Progressive Loss of Cardiac Sympathetic Innervation in Parkinson’s Disease

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Progressive Loss of Cardiac Sympathetic Innervation in Parkinson’s Disease

Sheng-Ting Li, MD, PhD, Raghuveer Dendi, MD, Courtney Holmes, CMT,

and David S. Goldstein, MD, PhD

This study addressed whether cardiac sympathetic denervation progresses over time in Parkinson’s dis- ease. In 9 patients without orthostatic hypotension, 6-[¹⁸F]fluorodopamine positron emission tomography scanning was repeated after a mean of 2 years from the first scan. 6-[¹⁸F]fluorodopamine-derived radioactivity was less in the second scan than in the first scan, by 31% in the left ventricular free wall and 16% in the septum. In Parkinson’s disease, loss of cardiac sympa- thetic denervation progresses in a pattern of loss sug- gesting a dying-back mechanism.

Ann Neurol 2002;52:220 –223

All of at least a dozen studies have agreed that patients with Parkinson’s disease have a high prevalence of neuroimaging evidence for decreased sympathetic innervation of the heart. Low myocardial concentrations of radioactivity have been noted after injection of the sympathoneural imaging agents ¹²³I-metaiodobenzylguanidine^1–12 and 6-[¹⁸F]fluorodopamine.¹³ Neuro- chemical assessments during right heart catheterization have confirmed that low concentrations of radioactivity result from loss of functional cardiac sympathetic nerve terminals.¹³

Although all patients with Parkinson’s disease and orthostatic hypotension have diffusely decreased sympathetic innervation throughout the left ventricular myocardium, among patients who do not have orthostatic hypotension, about half have diffusely decreased innervation and about half have normal or only locally

decreased innervation.¹³ The latter finding afforded an opportunity to determine whether the loss of cardiac sympathetic innervation in Parkinson’s disease progresses over time and, if so, with what timing, pattern, and consistency across patients. This report de- scribes the results of retesting such patients with 6-[¹⁸F]fluorodopamine positron emission tomography scanning after an average of 2 years.

Patients and Methods

The study protocol was approved by the Intramural Research Board of the National Institute of Neurological Disorders and Stroke. Each patient gave informed, written consent.

Patients

Thoracic positron emission tomography scanning was performed after intravenous injection of 6-[¹⁸F]fluorodopamine in 9 patients with Parkinson’s disease (age:

mean, 60 years; SEM, 3 years). None of the patients had orthostatic hypotension, which was defined as a decrease in systolic blood pressure greater than 20mm Hg and decrease in diastolic pressure greater than 5mm Hg between the supine position and standing for 5 minutes. Caffeine- containing beverages, cigarettes, and alcohol were not allowed for at least 24 hours before the scanning. Patients were allowed to take their usual medications, including

L-dopa, except for medications known to inhibit neuronal uptake of catecholamines.

Positron Emission Tomography Scanning

6-[¹⁸F]fluorodopamine, synthesized as described previously,¹⁴ was infused intravenously at a constant rate for 3 minutes.

Tomography images (35 contiguous transaxial slices 4.25mm apart) were acquired for up to 30 minutes. Three- dimensional positron emission tomography scans were obtained with an Advance whole-body scanner (General Elec- tric, Milwaukee, WI). Transmission scans of 2 minutes and 8 minutes, with rotating ⁶⁸Ge/⁶⁸Ga pin sources, were obtained for attenuation correction and for confirming proper positioning in the scanner.

Follow-up scanning was performed 1 to 4 years (mean, 2.0 years; SEM, 0.3 years) after the first scan, with the iden- tical scanning procedure. None of the patients had orthostatic hypotension at the time of either test. Of the 9 patients, 2 had normal 6-[¹⁸F]fluorodopamine-derived radioactivity and 7 had locally decreased 6-[¹⁸F]- fluorodopamine-derived radioactivity in the left ventricular myocardium at the time of the first test.

Data Analysis and Statistics

Tomography images were reconstructed after correction for attenuation and for physical decay of ¹⁸F. Cardiac images were analyzed as described previously.¹⁴Briefly, circular regions of interest approximately half the ventricular wall thickness were placed on images of the septum, with time- From the Clinical Neurocardiology Section, National Institute of

Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.

Received Nov 28, 2001, and in revised form Feb 28 and Mar 7, 2002. Accepted for publication Mar 7, 2002.

Published online Jun 23, 2002, in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.10236

Address correspondence to Dr Li, Building 10, Room 6N252, Na- tional Institute of Neurological Disorders and Stroke, National In- stitutes of Health, 10 Center Drive, MSC-1620, Bethesda, MD 20892-1620. E-mail: lishen@ninds.nih.gov

This article is a US Government work and, as such, is in the public domain in the United States of America.

BRIEF COMMUNICATIONS

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averaged pictures of a single slice. Left ventricular septal radioactivity was averaged from two regions of interest for the 5-minute scanning interval with a midpoint about 8 minutes after initiation of the infusion. The same time interval was used for radioactivity in the liver and kid- ney. For radioactivity in structures of the head and neck, static three-dimensional data were obtained for 10 to 15 minutes. Images of noncardiac structures, including the liver, spleen, renal cortex, renal pelvis, salivary glands, na- sopharyngeal mucosa, and thyroid, were reconstructed and analyzed by manual drawing of the regions of interest out- lining the structures. Radioactivity concentrations were normalized by correction for the radioactivity concentration for the administered dose of radioactive drug per unit of body mass of the subject and were expressed as nCi-kg/cc- mCi.¹⁴

Mean values for 6-[¹⁸F]fluorodopamine-derived radioactivity were compared with pairedttests. Differences between groups in trends over time of 6-[¹⁸F]fluorodopamine-derived radioactivity were assessed by analyses of variance for repeated measures. A p value of less than 0.05 defined statis- tical significance.

Results

At the time of the first scan, patients had had Parkin- son’s disease for 5.7⫾ 1.2 years (range, 0.3–13 years).

Disease severity averaged 2.2 ⫾ 0.2 (range, 1–3) of a maximum of 5. Heart rate and beat-to-beat systolic blood pressure changes during phase II of the Valsalva maneuver averaged 11 ⫾2bpm and ⫺43⫾ 5mm Hg for a mean arterial baroreflex-cardiovagal gain of 2.3⫾ 0.4ms/mm Hg (normal: mean, 8.5ms/mm Hg; SEM, 2.2ms/mm Hg). Plasma catecholamine levels (norepi- nephrine: mean, 2.34nmol/L; SEM, 0.37nmol/L; epi- nephrine: mean, 0.23nmol/L; SEM, 10nmol/L) were approximately normal. Most patients had tremor and

urinary frequency. None of the patients developed orthostatic hypotension between the first and second scans.

At the time of the first scan, 2 patients had normal myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity, and 7 had decreased myocardial 6-[¹⁸F]- fluorodopamine-derived radioactivity confined to the lateral wall or apex, so that no patient had 6-[¹⁸F]fluorodopamine-derived radioactivity more than two standard deviations below the normal mean in both the lateral wall and interventricular septum.

All 9 patients had lower lateral wall concentrations of 6-[¹⁸F]fluorodopamine-derived radioactivity in the second scan than in the first scan (Fig 1).

Left ventricular myocardial mean concentrations of 6-[¹⁸F]fluorodopamine-derived radioactivity decreased by 23% between the first scans (mean, 5,122nCi-kg/

cc-mCi; SEM, 564nCi-kg/cc-mCi) and second scans (mean, 6,634nCi-kg/cc-mCi; SEM, 447nCi-kg/cc-mCi;

p ⫽ 0.003). Lateral wall radioactivity decreased by 31% between the first scans (mean, 4,107nCi-kg/

cc-mCi; SEM, 535nCi-kg/cc-mCi) and second scans (mean, 5,991nCi-kg/cc-mCi; SEM, 537nCi-kg/cc-mCi;

p ⫽0.003), and septal radioactivity decreased by 16%

between the first scans (mean, 6,137nCi-kg/cc-mCi;

SEM, 716nCi-kg/cc-mCi) and second scans (mean, 7,278nCi-kg/cc-mCi; SEM, 385nCi-kg/cc-mCi; p ⫽ 0.05; Fig 2, Table). In 1 patient, the lateral ventricular wall was not visualized in the second scan, and the tissue concentration was assumed to be equal to the left ventricular chamber concentration.

With the exclusion of data from the patient for whom the left ventricular wall was not visualized in the second scan, the percentage decrease in lateral wall radioactivity between the first and second scans (mean,

Fig 1. Progressive loss of myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity in a patient with Parkinson’s disease.

Li et al: Sympathetic Innervation in Parkinson’s Disease 221

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32%; SEM, 7%) exceeded the percentage decrease in septal wall radioactivity (mean, 13%; SEM, 7%; t ⫽ 2.5, p ⫽ 0.04).

Tissue concentrations of 6-[¹⁸F]fluorodopamine- derived radioactivity in the liver, renal cortex, renal pelvis, salivary glands, and thyroid did not change between the two scans (see Table). Radioactivity in the spleen, however, was lower in the second scan (mean, 5,020nCi-kg/cc-mCi; SEM, 137nCi-kg/cc-mCi) than in the first scan (mean, 6,495nCi-kg/cc-mCi; SEM, 364nCi-kg/cc-mCi; p ⫽ 0.001).

Discussion

These findings, based on sympathetic neuroimaging with 6-[¹⁸F]fluorodopamine positron emission tomography scanning, indicate that in patients with Parkin- son’s disease who have normal or only locally decreased cardiac sympathetic innervation, the loss of innervation progresses over time, especially in the lateral ventricular wall, in which 6-[¹⁸F]fluorodopamine-derived radioactivity decreased by about 30% over an average of 2

years. This rate of loss of sympathetic terminals appears to be at least as high as the rate of loss of nigrostriatal dopamine terminals.¹⁵

So far in our ongoing series, all patients with Par- kinson’s disease and orthostatic hypotension have had evidence of diffuse loss of cardiac sympathetic innervation at the time of initial testing.¹³ About half of patients with Parkinson’s disease without orthostatic hypotension have also had evidence of diffuse cardiac sympathetic denervation, and because of the likeli- hood of a floor effect, data from these patients were not included in this study. Given these results, and the present findings, based on the remaining patients with Parkinson’s disease who did not have either orthostatic hypotension or diffuse cardiac sympathetic denervation at the time of initial testing, indicate that progressive loss of cardiac sympathetic innervation characterizes the disease. As of the time of the second scan, none of the patients developed orthostatic hypotension.

The sympathetic innervation of the myocardium travels with the coronary arteries. The finding of more severely decreased 6-[¹⁸F]fluorodopamine-derived radioactivity in the lateral wall than in the interventricular septal wall leads to a suggestion of a dying-back mechanism for the loss of sympathetic terminals, as opposed to death of the cell bodies followed by loss of the terminals (as in Wallerian degeneration). In agreement with this notion, about one half of patients with Parkinson’s disease who do not have orthostatic hypotension already have decreased concentrations of 6-[¹⁸F]fluorodopamine-derived radioactivity throughout

Table. Tissue Concentrations of 6-[¹⁸F]Fluorodopamine- Derived Radioactivity (nCi-kg/cc-mCi) in Patients with Parkinson’s Disease

Organ

First Scan Second Scan

Mean SEM Mean SEM

Left lateral wall 5,991⫾537 4,107⫾535^a

Septum 7,278⫾385 6,137⫾716^a

Right myocardium 5,889⫾564 5,390⫾485 Right chamber 4,799⫾411 4,240⫾263 Left chamber 4,971⫾517 4,725⫾423

Liver 6,897⫾724 7,165⫾869

Spleen 6,495⫾364 5,020⫾137^a

Renal cortex 23,564⫾2,412 20,716⫾2,070 Renal pelvis 27,667⫾3,874 23,278⫾5,203 Nasophanrynx 1,431⫾162 1,501⫾163

Parotid 1,832⫾170 1,698⫾221

Submandibular gland 1,870⫾239 1,782⫾267

Thyroid 1,933⫾187 1,624⫾250

aSignificantly different from first scan.

SEM⫽standard error of the mean Fig 2. Concentrations (mean⫾standard error of the mean) of

6-[¹⁸F]fluorodopamine-derived radioactivity in the (top) lateral left ventricular wall and (bottom) interventricular septum in normal control subjects (open circles), patients with Parkin- son’s disease at the time of the first scan(filled squares), and the same patients at the time of the second scan an average of 2 years later(open squares).

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the left ventricular myocardium, and of the remaining half, most have decreased 6-[¹⁸F]fluorodopamine- derived radioactivity in the lateral ventricular wall or apex, with relative sparing of the interventricular septum.¹³

Because the patients did not have a progressive loss of 6-[¹⁸F]fluorodopamine-derived radioactivity in the liver or renal cortex but did in the heart and spleen, rates of loss of sympathetic innervation appear to vary across organs. This fits with the notion of cardioselec- tive sympathetic denervation in Parkinson’s disease.^11,12

The results lead to the general inference that Parkin- son’s disease features progressive neurodegeneration not only in the nigrostriatal dopaminergic system but also in the sympathetic noradrenergic system.

We gratefully acknowledge the assistance of Sandra Brentzel, RN, and the Positron Emission Tomography Department of the Na- tional Institutes of Health.

References

1. Braune S, Reinhardt M, Bathmann J, et al. Impaired cardiac uptake of meta-[123I]iodobenzylguanidine in Parkinson’s disease with autonomic failure. Acta Neurol Scand 1998;97:

307–314.

2. Braune S, Reinhardt M, Schnitzer R, et al. Cardiac uptake of [123I]MIBG separates Parkinson’s disease from multiple system atrophy. Neurology 1999;53:1020 –1025.

3. Takatsu H, Nishida H, Matsuo H, et al. Cardiac sympathetic denervation from the early stage of Parkinson’s disease: clinical and experimental studies with radiolabeled MIBG. J Nucl Med 2000;41:71–77.

4. Takatsu H, Nagashima K, Murase M, et al. Differentiating Par- kinson disease from multiple-system atrophy by measuring cardiac iodine-123 metaiodobenzylguanidine accumulation. JAMA 2000;284:44 – 45.

5. Orimo S, Ozawa E, Nakade S, et al. (123)I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease.

J Neurol Neurosurg Psychiatry 1999;67:189 –194.

6. Yoshita M, Hayashi M, Hirai S. Iodine 123-labeled metaiodobenzylguanidine myocardial scintigraphy in the cases of idiopathic Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Rinsho Shinkeigaku 1997;37:

476 – 482.

7. Yoshita M. Differentiation of idiopathic Parkinson’s disease from striatonigral degeneration and progressive supranuclear palsy using iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. J Neurol Sci 1998;155:60 – 67.

8. Druschky A, Hilz MJ, Platsch G et al. Differentiation of Par- kinson’s disease and multiple system atrophy in early disease stages by means of I-123-MIBG-SPECT. J Neurol Sci 2000;

175:3–12.

9. Satoh A, Serita T, Tsujihata M. Total defect of metaiodobenzylguanidine (MIBG) imaging on heart in Parkinson’s disease:

assessment of cardiac sympathetic denervation. Nippon Rinsho 1997;55:202–206.

10. Satoh A, Serita T, Seto M, et al. Loss of 123I-MIBG uptake by the heart in Parkinson’s disease: assessment of cardiac sympathetic denervation and diagnostic value. J Nucl Med 1999;40:

371–375.

11. Reinhardt MJ, Jungling FD, Krause TM, Braune S. Scinti- graphic differentiation between two forms of primary dysauto- nomia early after onset of autonomic dysfunction: value of cardiac and pulmonary iodine-123 MIBG uptake. Eur J Nucl Med 2000;27:595– 600.

12. Taki J, Nakajima K, Hwang EH, et al. Peripheral sympathetic dysfunction in patients with Parkinson’s disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med 2000;27:566 –573.

13. Goldstein DS, Holmes C, Li ST, et al. Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 2000;133:

338 –347.

14. Goldstein DS, Eisenhofer G, Dunn BB, et al. Positron emission tomographic imaging of cardiac sympathetic innervation using 6-[18F]fluorodopamine: initial findings in humans. J Am Coll Cardiol 1993;22:1961–1971.

15. Poewe WH. The natural history of Parkinson’s disease. Ann Neurol 1998;44(suppl 1):1–9.

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No Mutation in the TRKA (NTRK1) Gene Encoding a Receptor Tyrosine Kinase for Nerve Growth Factor in a Patient with Hereditary Sensory and Autonomic Neuropathy Type V

Ennio Toscano, MD, PhD,¹ Alessandro Simonati, MD,² Yasuhiro Indo, MD, PhD,³ and Generoso Andria, MD¹

Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) and type V (HSAN-V) are autosomal reces- sive genetic disorders, both characterized by a lack of pain sensation. We report a girl with clinical and neuro- physiological findings consistent with a diagnosis of HSAN-V. We sequenced her TRKAgene, encoding a re- ceptor tyrosine kinase for nerve growth factor and re- sponsible for HSAN-IV, but we could not detect any mu- tation. These data indicate that a gene (or genes) other thanTRKAis probably responsible for HSAN-V in some patients.

Ann Neurol 2002;52:224 –227

Hereditary sensory and autonomic neuropathy (HSAN) are classified into 5 different types according to Dyck.¹ We have demonstrated that the TRKA (NTRK1) gene, encoding a receptor tyrosine kinase that is phosphorylated in response to nerve growth factor, is responsible for HSAN-IV.² HSAN-IV is characterized by febrile episodes, anhidrosis, insensitivity to pain, self-mutilating behavior, and mental retardation.

Pathological features of HSAN-IV are severe reduction of small-diameter afferent neurons, which are activated by tissue-damaging stimuli,^3,4and a loss of sympathetic neurons innervating eccrine sweat glands.⁵

HSAN-V also is characterized by absent reaction to

noxious stimuli but usually lacks anhidrosis and mental retardation. Some patients with possible HSAN-V were described before 1960 (see Landrieu and colleagues⁶ for references), and 3 families with HSAN-V subse- quently were described in which were demonstrated a selective severe decrease of the small myelinated fibers^7,8and a small reduction in unmyelinated fibers⁹of the sural nerve. HSAN-V is likely an autosomal recessive disorder, but Landrieu and colleagues⁶reported in a family 2 dominantly transmitted cases with normal nerve biopsy. Therefore, a clinical entity, also called congenital indifference to pain, is genetically heteroge- neous and probably includes HSAN-IV or HSAN-V, as suggested by Dyck.¹

Recently, Houlden and colleagues¹⁰ described a boy with febrile episodes and a lack of pain sensation that they diagnosed as HSAN-V, according to the typical findings in a nerve biopsy.⁹ DNA analysis showed that he had a homozygous mutation in the TRKA gene.

They stated that HSAN-IV and HSAN-V are likely to be allelic.

Here we present a girl with clinical features consistent with HSAN-V, namely, a lack of pain sensation, but no febrile episodes and normal sural nerve biopsy.

We sequenced her TRKA gene and detected no mutation. Therefore, these data indicate that a gene (or genes) other than TRKA is probably responsible for HSAN-V in some patients, arguing against a previously cited report.¹⁰We also discuss the differential diagnosis of HSAN-IV versus HSAN-V.

Case Report

I.F., a girl, was the second child of consanguineous parents (first cousins). She was born at term (birth weight, 3,400gm) with Apgar scores of 9 and 10. She was found to have insensitivity to painful stimuli, and multiple traumatic episodes were experienced from early life. She bit off the tip of her tongue, and she did not cry when she fell or during blood sampling. At the ages of 3, 4, and 5 years, she had episodes of left hip dislocation without pain perception. At the age of 6 years, she suffered from bilateral osteochondritis of the feet. Her psychomotor development was apparently normal, and she never exhibited behavioral problems or attention deficit problems. She never had thermoregulatory or feeding problems, vomiting, bowel dysfunction, or other signs or symptoms of gastrointestinal dysmotility.

Results

Clinical examination of the girl when she was 11 years old showed reduced response to painful stimuli and anosmia; thermic sensation appeared to be conserved.

Fungiform papillae of the tongue, corneal reflexes, and overflow tears were present. Intelligence and deep ten- don reflexes were normal. Blood pressure was normal in both supine and standing positions. An intradermal injection of histamine evoked axonal reflex as observed in a normal control. She could control her body tem-

From the¹Department of Pediatrics, “Federico II” University, Na- ples, Italy;²Section of Clinical Neurology, Department of Neuro- logical and Visual Sciences, University of Verona, Verona, Italy; and

3Department of Pediatrics, Kumamoto University, Honjo, Ku- mamoto, Japan.

Received Aug 21, 2001, and in revised form March 11, 2002. Ac- cepted for publication March 11, 2002.

Address correspondence to Dr Andria, Department of Pediatrics,

“Federico II” University, Via S. Pansini 5, I-80131 Naples, Italy.

E-mail: andria@unina.it

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perature well under hot environmental conditions. Pi- locarpine ionophoresis and sympathetic skin response were normal.

A right sural nerve biopsy was performed and pro- cessed according to routine procedures for both morphological and morphometrical investigations.¹¹ Fea- tures of the nerve fascicle were normal. At the ultrastructural level, unmyelinated fibers were regularly detected; neither denervated Schwann cells nor colla- gen pockets were seen (Fig 1). Myelinated fiber density was within normal ranges; the shape of the histogram was bimodal, showing the small-caliber fiber peak (Fig 2). Skin biopsy was examined on plastic sections only.

Glands were present; both myelinated and unmyelinated fibers were present in the intradermal nerve fas- cicles.

We sequenced all 17 exons of the TRKA gene of the patient, including their flanking intronic sequences,¹² and detected no putative mutation. Furthermore, we analyzed 8 polymorphic sites in this gene and found that the patient is heterozygous at the intragenic polymorphic site (c. 1,953 cytosine/thymine).¹³ This fur-

ther supports that the patient has no mutation in the TRKA locus because the parents are consanguineous.

Discussion

The patient reported here probably presents a hereditary autosomal recessive sensory neuropathy with selective loss of pain sensation. Autonomic abnormalities apparently were not observed. Reduced sweating was mentioned once, but she can maintain her body temperature under hot environmental conditions. This is compatible with the findings in her nerve and skin bi- opsies. These clinical and laboratory data suggest that the patient suffers from HSAN-V. Similar features, to- gether with apparently intact peripheral nerves, were described in some classic reports of congenital indifference to pain.⁶ The patient reported by Low and colleagues,⁷ presenting indifference to pain and selective loss of small myelinated fibers without sweating abnormality, was classified as HSAN-V. Dyck and colleagues⁹ described a patient with indifference to pain, sweating abnormality, and a severe decrease in small- diameter myelinated fibers with a mild reduction of unmyelinated fibers. It is their view that most earlier cases of indifference to pain may have had either HSAN-IV or HSAN-V.^1,9

In contrast, HSAN-IV is a distinct clinical entity characterized by recurrent episodic fever, anhidrosis, insensitivity to pain, self-mutilating behavior, and mental retardation.^3,14 Mental retardation is variable, Fig 1. Sural nerve biopsy. (A) Semithin section; toluidine blue

stain. Normal features of the nerve fascicle showing myelinated fibers of both small and large calibers. Bar⫽12.5␮m. (B) Thin section; uranyl acetate and lead citrate stain. Representa- tive clusters of normal unmyelinated fibers. Bar⫽3␮m.

Fig 2. Size distribution (X-axis) of the myelinated fibers of the index case and an age-matched control. Note the normal, bi- modal pattern of the histogram; small-caliber fibers are simi- larly represented in both the patient and the control. Numbers on the Y-axis refer to the absolute figures of the measured fibers.

Toscano et al: No Mutation in TRKAGene in HSAN-V 225

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from severe to mild, and some patients were apparently normal, but later mild retardation was showed by a formal assessment (patients KI-108 and KI-116 reported by Mardy and colleagues¹² and Indo and colleagues,¹⁵ respectively). Sweating may be variable but should be evaluated cautiously, as we recently reported.¹⁵ We think that a fundamental phenotype of HSAN-IV consists of insensitivity to pain, anhidrosis, and mental retardation, each of variable degree. Recur- rent hyperpyrexia, self-mutilating behaviors, traumas, and bone fractures can be devastating and often lead to crippling or fatal consequences.

Nerve growth factor supports the survival of sympathetic ganglion neurons and nociceptive sensory neurons in dorsal root ganglia and ascending cholinergic neurons of the basal forebrain.¹⁶ Eccrine sweat glands, innervated by sympathetic cholinergic fibers, are well developed in humans. Therefore, the nerve growth factor-TRKA system has a crucial role in the development and function of the nociceptive reception and es- tablishment of thermoregulation via sweating.² A negative result of the intradermal histamine test, an important diagnostic criterion in HSAN-IV, probably also can be explained by defective peripheral sympathetic neurons. Therefore, anhidrosis and associated failure to maintain body temperature are characteristic features of HSAN-IV.

Recently, Houlden and colleagues¹⁰ described a boy 9 years of age, born to healthy consanguineous parents, presenting anhidrosis and loss of pain and temperature sensation. Sural nerve biopsy demonstrated severe reduction in small-caliber myelinated fiber density but only modest reduction in unmyelinated axons. The authors did not mention either a skin biopsy or a histamine test, which provide important diagnostic criteria for the group of hereditary peripheral neuropathies.¹⁷ They detected a homozygous missense mutation in the TRKA gene, changing a tyrosine to a cysteine at codon 359. According to this case, they concluded that the 2 disorders, HSAN-IV and HSAN-V, are likely to be allelic. However, we propose an alternative interpretation of Houlden and colleagues’ report. Their patient may suffer from HSAN-IV, but not HSAN-V. They argued for the diagnosis of HSAN-V, mainly basing their ar- gument on the finding of nerve biopsy with modest reduction of unmyelinated fibers. However, anhidrosis observed in the patient strongly indicates dysfunction of the most distal intradermal portions of the sympathetic axons. That also might account for the normal appearance of the more proximal unmyelinated fibers observed after sural nerve. Furthermore, it would be important to confirm the functional significance of the missense mutation by an expression study, such as that reported recently.¹⁸

We stress the importance of the molecular analysis of the TRKA gene in all cases with lack of pain sensa-

tion to distinguish overlapping phenotypes of HSAN-IV and HSAN-V, both characterized by a lack of pain sensation. Most patients with HSAN-IV probably have mutations in the TRKA gene,^2,12,13although we cannot rule out the possibility that a mutation (or mutations) in another gene (or genes) is responsible for similar clinical phenotypes. The patient presented here suffers from HSAN-V, but not HSAN-IV, because she does not show anhidrosis or mental retardation. The presence of myelinated and unmyelinated fibers in nerve biopsy and the normal intradermal histamine test further support this diagnosis. We could not detect any putative mutation in the TRKA gene, whereas we found that the patient is heterozygous for this locus, despite the parental consanguinity. These findings strongly indicate that defects of a gene (or genes) other than TRKA is likely responsible for at least some patients with HSAN-V.

It remains unknown whether peripheral nociceptive transmission or central processing might be involved in our case and in some cases with similar phenotypes reported as having HSAN-V. Anosmia observed in our case remains to be examined and may give us some clue for studying a mechanism underlying the defect in pain sensation. Some patients diagnosed as having HSAN-V do not show an apparent abnormality of peripheral nerve fibers. Therefore, their manifestations might be caused by defects in peripheral nociceptor or transduction and transmission of pain sensation or even central processing, such as a lack of concern for a painful stimulus well received by the peripheral nervous system, according to the classic definition of indifference to pain.¹⁹

References

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12. Mardy S, Miura Y, Endo F, et al. Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor.

Am J Hum Genet 1999;64:1570 –1579.

13. Miura Y, Mardy S, Awaya Y, et al. Mutation and polymor- phism analysis of the TRKA (NTRK1) gene encoding a high- affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families. Hum Genet 2000;106:116 –124.

14. Swanson AG. Congenital insensitivity to pain with anhidrosis.

Arch Neurol 1963;8:299 –306.

15. Indo Y, Mardy S, Miura Y, et al. Congenital insensitivity to pain with anhidrosis (CIPA): novel mutations of TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor, a putative uniparental disomy and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency. Hum Mutat 2001;18:308 –318.

16. Levi Montalcini R. The nerve growth factor: thirty-five years later. EMBO J 1987;6:1145–1154.

17. Axelrod FB, Pearson J. Congenital sensory neuropathies. Am J Dis Child 1984;138:947–954.

18. Mardy S, Miura Y, Endo F, et al. Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor. Hum Mol Genet 2001;

10:179 –188.

19. Jewesburry ECO. Congenital indifference to pain. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. Vol 8.

Amsterdam: Elsevier, 1979:187–204.

X-Linked Creatine

Deficiency Syndrome: A Novel Mutation in Creatine Transporter Gene SLC6A8

Alberto Bizzi, MD,¹ Marianna Bugiani, MD,²

Gajja S. Salomons, PhD,³ Donald H. Hunneman, PhD,⁴ Isabella Moroni, MD,²Margherita Estienne, MD,² Ugo Danesi, PhD,¹Cornelis Jakobs, PhD,³ and Graziella Uziel, MD²

Among creatine deficiency syndromes, an X-linked con- dition related to a defective creatine transport into the central nervous system has been described recently. Hall- marks of the disease are the absence of a creatine signal at brain spectroscopy, increased creatine levels in blood and urine, ineffectiveness of oral supplementation, and a mutation in the SLC6A8(Online Mendelian Inheritance in Man [OMIM] 300036) creatine transporter gene. We report on a patient in whom a novel mutation (1221- 1223delTTC) was identified.

Ann Neurol 2002;52:227–231

Creatine deficiency syndromes are recently identified inborn errors of metabolism resulting in a progressive encephalopathy with early onset and mental retardation, extrapyramidal features, and drug-resistant epilepsy.^1–3 Symptoms are related to a depletion of the creatine/phosphocreatine pool within the central nervous system, making this condition easily detectable by brain spectroscopy. Most of the cases reported so far were caused by a defect of the second enzyme involved in creatine biosynthesis: guanidino-acetate methyltransferase (GAMT; OMIM 601240). This defect results in increased guanidino-acetate (GAA) and reduced creatine levels in blood and urine.^4,5 GAMT-deficient patients benefit from oral creatine monohydrate supplementation, which helps to control movement disorders and epilepsy, partially recovers mental impairment, and restores neurological development over time.⁶ The ab-

From the¹Departments of Neuroradiology and²Child Neurology, Istituto Nazionale Neurologico “C. Besta,” Milano, Italy;³Metabol- ic Unit, VU Medical Center, Amsterdam, The Netherlands; and

4University Kinderklinik, Gottingen, Germany.

Received Nov 6, 2001, and in revised form Mar 11, 2002. Accepted for publication Mar 11, 2002.

Address correspondence to Dr Uziel, Department of Child Neurol- ogy, Istituto Nazionale Neurologico “C. Besta,” Via Celoria 11, 20133 Milano, Italy. E-mail: uziel@istituto-besta.it

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sence of complete recovery can be explained by neurotoxic GAA accumulation or by an imbalance of brain creatine and high-energy phosphates.^7,8 Very recently, Item and colleagues^9,10described 2 sisters with mental impairment, low GAA levels in urine, and undetectable activity of arginine to glycine amidinotransferase (AGAT; OMIM 602360), the first enzyme involved in creatine biosynthesis. A homozygous nonsense mutation in AGAT gene was detected. Clinical symptoms and brain creatine deficiency were partially recovered by means of creatine supplementation. A different disease due to impairment of creatine transport into the brain was reported by Salomons and colleagues^11,12 in a boy with language delay, short attention span, epilepsy, and increased creatine levels in blood and urine.

A nonsense mutation in the X-linked creatine transporter gene SLC6A8 was demonstrated. Creatine supplementation in this boy was totally ineffective. This article reports on a second case caused by defective creatine transport into the central nervous system.

Case Report

The patient was the second-born son of healthy, nonconsan- guineous parents. The child’s prenatal and perinatal history was unremarkable. Since the first months of life, he presented with motor delay, reduced interest in surroundings, and no language acquisition. At 8 months, he was admitted

to the hospital after a febrile seizure. An electroencephalogram recording and a magnetic resonance imaging scan were normal. Routine blood and urine analysis and investigation for infectious (screening for rubella, cytomegalovirus, toxo- plasma, herpes simplex, Coxsackie virus, and Mycoplasma pneumoniae) and neurometabolic disorders (plasma lactate and metabolic screening of a 24-hour urine sample with an assessment of amino acids, organic acids, and mucopolysac- charides) were normal. Since 16 months of age, he experienced complex partial seizures with secondary generalization, responding to sodium valproate. Serial electroencephalogram tracings showed a progressive instability of background activity with abundant fast activity and epileptic discharges from frontal and temporal leads during sleep. Physical examination at 3 years and 9 months showed a severe delay in speech and language functions with behavioral disturbances in agreement with an autistic disorder. He did not follow commands or speak, he presented with stereotypical motor behaviors, and he could not engage in any structured play. Gross and fine motor functions were normal.

A second magnetic resonance imaging showed mild atrophy with signal abnormality in the right hippocampus, suggesting mesial temporal sclerosis. Proton magnetic resonance spectroscopic imaging (H-MRSI) was performed as part of the diagnostic workup for mesial temporal sclerosis con- ducted at our institution and showed a normal N-acetylas- partate/choline ratio in both hippocampi without abnormality in the asymmetry index. The surprising feature was the absence of the creatine peak in the whole brain (Fig), indi-

Fig. Proton magnetic resonance spectroscopic imaging shows a complete absence of the creatine peak in both white and gray matter (1A, 2A, 3A, 4A). The position of selected voxels is indicated on the T2-weighted magnetic resonance image at the level of the cen- trum semiovale. There was no restoration of the creatine pool after 3 months of oral creatine monohydrate supplementation at 400mg/kg/day (1B) and after 8 months of supplementation at 700mg/kg/day (1C). There were no significant changes in choline and N-acetylaspartate levels. A normal spectrum from an age-matched control is given for comparison: the peaks of choline (Cho;

3.2ppm), creatine (Cr; 3.02ppm), and N-acetylaspartate (NAA; 2.02ppm) are indicated.

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cating a creatine deficiency syndrome, without any abnormal peak in the expected frequency of GAA (3.8ppm). Creatine and GAA, therefore, were measured in plasma and urine, and oral creatine monohydrate supplementation (400mg/kg/

day) was started. Because H-MRSI showed no creatine recovery after 3 months of therapy, supplementation was increased to 700mg/kg/day. Eight months later, a follow-up H-MRSI examination confirmed no appearance of brain creatine. By this time, clinical symptoms were not improved, and therapy was discontinued. Currently, the patient is 5 years old, and his clinical symptoms are grossly unchanged.

The very recent identification of the first patient with a creatine transporter defect^11,12 suggested that our patient suffered from a creatine uptake defect as well, which was in line with the ineffectiveness of creatine supplementation and with biochemical data. Mutational analysis of the SLC6A8 gene, therefore, was performed.

Methods

Before therapy, H-MRSI (two-dimensional phase encoding point resolved spectroscopy repetition (PRESS) technique:

recovery time/echo time, 1,500/136msec; field of view, 160mm; matrix, 16 ⫻16; 20mm slice thickness) was performed from 3 separate sections at the level of the centrum semiovale, basal nuclei, and hippocampi. During therapy, H-MRSI was performed at the level of the centrum semiovale. Single-voxel spectra (PRESS: recovery time/echo delay time, 1,500/34msec) were acquired from a 30ml volume in the frontoparietal parasagittal cortical gray matter before and during therapy. Raw data were transferred to a SUN work- station and reconstructed with custom-made software.¹³

Mutational analysis complementary DNA–based sequence analysis was performed according to methods described else- where.¹²DNA was isolated from blood cells with a QIAamp blood kit (Qiagen, Chatsworth, CA) for conformation of the mutation at the genomic level. Primers specific for exon 8 of the SLC6A8 gene were designed: forward 5⬘TCCCAGC- CCCTGCCGCAC and reverse 5⬘TACAAACTGTGGC- CAGGGC.

Results

Creatine and GAA levels before, during, and after the withdrawal of creatine supplementation are shown in Table 1. Sequence analysis of the creatine transporter geneSLC6A8identified an hemizygous 3bp deletion in exon 8 involving nucleotides TTC in position 1221- 1223 (1221-1223delTTC; GenBank accession number,

NM 005629). This mutation resulted in the deletion of a single phenylalanine at residue 408 of the protein (delF408). The patient’s mother was heterozygous for the mutation.

Discussion

The failure of creatine supplementation to restore brain creatine by H-MRSI and to improve clinical symptoms and normal plasma and urine GAA levels ruled out a defect of creatine biosynthesis and prompted a search for molecular defects in theSLC6A8gene.^12,14A novel hemizygous deletion located in a short repeat of 3 phe- nylalanines in exon 8 was detected. The repeat is part of transmembrane domain VIII, which is a very conserved region among the Na^⫹- and Cl^⫺-dependent neurotransmitter family.¹⁵The mutation, resulting in a phenylalanine deletion at position 408, most likely causes a partial or even complete loss of creatine transport function. The activity of the transporter could not be tested in fibroblasts because the parents refused consent to a skin biopsy.

To our knowledge, this is the first creatine deficiency case studied with the multivoxel H-MRSI technique, which has better spatial resolution and allows an evaluation of lesion heterogeneity in the shortest amount of time. We did not find any significant difference in creatine levels across the brain regions examined, suggesting that the transporter defect does not spare any brain area.

Symptoms of creatine deficiency have been related previously to a defect in creatine transport by Salomons and colleagues,^11,12 who described a male patient with mental retardation and severe delay in ex- pressive speech and language function presenting a hemizygous nonsense mutation in the SLC6A8 gene.

As in our case, a lack of creatine transport into the central nervous system resulted in the failure of creatine supplementation to reverse clinical symptoms and brain spectroscopy abnormality. Very recently, another unrelated family with a creatine transporter defect was recognized by the same authors.¹⁶ The biochemical profile of our patient showed a massive loss of creatine in urine, but in contrast with the first reported index case, creatine levels in plasma were normal even during creatine supplementation.

Table 1. Laboratory Results before, during, and after Withdrawal of Oral Creatine Monohydrate Supplementation (700mg/kg/day)

Result

Blood Urine

(␮mol/L)GAA Creatine

(␮mol/L) GAA

(mmol/mol creatinine)

Creatine (mmol/mol creatinine)

Normal values 0.4–3 10–200 10–125 40–360

Prior 1.8 83 79 4,519

During ND 174 28 21,315

After ND 66 46 3,102

GAA⫽guanidino-acetate; ND⫽not determined.

Bizzi et al: Creatine Transporter Defect 229

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The mother underwent a brain H-MRSI that demonstrated a mildly reduced creatine signal compared with that of age-matched controls. Moreover, the results showed that she was heterozygous for the mutation identified in her son. However, no learning dis- abilities were reported for the patient’s female relatives, in contrast with what was encountered in 2 of 3 female carriers in the first family described.¹²These data agree with skewed X inactivation (mosaic expression of mutant and wild-type alleles), resulting in a variably favor- able mosaic expression of the wild-type allele.

The 3 creatine deficiency syndromes described so far (ie, GAMT and AGAT defects and impairment of creatine transport) share overlapping symptoms of mental retardation with severe language impairment, autistic behavior, and epilepsy. Movement disorders have been reported only in patients with GAMT deficiency, suggesting that extrapyramidal features may result from neurotoxic GAA accumulation rather than from reduced creatine availability in brain. The major involvement of higher cortical functions and the frequent finding of epilepsy suggest that the cerebral cortex may be selectively vulnerable to creatine deficiency. How creatine deficiency adversely affects cortical functions is still to be established. It is conceivable that creatine plays a role in the latest stages of cortical organization, including syn- aptogenesis, a process that continues after birth. This could explain the homogeneity of clinical presentation and age at onset in the 3 creatine deficiency syndromes, even though in children with biosynthesis defects, creatine is supplied through the placenta during fetal life, whereas patients with a transporter defect suffer from creatine depletion already in utero.

Spectroscopy alone cannot always distinguish between synthesis and transport defects. In GAMT deficiency, brain spectroscopy at a short echo time can identify an abnormal peak that is assigned to GAA (3.8ppm), but this elevation may be subtle, and it has been reported only in a few cases. Therefore, all patients in whom a diagnosis of creatine deficiency is reached should un- dergo a careful biochemical evaluation to assess creatine and GAA levels in blood and urine (Table 2). Brain spectroscopy is becoming more available; a quick auto- mated spectrum acquisition can be performed at the

time of conventional magnetic resonance imaging and may practically disclose creatine or other metabolites depletion: just recently, the first case of N-acetylaspartate brain deficiency was reported in a patient with mental retardation and severe language impairment.¹⁷

Clinical features of mental impairment, language delay, and autistic behavior with epilepsy frequently are encountered in infancy. Conceivably, creatine deficiency could be underdiagnosed, and if brain spectroscopy cannot be easily achieved, an assessment of blood and urinary creatine should always be performed.

We thank Dr S. J. M. van Dooren and D. Brunea for excellent tech- nical support to Dr G. S. Salomons.

Electronic Database Information: OMIM. www.ncbi.nlm.nih.gov/

omim; GenBank. www.ncbi.nlm.nih.gov/genbank.

References

1. Stockler S, Isbrandt D, Hanefeld F, et al. Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am J Hum Genet 1996;58:914 –922.

2. Stockler S, Marescau B, De Deyn PP, et al. Guanidinoacetate methyltransferase deficiency, a new inborn error of creatine synthesis. Metabolism 1997;46:1189 –1193.

3. Ganesan V, Johnson A, Connelly A, et al. Guanidinoacetate methyltransferase deficiency: new clinical features. Pediatr Neu- rol 1997;17:155–157.

4. Schulze A, Hess T, Wevers R, et al. Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency:

diagnostic tools for a new inborn error of metabolism. J Pediatr 1997;131:626 – 631.

5. Ilas J, Muhl A, Stockler-Ipsiroglu S. Guanidinoacetate methyltransferase deficiency: non-invasive enzymatic diagnosis of a newly recognized inborn error of metabolism. Clin Chim Acta 2000;290:179 –188.

6. Stockler S, Hanefeld F, Frahm J. Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism. Lancet 1996;348:789 –790.

7. van der Knaap MS, Verhoeven NM, Maaswinkel-Mooij P, et al.

Mental retardation and behavioural problems as presenting signs of a creatine synthesis defect. Ann Neurol 2000;47:540 –543.

8. Leuzzi V, Bianchi MC, Tosetti M, et al. Brain creatine depletion: guanidinoacetate methyltransferase deficiency (im- proving with creatine supplementation). Neurology 2000;55:

1407–1409.

9. Bianchi MC, Tosetti M, Fornai F, et al. Reversible brain creatine deficiency in two sisters with normal blood creatine level.

Ann Neurol 2000;47:511–513.

Table 2. Creatine and GAA Levels in GAMT and AGAT Defects and in Creatine Transporter Gene(SLC6A8) Mutations

Defect or mutation

Blood Urine Brain

Creatine GAA Creatine GAA Creatine GAA

GAMT Decrease Increase Decrease Increase Decrease Undetectable/Increase

AGAT Normal Normal ND Decrease Decrease Undetectable

SLC6A8 Normal/Increase Normal Increase Normal Decrease Undetectable

AGAT⫽arginine to glycine amidinotransferase; GAA⫽guanidino-acetate; GAMT⫽guanidino-acetate methyltransferase; ND⫽not determined.

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10. Item CB, Stockler-Ipsiroglu S, Stromberger C, et al. Arginine:

glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 2001;69:

1127–1133.

11. Cecil KM, Salomons GS, Ball WS, et al. Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect? Ann Neurol 2001;49:401– 404.

12. Salomons GS, van Dooren SJM, Verhoeven NM, et al.

X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 2001;68:

1497–1500.

13. Soher BJ, van Zijl PCM, Duyn JH, et al. Quantitative proton spectroscopic imaging of the human brain. Magn Reson Med 1996;35:356 –363.

14. Gregor P, Nash SR, Caron MG, et al. Assignment of the creatine transporter gene (SLC6A8) to human chromosome Xq28 telomeric to G6PD. Genomics 1995;25:332–333.

15. Nash SR, Giros B, Kingsmore SF, et al. Cloning, pharmacolog- ical characterization and genomic localization of the human creatine transporter. Receptors Channels 1994;2:165–174.

16. Salomons GS, Dooren SJ, Verhoeven NM, et al. X-linked creatine transporter defect: the second family. J Inherit Metab Dis 2001;24(suppl 1):119.

17. Martin E, Capone A, Schneider J, et al. Absence of N-acetylaspartate in the human brain: impact on neurospectros- copy? Ann Neurol 2001;49:518 –521.

Vertebrobasilar Stroke as a Late Complication of a Blalock-Taussig Shunt

Philippe Gailloud, MD,¹Argye Hillis, MD,² Bruce Perler, MD,³ and Kieran J. Murphy, MD¹

We describe a 39-year-old patient with a cerebellar in- farct and a history of a tetralogy of Fallot corrected dur- ing childhood. This is the first documented case of ver- tebrobasilar stroke occurring as a late complication of a Blalock-Taussig shunt followed by total cardiac repair.

Ann Neurol 2002;52:231–234

The Blalock-Taussig shunt, first performed in 1944 at the Johns Hopkins Hospital,¹ is a surgical anastomosis established between a subclavian artery and the ipsilateral pulmonary artery. In patients with a tetralogy of Fallot, this procedure allows deferment of the definitive cardiac repair to a more robust stage of life by bypass- ing the pulmonary artery stenosis. The Blalock-Taussig shunt, however, creates the permanent anatomical condition of a subclavian steal phenomenon (Fig 1). The subclavian steal phenomenon, initially described by Reivich and colleagues in 1961,² is related to a proximal subclavian artery stenosis or occlusion responsible for the occurrence of retrograde collateral flow in the ipsilateral vertebral artery. A few reports have suggested a possible link between a Blalock-Taussig shunt and the late occurrence of cerebrovascular disease. We report the first documented case of vertebrobasilar stroke occurring as a late complication of a Blalock-Taussig shunt followed by total cardiac repair during childhood.

Case Report

A 39-year-old man was admitted to our hospital because of an acute episode of nausea without vomiting, vertigo, and decreased hearing on the right side, rapidly followed by right facial numbness as well as weakness and decreased sensation in the left arm. The patient also described a visual distur- bance consistent with nystagmus. These symptoms appeared without an identifiable precipitating factor and lasted for approximately 20 to 30 minutes. The patient was known to have tetralogy of Fallot treated by a Blalock-Taussig shunt at the age of 2 years followed by definitive surgical repair at the age of 9 years. He had been in good health since then. The review of risk factors for cerebrovascular disease, including obesity, tobacco use, hyperlipidemia, and hypertension, was negative. The social and familial histories showed only hypertension and hyperlipidemia in both parents.

On admission, the general and neurological examinations were normal except for asymmetrical upper extremity blood pressure measurements (125/80mm Hg on the right, 146/

95mm Hg on the left) and unpalpable distal arterial pulses in the right arm. According to the patient, this discrepancy had been known since his second cardiac surgery. The laboratory values were unremarkable; in particular, the lipid profile was normal, and there was no evidence of a hyper- coagulable state (the protein C and S antigens, antithrom- bin III activity, dilute Russell’s viper venom time test, and homocysteine level were within normal ranges; the factor V Leiden mutation was negative). Computed tomography of the brain was normal. Magnetic resonance imaging showed signal anomalies in the inferior aspect of the right cerebellar hemisphere consistent with an acute ischemic lesion in the right posterior inferior cerebellar artery territory (Fig 2A).

Magnetic resonance imaging incidentally showed inflammatory changes in the maxillary sinus and ethmoid cells bilat- erally, whereas the sphenoid and frontal sinuses were unremarkable. The patient was not treated for this asymptomatic inflammatory sinus disease. A transesophageal echocardiogram, including a bubble study performed to From the Department of ¹Radiology and Radiological Sciences,

2Neurology, and³Vascular Surgery, Johns Hopkins Hospital, Balti- more, MD.

Received May 15, 2000, and in revised form Feb 28, 2002. Ac- cepted for publication Mar 12, 2002.

Address correspondence to Dr Gailloud, Department of Radiology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Radiology B-100, Baltimore, MD 21287.

E-mail: phg@jhmi.edu

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rule out potential cardioembolic sources, was unremarkable except for a mildly dilated right ventricular cavity. Reverse flow in the right vertebral artery was by documented transcranial Doppler. The transcranial Doppler bubble test was negative for embolic events at rest and during Valsalva maneuver and coughing. Cerebral digital subtraction angiography then was performed. The aortic arch study showed interruption of the right subclavian artery at its origin (see Fig 2B). Selective injections of the left vertebral artery confirmed the presence of a left-to-right subclavian steal phenomenon. Revascularization of the right upper extremity was provided by retrograde filling of several subclavian ar-

tery branches, including the right vertebral artery and the right ascending and deep cervical arteries (see Fig 2C). The cerebral vasculature was otherwise unremarkable. There was in particular no evidence of intracranial or extracranial ath- eromatous disease and no arterial or venous anomalies po- tentially associated with stroke.

The patient was discharged without sequelae from his stroke. However, he continued to report frequent episodes of dizziness, associated once with facial numbness and dip- lopia, despite being anticoagulated with warfarin at a ther- apeutic level. At this stage, surgical correction of his vascular anomaly was advised to the patient, who wished to proceed with this option after the exposition of its potential risks and benefits. Interposition of a synthetic graft (Hemoshield Dacron Graft, Boston Scientific Corporation, Natick, MA) between the right common carotid and subclavian arteries was performed uneventfully, allowing antegrade flow to be reestablished in the right vertebral artery.

After surgery, his episodic symptoms attributable to brain- stem ischemia resolved. He has remained asymptomatic for more than 1 year.

Discussion

We report the case of a 39-year-old man presenting with a vertebrobasilar stroke in the absence of identifiable cerebrovascular risk factors. The symptoms described by our patient pointed to a lesion in the territory of the right posterior inferior cerebellar artery, which was confirmed by neuroimaging. In our patient, the co-occurrence of a vertebrobasilar infarct and a subclavian steal phenomenon strongly suggest a caus- ative relationship between the 2 events, that is, a subclavian steal syndrome secondary to the cardiac surgery undergone during childhood. Although an embolic mechanism cannot be completely excluded because of normal transesophageal echocardiogram and transcranial Doppler, both with negative bubble tests, that the involved branch (the right posterior inferior cerebellar artery) originates from the vertebral artery with reverse flow renders this explanation very unlikely. Conversely, this anatomical situation is consistent with an increased risk of preferential hypoperfusion in the right posterior inferior cerebellar artery territory.

The possible association between a Blalock-Taussig shunt and a subclavian steal phenomenon initially was proposed by Folger and Shah in 1965.³ By reviewing 123 cardiac angiograms performed on patients with a Blalock-Taussig shunt, these authors could identify late opacification of a subclavian artery suggestive of a subclavian steal phenomenon in 12 instances. The steal phenomenon was associated with dizziness in 3 patients and with visual disturbances in 2 patients. How- ever, in those patients and in other case reports de- scribing early cerebrovascular events after a Blalock- Taussig shunt,^4,5 the vertebrobasilar manifestations occurred after the creation of the shunt but before definitive repair of the tetralogy of Fallot. In these pa- Fig 1. Schematic representation of the morphological changes

associated with a Blalock-Taussig shunt. The pulmonary trunk and arteries are represented in light gray; the aortic arch (1) and supra-aortic trunks are in dark gray. The Blalock-Taussig shunt is established between the proximal right subclavian artery (6) and the right pulmonary artery (8) by interposition of a synthetic graft (7). The subclavian steal phenomenon, that is, antegrade flow in the left vertebral artery and retro- grade flow in the right vertebral artery (4), provides blood supply to the right arm (direction of blood flow as indicated by the arrows). The figure also shows the right common ca- rotid artery (2), the right carotid bifurcation (3), and the basilar artery (5).

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tients, contributing factors related to cardiac dysfunction, such as hypoxia, polycythemia, bacterial endocarditis, and mural or valvular thrombosis, have to be considered.⁶ The association of a Blalock-Taussig shunt with delayed ischemic complications occurring

after total cardiac repair of the tetralogy of Fallot was suggested in 1984 by Kurlan and colleagues.⁶ These authors described a 38-year-old patient developing transient vertebrobasilar ischemia 31 years after a Blalock-Taussig shunt and 4 years after total repair of Fig 2. (A) Magnetic resonance imaging study of the brain. This axial T2-weighted image shows increased signal in the lower portion of the right cerebellar hemisphere associated with mini- mal mass effect on the right posterior-lateral aspect of the brain- stem and subtle leftward midline shift. A small area of hypersig- nal also is seen in the right side of the myelencephalon

(arrowhead). This pattern of abnormal signal is consistent with an ischemic lesion in the territory of the right posterior-inferior cerebellar artery. Note the incidental finding of chronic maxil- lary sinus inflammation. (B) Digital subtraction angiography of the aortic arch, left anterior oblique view. The aortic arch, the right common carotid artery (RCC), the left common carotid artery (LCC), and the left subclavian artery (LSC) are unre- markable. The right subclavian artery is interrupted close to its origin from the innominate artery (arrow). (C) Selective digital subtraction angiography of the left vertebral artery, anteroposte- rior view. The catheter tip(arrowhead)is placed at the origin at the left vertebral artery (LV). Retrograde flow in the right vertebral artery (RV) and in several cervical branches allows for late opacification of the right subclavian artery (arrow).

Gailloud et al: Blalock-Taussig Shunt and Stroke 233