised form 21 January 1999; accepted 25 March 1999
Abstract The clinical data and the imaging ®ndings of the positron emission tomography (PET) and the magnetic resonance imaging (MRI) studies in ®ve patients, previously diagnosed to have propionic acidemia, were retrospectively reviewed. The patients were all normal at birth. The ®rst clinical signs, typically hypotonia and failure to thrive, appeared during the ®rst 2 years of life. With progression of the disease, the neurological ®ndings consisted of variable degrees of dementia and extrapyramidal symptoms, notably dystonia, choreoathetosis and rigidity of variable degrees. Initial cerebral PET and MRI studies were normal. Follow-up MRI examinations showed progressive basal ganglia degeneration, with evidence of atrophy and signal abnormalities within the caudate nuclei and the putamina. The thalamic structures were normal. The PET studies demonstrated increased uptake in the basal ganglia and thalami, followed by decreased uptake in the basal ganglia at a later stage of the disease. The structural (MRI) and the functional (PET) studies of the brain were found to be complementary in the evaluation of propionic acidemia, and were in good correlation with the clinical ®ndings. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Propionic acidemia; 18FDG PET, and MRI brain scans; Neurological ®ndings
1. Introduction Propionic acidemia is an autosomal recessive metabolic disorder. It is caused by the de®ciency of propionyl carboxylase, an enzyme involved in the metabolism of l-isoleucine [1,2]. The disease often presents with precipitous neonatal metabolic decompensation of such severity that most neonates probably die before a diagnosis is reached. In other patients, the disease is characterised by progressive encephalopathy with central hypotonia of varying severity [3], and in severe cases, by symptoms of basal ganglia disease [4,5]. A more indolent form may manifest later in infancy, with either extrapyramidal symptoms or with seizure disorders. Propionic acidemia is a rare disorder in Western countries. Its incidence is reported between 1:50 000 [6] and 1:500 000 births [7]. Conversely, the disease is encountered
* Corresponding author. Department of Pediatrics, MBC #58, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211 Saudi Arabia, Tel.: 1 966-1-442-7762; fax: 966-1-442-7858/7784. E-mail address: [email protected] (P.T. Ozand)
as a relatively common organic acidemia in Saudi Arabia, occurring in 1:2000±5000 births depending on the region [8,9]. This may be due to the high consanguinity among the population and to a high identi®cation rate through the nation-wide neonatal metabolic screening program. We present our experience based on the brain 18¯uoro-2-deoxyglucose PET and the MRI studies of ®ve paediatric patients and correlate the results with the clinical ®ndings. 2. Materials and methods The Inborn Errors of Metabolism Unit at King Faisal Specialist Hospital and Research Centre is a referral Centre in Saudi Arabia for the management of patients with diverse metabolic disorders. Our ®les contain the data on approximately 2000 patients with various con®rmed congenital metabolic disorders, including 50 patients with propionic acidemia. The diagnosis of propionic acidemia is made using a standard technique of blood tandem mass spectrometry (MS/MS) and urine gas chromatography/mass spectrometry (GC/MS), as described previously [10]. Five patients (age range: 2±5 years) had both cerebral
0387-7604/99/$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S03 87-7604(99)0003 0-3
M. Al-Essa et al. / Brain & Development 21 (1999) 312±317
313
Table 1 Presentation of patients with propionic acidemia and their current clinical status a Current Age at onset Age Patient #1 5 years Patient #2 3 1/2 years Patient #3 4 1/2 years Patient #4 2 years Patient #5 2 years
Age at diagnosis
Consanguinity (Neonatal deaths)
Sex Lethargy, poor Seizure Mental feeding, retardation acidosis
Extrapyramidal Hypotonia Failure to signs thrive
Birth Birth
15 Days 24 Days
Yes (2) Yes (2)
F M
1 111
Yes Yes
Moderate Moderate
Moderate Moderate
Severe Moderate
Moderate Moderate
6 Days
17 Days
Yes (±)
F
1
No
Mild
Mild
Mild
2 Days Discovered by screening program
13 Days 1 Day
Yes (±) Yes (3)
F M
11 2
No No
No No
Mild to Moderate Mild Mild
Mild Mild
Mild Mild
a Extrapyramidal signs (involuntary movements and alterations in muscle tone); mild: barely noticeable, moderate: clinically obvious and affecting posture, standing and walking, severe: present at sleep. Mental retardation as determined by intelligence quotient (I.Q.): mild, I.Q. 52-67; moderate, I.Q. 36-51; severe, I.Q. 20-35.
18
¯uoro-2-deoxyglucose PET and MRI examinations of the brain. The imaging studies were performed within a onemonth interval; therefore, they were felt to be comparable. The patients were sedated if necessary for the examinations by 75 mg/kg orally administered chloral hydrate. All brain MRI studies were performed on 1.5 Tesla superconductive magnets. Typical imaging protocols included conventional non-enhanced sagittal and transverse T1weighted spin echo, axial proton density, and T2-weighted spin echo or fast echo sequences, using circularly polarised head coils [4]. The 18¯uorine was produced in-house, using a 30 MeV cyclotron and 18¯uoro-2-deoxyglucose ( 18FDG) was produced using a commercial automated synthesis technique (CTI, Knoxville, TN.) All patients were studied after fasting for at least 4 hours. Normoglycemia was con®rmed by plasma glucose determination prior to injection. The patients were injected while comfortably resting in a quiet, dimly lit room. Each patient was injected with 100 to 370 MBq of 18FDG (adjusted according to patient's weight), given as a bolus intravenously. Imaging began 45 to 60 min later. Data was acquired for 30 min, using Siemens Exact 47 PET scanner (Siemens Medical System, Hoffman Estates IL) and reconstruction was performed, using Shepp 0.34 ®lter and the manufacturer's autoattenuation software. Images reconstructed at a slice thickness of 0.3375 cm were then analysed directly on the computer monitor [11]. When necessary, images were compared with available CT and/or MRI studies in order to accurately localise relevant structures on the PET images. A consensus reading to arrive at the ®nal interpretation of all individually interpreted PET scans combined the interpretations of twoexperienced nuclear medicine physicians. Only visual analysis was performed and the metabolic activity of the different cerebral structures was graded as increased, normal, absent, mildly reduced, moderately reduced, or severely reduced.
3. Results 3.1. Clinical data All ®ve patients were born in consanguineous families. They presented with vomiting, lethargy and acidosis early in life, typically during the ®rst month of life. In three subjects, there was a positive family history of early neonatal deaths. Ages varied between 2 and 5 years. Failure to thrive was evident in all subjects. This was felt to be due to poor nutrition and repeated acidotic crisis with vomiting. Neurologically, three patients had mild hypotonia and extrapyramidal signs; however, their mental status remained normal. Two patients had moderate to severe hypotonia, extrapyramidal signs, and mental retardation with frequent tonic-clonic seizures. Table 1 summarises the initial clinical presentation, family history, and current neurological status of the ®ve patients. 3.2. PET ®ndings The cerebral PET scans performed in two patients at 1 month of age were found to be normal in one (Fig. 1A), and in the other who exhibited a secondarily generalised seizure disorder (electroencephalogram showed left temporal lobe spike discharges), the PET images (done within 3 days of the seizures) were also normal; however, a focal area of increased uptake in the medial portion of the left temporal lobe was detected, this was believed to correspond to the seizure focus (Fig. 1B). With further progress of the disease and the appearance of mild extrapyramidal symptoms as described above, the PET studies performed in two patients, showed increased 18FDG uptake in the thalami and basal ganglia bilaterally (Fig. 1C). At a later stage, approximately 2 years of age, follow-up PET scan in two patients with moderate to severe extrapyramidal symptoms, revealed a generalised decreased uptake of 18FDG in the basal ganglia (Fig. 1D).
314
M. Al-Essa et al. / Brain & Development 21 (1999) 312±317
Fig. 1. 18FDG PET images of the brain in propionic acidemia. (A) At 1 month of age: the PET scan is normal (patient # 4). (B) In this patient (who had a seizure disorder at one month of age) a striking focal area of increased uptake in the medial portion of left temporal lobe is conspicuous (patient # 1). (C) Initially there is diffuse uptake of the tracer in the thalami and basal ganglia (involving the putamen and the caudate nuclei). There is a relatively decreased cortical uptake (patient # 5 at 2 months of age). (D) Finally, parallel to the disease progress, signi®cant decreased uptake in the head of the caudate nuclei and moderate reduced metabolic activity in the putamina become apparent. The thalamic activity normalises (patient # 2 at 2 years of age).
3.3. MRI ®ndings The MR images were evaluated for morphological and signal abnormalities of the brain and in particular, the basal ganglia. The results showed good correlation with those of the PET studies. The MR images performed in two patients at 1 month of age were normal (Fig. 2A,B). Parallel to the clinical progression of the disease, symmetrical involvement of the basal ganglia became apparent, consisting of abnormal faintly increased signal intensity on the T2-weighted fast spin echo images (Fig. 2D), at the level of the putamina, globi pallidi and the heads of the caudate nuclei in conjunction with a suggestion of swelling. Signal abnormalities are not conspicuous on the T1weighted image. Typically, the thalamic structures remained essentially normal (Fig. 2C).
In the advanced stage of the disease, atrophy (Fig. 2E), and abnormal hypersignal of the heads of the caudate nuclei, the anterior parts of the putamina, and the globi pallidi become evident (Fig. 2F). Also, diffuse white matter signal abnormalities, consistent with delayed mylination and/or dysmylination and brain atrophy were seen. The degree of central nervous system involvement as imaged by these two techniques may vary from one patient to another; however, the observed abnormalities showed the same pattern of progression. 4. Discussion Propionic acidemia is an autosomally inherited inborn
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Fig. 2. Brain MR imaging ®ndings in propionic acidemia (T1- and T2-weighted images). Initial MRI in a 1-month-old child shows normal morphology with no abnormal signal intensity of the basal ganglia (A, B) (patient #1). Parallel to the progression of the disease, the T2-weighted image (D) shows an abnormal, faintly increased signal intensity appearance of the putamina, the heads of the caudate nuclei and the globi pallidi in conjunction with a suggestion of swelling. Signal abnormalities are not conspicuous on the T1-weighted image (C). The thalamic structures are normal (patient # 4 at 1 year of age). In the advanced stage of the disease, atrophy (E), and abnormal hypersignal of the heads of the caudate nuclei, the anterior parts of the putamina, and the globi pallidi, and diffuse cerebral atrophy are evident (F) (patient # 2 at 3 years of age).
error of L-isoleucine metabolism. It may present both as an acute or chronic metabolic disorder of the organic acidemia type. In the neonatal period, it is characterised by a prodrome of feeding dif®culty, lethargy and vomiting, commonly confused with pyloric stenosis [12,13]. If not diagnosed and treated promptly, the disease progresses rapidly leading to frank metabolic acidosis and coma. Eventually, severe thrombocytopenia develops and it is not uncommon for infants to expire due to intracranial bleeding [8,14]. If the patient survives the initial metabolic crisis, the early manifestation of the disease is central hypotonia
[8,15], and in severe cases, extrapyramidal symptoms (rigidity, dystonia and choreoathetosis) appear due to basal ganglia degeneration [4,5]. The disease may be asymptomatic [16] or present in adulthood as chorea and dementia [17]. In our series, there was no apparent correlation between the severity of the disease (Table 1) and the biochemical parameters tested (plasma propionylcarnitine level and propionylcarnitine/acetylcarnitine ratio as assessed by MS/ MS, and urinary 3-hydroxypropionic acid and propionylglycine levels as assessed by GC/MS). To our knowledge, at
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present there are no markers that can be used reliably to monitor the clinical progression of the disease. Despite the unequivocal laboratory evidence of propionyl-CoA carboxylase de®ciency, the neurological symptoms may not develop at all in some individuals, including adults [16]. The explanation for this is poorly understood. The pathogenesis of the disease is not clear and may be related to the toxicity of the propionic acid itself [18]. A patient with propionic acidemia presents a management challenge. The recent availability of carnitine [19,20], particularly the intravenous form, has facilitated both the acute and chronic care. Unfortunately, repeated episodes of infections, vomiting and anorexia [21] create a vicious circle ultimately resulting in chronic malnutrition and the patients fail to thrive. Our experience suggests that during an episode of acute metabolic decompensation, the patient should be treated vigorously with IV carnitine, with 10% dextrose or total parenteral nutrition, and in severe cases with insulin [22]. Recently, aminoacid mixture, restricted to the appropriate amino acids has become available for this purpose [23]. It is advisable to give these patients metronidazole to decrease the production of propionic acid by intestinal bacteria [24,25]. All patients should receive biotin [26]. Despite of the intensive treatment with these therapeutic modalities, some of our patients advanced to the terminal stage of the disease, which may re¯ect the natural progression of the severe phenotypic variety. 18 Fluoro-2-deoxyglucose PET scanning has been found to be a sensitive indicator of the altered brain metabolism in diverse pathologies of the central nervous system [11]. However, we are unaware of any report of PET ®ndings in propionic acidemia. Our data suggests that in the initial stages of propionic acidemia both the MRI and PET studies of the brain indicate normal ®ndings (Figs.1A and 2A). With progression of the disease, an increased uptake of 18FDG in the striatum is followed by the absence of glucose metabolism. This is demonstrated by PET and ®ndings correlated at a latter stage with the morphological changes visualised by MRI. These neuroimaging ®ndings indicate the particular vulnerability of these structures. As expected, the basal ganglia disease invariably presented with extrapyramidal symptoms in the form of rigidity, choreoathetosis and dystonia. We speculate that the degeneration of the fronto-striatal system, which plays an important role in cognitive and motor functions, may be a determinant in the pathophysiology of neurological abnormalities in propionic acidemia. The global developmental delay as observed in some patients is partly explained by repeated acidotic attacks, vomiting, poor feeding, recurrent infections, and chronic propionate toxicity leading to poor nutrition, failure to thrive, and inertia. This is manifested as a progressive encephalopathy and re¯ected by generalised brain atrophy (Fig. 2E) and decreased 18FDG cortical uptake (Fig. 1C). In our experience, the cerebral PET and MRI ®ndings generally show good correlation with the clinical severity
of the disease. PET scan studies showed decreased 18FDG uptake in the basal ganglia, notably at the level of the heads of the caudate nuclei and putamina in an advanced stage of the disease, which preceded the MRI morphological changes. This is not surprising, since this patient had frank extrapyramidal symptoms at the time of the imaging work-up. It is interesting that one patient (Fig. 1B) had a seizure detected by PET scan as a striking focal area of increased uptake in the medial portion of the left temporal lobe. His MRI and PET examinations were otherwise normal. The degree of the central nervous system involvement, as assessed by these two techniques, may vary from one patient to another, however the pattern and the progression of the imaging abnormalities are similar. The thalami in all patients were normal by MRI. PET scan revealed initial increased uptake followed by normalisation of glucose metabolism in these structures. However, PET could not identify the white matter abnormalities that are readily detected by MRI. 5. Conclusion 18
Fluoro-2-deoxyglucose PET of the brain is a highly sensitive technique for detecting early metabolic abnormalities (i.e. decreased glucose uptake) in the basal ganglia and the cerebral cortex in propionic acidemia patients. Magnetic resonance imaging was found to be more accurate in the detection of morphological changes, such as brain atrophy and necrosis of the basal ganglia, and white matter abnormalities. The functional changes indicated by 18FDG PET and the structural abnormalities shown on MRI were found to be complementary in the imaging evaluation of propionic acidemia. Acknowledgements The authors would like to thank Dr. Sultan Al-Sedairy, the Executive Director of the Research Centre, King Faisal Specialist Hospital and Research Centre, for his kind and continuous support. Part of this work was done under funds provided by Sheikh Ra®q Al-Hariri (Research Centre Grant #85-0030). References [1] Barnes ND, Hull D, Balgobin L, Gompertz D. Biotin-responsive propionic acidemia. Lancet 1970;2:244±245. [2] Brandt IK, Hsia YE, Clement DH, Provence SA. Propionic acidemia (ketotic hyperglycinemia): dietary treatment resulting in normal growth and development. Pediatrics 1974;53:391±395. [3] Surtees RA, Matthews EE, Leonard JV. Neurologic outcome of propionic acidemia. Pediatr Neurol 1992;8:333±337. [4] Brismar J, Ozand PT. CT and MR of the brain in disorders of the propionate and methylmalonate metabolism. Am J Neuroradiol 1994;15:1459±1473.
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