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Figure 1.
 Regions of interest (ROIs) on axial (A) and sagittal (B) magnetic resonance images of a patient’s brain. The white squares show the location of the ROIs. A, The sensorimotor ROIs were centered on the medial sensorimotor regions bilaterally, corresponding to lower extremities and trunk. B, Additional ROIs were positioned at the midline in the posterior occipital region, cingulate cortex, and pons.

Regions of interest (ROIs) on axial (A) and sagittal (B) magnetic resonance images of a patient’s brain. The white squares show the location of the ROIs. A, The sensorimotor ROIs were centered on the medial sensorimotor regions bilaterally, corresponding to lower extremities and trunk. B, Additional ROIs were positioned at the midline in the posterior occipital region, cingulate cortex, and pons.

Figure 2.
 Proton magnetic resonance 2-dimensional J-resolved spectra of the sensorimotor cortex in a healthy control subject obtained as cross sections through the 2-dimensional J-resolved spectrum. The horizontal axis represents chemical shift and the vertical axis represents relative signal intensity (modulus). Spectrum represents the 1-dimensional profile along the J = 0 axis of the 2-dimensional J-resolved acquisition (J0 subspectrum). Peaks from N-acetyl aspartate (NAA), creatine (Cre), and choline (Cho) and the central peak of the γ-aminobutyric acid (GABA) α-CH2 resonance (2.31 ppm) are marked. The adjacent central peak of the γ-CH2 glutamate resonance at 2.36 ppm is also seen.

Proton magnetic resonance 2-dimensional J-resolved spectra of the sensorimotor cortex in a healthy control subject obtained as cross sections through the 2-dimensional J-resolved spectrum. The horizontal axis represents chemical shift and the vertical axis represents relative signal intensity (modulus). Spectrum represents the 1-dimensional profile along the J = 0 axis of the 2-dimensional J-resolved acquisition (J0 subspectrum). Peaks from N-acetyl aspartate (NAA), creatine (Cre), and choline (Cho) and the central peak of the γ-aminobutyric acid (GABA) α-CH2 resonance (2.31 ppm) are marked. The adjacent central peak of the γ-CH2 glutamate resonance at 2.36 ppm is also seen.

Figure 3.
 Proton magnetic resonance 2-dimensional J0 subspectrum from sensorimotor cortex in patient with stiff-person syndrome. Peaks from N-acetyl aspartate (NAA), creatine (Cre), and choline (Cho) and the central peak of the γ-aminobutyric acid (GABA) α-CH2 resonance (2.31 ppm) are marked. Note the lower GABA α-CH2 peak in this patient with stiff-person syndrome compared with the corresponding GABA peak in the healthy control subject (Figure 2).

Proton magnetic resonance 2-dimensional J0 subspectrum from sensorimotor cortex in patient with stiff-person syndrome. Peaks from N-acetyl aspartate (NAA), creatine (Cre), and choline (Cho) and the central peak of the γ-aminobutyric acid (GABA) α-CH2 resonance (2.31 ppm) are marked. Note the lower GABA α-CH2 peak in this patient with stiff-person syndrome compared with the corresponding GABA peak in the healthy control subject (Figure 2).

Table.  
 GABA Levels in Different Brain Regions
GABA Levels in Different Brain Regions
1.
Moersch  FPWoltman  HW Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome): report of a case and some observations in 13 other cases. Mayo Clin Proc 1956;31421- 427
PubMed
2.
Toro  CJacobowitz  DMHallett  M Stiff-man syndrome. Semin Neurol 1994;14154- 158
PubMedArticle
3.
Meinck  HMRicker  KHulser  PJSchmid  EPeiffer  JSolimena  M Stiff man syndrome: clinical and laboratory findings in eight patients. J Neurol 1994;241157- 166
PubMedArticle
4.
Levy  LMDalakas  MCFloeter  MK The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of γ-aminobutyric acid. Ann Intern Med 1999;131522- 530
PubMedArticle
5.
Dalakas  MCFujii  MLi  MMcElroy  B The clinical spectrum of anti-GAD antibody–positive patients with stiff-person syndrome. Neurology 2000;551531- 1535
PubMedArticle
6.
Meinck  HMRicker  KHulser  PJSolimena  M Stiff man syndrome: neurophysiological findings in eight patients. J Neurol 1995;242134- 142
PubMedArticle
7.
Sandbrink  FSyed  NAFujii  MDDalakas  MCFloeter  MK Motor cortex excitability in stiff-person syndrome. Brain 2000;1232231- 2239
PubMedArticle
8.
Solimena  MFolli  FDenis-Donini  S  et al.  Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med 1988;3181012- 1020
PubMedArticle
9.
Saiz  AGraus  FValldeoriola  FValls-Sole  JTolosa  E Stiff-leg syndrome: a focal form of stiff-man syndrome. Ann Neurol 1998;43400- 403
PubMedArticle
10.
Dinkel  KMeinck  HMJury  KMKarges  WRichter  W Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol 1998;44194- 201
PubMedArticle
11.
Dalakas  MCFujii  MLi  MLutfi  BKyhos  JMcElroy  B High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 2001;3451870- 1876
PubMedArticle
12.
Dalakas  MCLi  MFujii  MJacobowitz  DM Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology 2001;57780- 784
PubMedArticle
13.
Molloy  FMDalakas  MCFloeter  MK Increased brainstem excitability in stiff-person syndrome. Neurology 2002;59449- 451
PubMedArticle
14.
Levy  LMHallett  M Impaired brain GABA in focal dystonia. Ann Neurol 2002;5193- 101
PubMedArticle
15.
Levy  LMZiemann  UChen  RCohen  LG Rapid modulation of GABA in sensorimotor cortex induced by acute deafferentation. Ann Neurol 2002;52755- 761
PubMedArticle
16.
Lee  HKYaman  ANalcioglu  O Homonuclear J-refocused spectral editing technique for quantification of glutamine and glutamate by 1H NMR spectroscopy. Magn Reson Med 1995;34253- 259
PubMedArticle
17.
Rothman  DLPetroff  OABehar  KLMattson  RH Localized 1H NMR measurements of γ-aminobutyric acid in human brain in vivo. Proc Natl Acad Sci U S A 1993;905662- 5666
PubMedArticle
18.
Bottomley  PA Human in vivo NMR spectroscopy in diagnostic medicine: clinical tool or research probe? Radiology 1989;1701- 15
PubMedArticle
19.
Ryner  LNSorenson  JAThomas  MA Localized 2D J-resolved 1H MR spectroscopy: strong coupling effects in vitro and in vivo. Magn Reson Imaging199513853869 [published correction appears in Magn Reson Imaging. 1995;13:1043]
PubMed
20.
Behar  KLOgino  T Assignment of resonance in the 1H spectrum of rat brain by two-dimensional shift correlated and J-resolved NMR spectroscopy. Magn Reson Med 1991;17285- 303
PubMedArticle
21.
Thomas  MARyner  LNMehta  MPTurski  PASorenson  JA Localized 2D J-resolved 1H MR spectroscopy of human brain tumors in vivo. J Magn Reson Imaging 1996;6453- 459
PubMedArticle
22.
Moffett  JRNamboodiri  MACangro  CBNeale  JH Immunohistochemical localization of N-acetylaspartate in rat brain. Neuroreport 1991;2131- 134
PubMedArticle
23.
Simmons  MLFrondoza  CGCoyle  JT Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies. Neuroscience 1991;4537- 45
PubMedArticle
24.
Cendes  FStanley  JADubeau  FAndermann  FArnold  DL Proton magnetic resonance spectroscopic imaging for discrimination of absence and complex partial seizures. Ann Neurol 1997;4174- 81
PubMedArticle
25.
Vion-Dury  JNicoli  FSalvan  AMConfort-Gouny  SDhiver  CCozzone  PJ Reversal of brain metabolic alterations with zidovudine detected by proton localised magnetic resonance spectroscopy. Lancet 1995;34560- 61
PubMedArticle
26.
Videen  JSMichaelis  TPinto  PRoss  BD Human cerebral osmolytes during chronic hyponatremia: a proton magnetic resonance spectroscopy study. J Clin Invest 1995;95788- 793
PubMedArticle
27.
Miller  BLChang  LBooth  R  et al.  In vivo 1H MRS choline: correlation with in vitro chemistry/histology. Life Sci 1996;581929- 1935
PubMedArticle
28.
Tedeschi  GLundbom  NRaman  R  et al.  Increased choline signal coinciding with malignant degeneration of cerebral gliomas: a serial proton magnetic resonance spectroscopy imaging study. J Neurosurg 1997;87516- 524
PubMedArticle
29.
Tillakaratne  NJMedina-Kauwe  LGibson  KM γ-Aminobutyric acid (GABA) metabolism in mammalian neural and nonneural tissues. Comp Biochem Physiol A Physiol 1995;112247- 263
PubMedArticle
30.
Erecinska  MSilver  IA Metabolism and role of glutamate in mammalian brain. Prog Neurobiol 1990;35245- 296
PubMedArticle
31.
Urenjak  JWilliams  SRGadian  DGNoble  M Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 1992;5955- 61
PubMedArticle
32.
Holtzman  D Brain creatine kinases and phosphocreatine: an update. Dev Neurosci 1996;18522- 523
PubMedArticle
33.
Tedeschi  GBertolino  ARighini  A  et al.  Brain regional distribution pattern of metabolite signal intensities in young adults by proton magnetic resonance spectroscopic imaging. Neurology 1995;451384- 1391
PubMedArticle
34.
Solimena  MFolli  FAparisi  RPozza  GDe Camilli  P Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990;3221555- 1560
PubMedArticle
35.
Voiculescu  VCalcaianu  GStanescu  A Abnormal reflexes in the “stiff-man” syndrome. Rev Roum Neurol 1970;7221- 226
PubMed
36.
Howard  FM A new and effective treatment for stiff-man syndrome: preliminary report. Mayo Clin Proc 1963;38203- 212
PubMed
37.
Stayer  CTronnier  VDressnandt  J  et al.  Intrathecal baclofen therapy for stiff-man syndrome and progressive encephalomyelopathy with rigidity and myoclonus. Neurology 1997;491591- 1597
PubMedArticle
38.
Seitz  RJBlank  BKiwit  JCBenecke  R Stiff-person syndrome with anti-glutamic acid decarboxylase autoantibodies: complete remission of symptoms after intrathecal baclofen administration. J Neurol 1995;242618- 622
PubMedArticle
39.
Silbert  PLMatsumoto  JYMcManis  PGStolp-Smith  KAElliott  BAMcEvoy  KM Intrathecal baclofen therapy in stiff-man syndrome: a double-blind, placebo-controlled trial. Neurology 1995;451893- 1897
PubMedArticle
40.
Vasconcelos  OMDalakas  MC Stiff-person syndrome. Curr Treat Options Neurol 2003;579- 90
PubMedArticle
41.
Jonas  PBischofberger  JSandkuhler  J Corelease of two fast neurotransmitters at a central synapse. Science 1998;281419- 424
PubMedArticle
42.
Solimena  MButler  MHDe Camilli  P GAD, diabetes, and stiff-man syndrome: some progress and more questions. J Endocrinol Invest 1994;17509- 520
PubMedArticle
43.
Ziegler  BAugstein  PSchroder  D  et al.  Glutamate decarboxylase (GAD) is not detectable on the surface of rat islet cells examined by cytofluorometry and complement-dependent antibody-mediated cytotoxicity of monoclonal GAD antibodies. Horm Metab Res 1996;2811- 15
PubMedArticle
Original Contribution
June 2005

Brain γ-Aminobutyric Acid Changes in Stiff-Person Syndrome

Author Affiliations

Author Affiliations: Neuroimaging Branch (Drs Levy and Levy-Reis) and Neuromuscular Diseases Section (Drs Fujii and Dalakas), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md; and Neuroradiology Section, George Washington University Medical Center, Washington, DC (Drs Levy and Levy-Reis).

Arch Neurol. 2005;62(6):970-974. doi:10.1001/archneur.62.6.970
Abstract

Background  Patients with stiff-person syndrome (SPS) have circulating antibodies against glutamic acid decarboxylase, the rate-limiting enzyme responsible for the synthesis of γ-aminobutyric acid (GABA). Although the patients’ symptoms of stiffness and unexpected spasms can be explained on the basis of reduced or impaired inhibitory neurotransmitters, such as GABA, it is unclear whether the level of GABA in the brains of these patients is reduced and, if so, whether the reduction is due to anti–glutamic acid decarboxylase antibodies.

Objective  To measure GABA levels in the brains of patients with SPS.

Design  Prospective case-control study.

Setting  National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md.

Patients  Eight patients with SPS with high titers of circulating anti–glutamic acid decarboxylase antibodies and typical clinical symptoms of SPS and 16 control subjects.

Main Outcome Measures  Results of brain magnetic resonance imaging and magnetic resonance spectroscopy, which measures GABA levels in specific brain regions.

Results  No abnormalities were noted on brain magnetic resonance images. A prominent and significant decrease in GABA level was, however, observed in the sensorimotor cortex and a smaller decrease in the posterior occipital cortex but not in the cingulate cortex or pons.

Conclusions  The reduction of brain GABA in patients with SPS supports the clinical symptoms and indicates that the inhibitory GABAergic pathways are involved in the disease. Regardless of the responsible autoantigens, in SPS autoantibodies block the function of GABAergic neurons and interfere with the synthesis of GABA but do not cause structural changes in the brain.

Stiff-person syndrome (SPS) is an often-overlooked disabling disorder characterized by muscle rigidity and episodic spasms involving axial and limb musculature.15 The hallmark sign of SPS is the co-contraction of agonist and antagonist muscles, with continuous motor unit firing at rest documented electrophysiologically.4,6,7

Up to 65% of patients with SPS have antibodies against glutamic acid decarboxylase (GAD-65), the rate-limiting enzyme for the synthesis of γ-aminobutyric acid (GABA) at the GABAergic nerve terminals.8,9 In vitro, anti-GAD antibodies inhibit GAD activity,10 but whether these antibodies exert the same effect in vivo and are of pathogenic relevance in patients with SPS remains unclear.11 Of interest, anti-GAD antibodies are produced intrathecally and the level of GABA appears reduced in the cerebrospinal fluid of these patients,12 but whether there is also reduction of GABA in certain brain regions is unknown. Demonstrating reduced GABA in the brain will strengthen the view that GABAergic pathways are affected, and will be consistent with the impairment of inhibitory pathways as the main mechanism of the patients’ symptoms of stiffness and spasms.9,13

In this study, we measured regional brain GABA levels in patients with SPS and in healthy control subjects, using a novel method of 2-dimensional (2D) J-resolved magnetic resonance (MR) spectroscopy that allows simultaneous quantification of multiple metabolites in defined brain regions within a single acquisition.14,15

METHODS
SUBJECTS

We studied 8 patients with SPS (mean ± SD age, 43.2 ± 9.3 years; 5 men and 3 women) and 16 age-matched healthy volunteers as control subjects (mean ± SD age, 45.3 ± 16 years; 8 men and 8 women). All controls had normal neurologic examinations and normal MR images. Informed consent was obtained for each subject under a protocol approved by the institutional review board of the National Institute of Neurological Disorders and Stroke, Bethesda, Md. Patients selected for the study fulfilled the clinical criteria for diagnosis of SPS.25 The mean ± SD duration of symptoms since onset of the disease was 6.6 ± 2.1 years (range, 1-17 years). At the time of the MR examination, clinical symptoms included characteristic muscular stiffness involving the lower extremities and lower back, and episodic spasms. The serum from all of our patients had very high titers of circulating anti-GAD antibodies, as determined by enzyme-linked immunosorbent assay, Western blot, and immunostaining of GABAergic neurons in the rat brain, as described previously.5 For each patient, MR scanning was repeated at monthly intervals during a 3-month period to obtain average baseline values and thereby minimize the known episodic variabilities in this disease. Of the 8 patients, 3 were receiving long-term treatment with benzodiazepines, 2 with baclofen, and 3 with both medications. In all patients, drug treatment was maintained at the lowest possible dosage beginning no later than 1 month before the study, and these dosages remained unchanged during the baseline evaluation period.

REGIONS OF INTEREST

The MR images of the brain were obtained by means of a 1.5-T MR imager (Signa; GE Medical Systems, Milwaukee, Wis) equipped with self-shielded gradients and a quadrature head coil. Each subject was placed midline in the head coil lying in a supine position on the gantry with the head immobilized by large Styrofoam pads pressed comfortably to either side of the head in the area of the ears. Conventional MR imaging included T1-weighted sagittal and axial spin-echo acquisitions (repetition time, 400 milliseconds; echo time, 15 milliseconds), spin density and T2-weighted axial fast spin-echo acquisitions (repetition time, 4000 milliseconds; echo times 15 and 105 milliseconds), 5-mm section thickness, 24-cm field of view, and matrix size of 256 × 256. From the conventional images, regions of interest (ROIs) were identified on the conventional scans in sensorimotor cortex regions corresponding to the extremities and trunk bilaterally, and at the midline in the posterior occipital cortex, cingulate cortex, and pons (Figure 1). Selection of these regions was based on the clinical symptoms of SPS5 as well as previous observations regarding motor cortex and brainstem excitability.7,13 The ROIs measured 2.5 × 2.5 × 2.0 cm (Figure 1). This ROI size was selected to provide adequate signal-noise ratios16 for GABA concentrations in the physiologic range of 1 mmol/L,17,18 while acquisition times were minimized to maintain sufficiently rapid temporal sampling rates.14

MR SPECTROSCOPY

Localized 2D J-resolved spectra were acquired by means of a modification of the standard point-resolved spectroscopy (PRESS) pulsing sequence, also known as a 2D J-PRESS sequence.14,19 Acquisition parameters included a repetition rate of 2000 milliseconds, echo time of 35 milliseconds, digital resolution of 1024 complex points, and sweep width of 1000 Hz. During each scan, evolution time progressively increased from 35 milliseconds in 64 increments with 10-millisecond steps and 2 averages per increment, resulting in a total acquisition time of 6 minutes per ROI spectrum. Global and local shimming and chemical shift-selective water suppression were performed for each acquisition.

DATA ANALYSIS AND METABOLITE MEASUREMENTS

Spectroscopic data analysis was performed on a workstation (Sun Microsystems, Santa Clara, Calif) using software developed at the National Institutes of Health and designed to analyze decoupled metabolite peaks. Homonuclear decoupled proton spectra from each ROI acquisition were postprocessed by means of locally developed conventional algorithms that included convolution solvent filtering, cosine-squared bell apodization, zero-filling twice, Fourier transform, and modulus calculation. The analysis of preselected spectral regions with known peak assignment was hypothesis driven, and metabolites were identified on the 2D spectra from their peak intensities.14,20 Metabolite peak intensities were measured by means of modulus peaks occurring along the J = 0 axis (J0 subspectrum) at the characteristic chemical shifts assigned to the largest resonances of N-acetyl aspartate (NAA) (CH3 at 2.02 ppm), creatine (Cre) (CH3 at 3.04 ppm), and choline (Cho) (CH3 at 3.2 ppm).14 The α-CH2 GABA peak (at 2.31 ppm) was chosen because it is the largest peak that does not overlap with either the NAA or Cre peaks. Similarly, the γ-CH2 glutamate (Glu) peak (at 2.36 ppm) was evaluated.14 Additional postprocessing included tilting, symmetrization, and baseline correction.21 Metabolite peak intensities were obtained directly from the tilted unsymmetrized 2D spectrum at the J0 axis to take advantage of the greater signal-noise ratios for the peaks occurring at J0 compared with the side peaks, and to avoid introducing errors from further data manipulation introduced by procedures such as symmetrization of the side peaks. Peak intensity measurement was performed by automated computer determination of the peak height at the characteristic assigned resonance of each metabolite.14 All signal-noise ratios were measured and calculated as ratios of the measured metabolite peak intensities to the root mean squared values of the measured background noise levels, the latter being the signal variance of background 2D spectral regions with few detectable metabolite peaks. For each patient, mean metabolite values were then calculated by averaging the respective metabolite results obtained from the baseline evaluation scans.

METABOLITES

N-acetyl aspartate is a compound localized exclusively in neurons,22,23 and its changes may reflect focal neuronal loss24 or neuronal injury.25,26 The concentration of Cho reflects cellular density and total membrane content27,28 and varies with the relative amounts of gray to white matter and of glial cells to neurons.27 Glutamate is the main excitatory neurotransmitter in the brain and participates in GABA metabolism; GABA is the main inhibitory neurotransmitter in the human brain29 and is produced from the glutamate pool through GAD.29,30 Creatine reflects the total amount of Cre and phosphocreatine,31,32 and ratios of various metabolites to Cre have been commonly used in spectroscopy studies for normalization purposes.33 For each spectroscopic determination, GABA, Glu, NAA, Cho, and Cre peaks were identified and measured. Levels of GABA, Glu, NAA, and Cho were expressed as ratios relative to levels of Cre in controls and patients and compared with the t statistic (2-tailed).

RESULTS

Conventional MR imaging studies in the patient group were unremarkable. The NAA, Cho, and Glu ratios to Cre did not show any significant differences in the different brain regions compared with the controls (Table). However, decreases in the GABA levels in several brain regions were observed in the patient group relative to the controls (Table, Figure 2, and Figure 3). The GABA/Cre ratios were significantly decreased in motor cortex bilaterally in patients with SPS relative to controls (29%-36%), and to a lesser extent in the posterior occipital cortex (12%). Mild reductions in GABA/Cre ratios were observed in the cingulate and pontine ROIs in patients compared with controls, but these were not statistically significant. No other differences in any metabolite level were found in patients or in controls.

Among the group of patients with SPS, 2 had the most severe symptoms and were wheelchair bound or bedridden. Their mean ± SEM motor cortex GABA/Cre levels (0.111 ± 0.006) were 32% less than those of other patients (0.162 ± 0.011; P<.004) and 52% less than those of controls (0.231 ± 0.025; P<.002).

COMMENT

Our study shows that in patients with SPS there are decreased GABA levels in several brain regions. The finding is consistent with impairment of GABAergic transmission as an explanation for the patients’ symptoms and supports the view that SPS is a central disorder.

The previous in vitro and in vivo experiments and studies14,15 demonstrate that the spectroscopy technique used in this study is capable of measuring GABA with appropriate resolution and accuracy. Some variability in the measurements may arise from the inherent limitations of spatial resolution in our study. To obtain ROIs, voxel size had to be large enough to obtain sufficient signal-noise ratios, and ROIs were maintained in the same brain regions during repeated scans to minimize variations. Possible sources of variability in our measurements may be related to the clinical status of the patient. Changes in the degree of impairment of GABA levels at the time of the MR examination may reflect the fluctuation of symptoms seen in SPS. Several patients were being treated with benzodiazepines before admission and may have had differences in residual drug effects. Repeating the MR spectroscopy examinations monthly for 3 consecutive months helped to reduce these effects.

Although the number of patients was small, the significant correlation between the decrease in GABA levels and the severity of symptoms in 2 patients suggests that inhibition of GABA function in the brains of patients plays a pivotal role in the clinical symptoms of SPS.

In SPS, a regional decrease in GABA levels in the motor cortex may impair the action of inhibitory pathways, leading to muscle rigidity and spasms.34In turn, the increased excitation to the spinal cord causes excessive firing by α-motoneurons as discussed previously.4Pharmacologic data are consistent with the view that a reduced level of GABA may be responsible for the patients’ stiffness. Drugs that enhance GABA activity or affect GABAergic transmission, such as diazepam,35,36vigabatrin, gabapentin, or baclofen,3740 help alleviate the symptoms of SPS. Transcranial magnetic stimulation studies in patients with SPS also indicate that the motor cortex is hyperexcitable, thereby reflecting a loss of intracortical inhibition by GABAergic neurons of the cerebral cortex.7,41

An observation from the present MR spectroscopy study is that GABAergic neurons do not appear to be uniformly affected in various brain regions of patients with SPS because the decrease in GABA levels was significant in the sensorimotor cortex and, to a lesser extent, in the occipital cortex. Whether these differential variations are due to statistical factors owing to our limited number of samples, or are inherently related to the disease process, is unclear. For example, differences in the antigenic determinants among regional neurons or in their accessibility to the circulating antibodies may make some populations of GABAergic neurons more vulnerable to immunologic attack. If GAD is the putative antibody, the proportions of GAD isoforms are not uniformly expressed in different GABAergic neurons and may have different cellular localization.42 The accessibility of different GAD antigens to antibodies may also differ depending on GAD antigen exposure on the cell surface during GABA exocytosis.43 Most importantly, other antigenic targets that have different properties and distribution may be responsible in SPS.

The theory of reduced brain GABA levels is also supported by a previous observation that GABA levels are also reduced in the cerebrospinal fluid of patients with SPS.12 Regardless of the responsible antigen and the type of pathogenic antibodies, it is clear that in SPS the symptoms can be explained on the basis of impaired GABAergic function resulting in impaired inhibitory neurotransmission. It is very likely that in SPS the responsible antibodies block function on still-intact cells rather than cause structural changes in GABAergic neurons, as supported by the lack of abnormal neurologic signs other than increased muscle tone, the absence of structural lesions on MR images, and the reversibility of the findings by successful immunotherapy.4,11,40

In patients with SPS, MR spectroscopy of the brain provides a tool to evaluate regional changes in the levels of brain GABA, correlate it with disease severity, and examine whether GABA levels change with response to therapies.

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Article Information

Correspondence: Lucien M. Levy, MD, PhD, Neuroimaging Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Building 10, 5N226, Bethesda, MD 20892 (llevy@mfa.gwu.edu).

Accepted for Publication: November 5, 2004.

Author Contributions:Study concept and design: Levy, Levy-Reis, and Dalakas. Acquisition of data: Levy, Levy-Reis, and Fujii. Analysis and interpretation of data: Levy. Drafting of the manuscript: Levy, Fujii, and Dalakas. Critical revision of the manuscript for important intellectual content: Levy, Levy-Reis, Fujii, and Dalakas. Statistical analysis: Levy. Administrative, technical, and material support: Levy-Reis, Fujii, and Dalakas. Study supervision: Levy and Dalakas.

Acknowledgment: The authors thank major collaborators, including Mian Li, MD, Sherry Thomas-Vorbach, Joan Kyhos, BSN, and Beverly McElroy, CNRN. We thank Mark Hallett, MD, for his support. We are indebted to Giovanni DiChiro, MD (deceased), for setting up the new spectroscopy program at the National Institutes of Health.

References
1.
Moersch  FPWoltman  HW Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome): report of a case and some observations in 13 other cases. Mayo Clin Proc 1956;31421- 427
PubMed
2.
Toro  CJacobowitz  DMHallett  M Stiff-man syndrome. Semin Neurol 1994;14154- 158
PubMedArticle
3.
Meinck  HMRicker  KHulser  PJSchmid  EPeiffer  JSolimena  M Stiff man syndrome: clinical and laboratory findings in eight patients. J Neurol 1994;241157- 166
PubMedArticle
4.
Levy  LMDalakas  MCFloeter  MK The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of γ-aminobutyric acid. Ann Intern Med 1999;131522- 530
PubMedArticle
5.
Dalakas  MCFujii  MLi  MMcElroy  B The clinical spectrum of anti-GAD antibody–positive patients with stiff-person syndrome. Neurology 2000;551531- 1535
PubMedArticle
6.
Meinck  HMRicker  KHulser  PJSolimena  M Stiff man syndrome: neurophysiological findings in eight patients. J Neurol 1995;242134- 142
PubMedArticle
7.
Sandbrink  FSyed  NAFujii  MDDalakas  MCFloeter  MK Motor cortex excitability in stiff-person syndrome. Brain 2000;1232231- 2239
PubMedArticle
8.
Solimena  MFolli  FDenis-Donini  S  et al.  Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med 1988;3181012- 1020
PubMedArticle
9.
Saiz  AGraus  FValldeoriola  FValls-Sole  JTolosa  E Stiff-leg syndrome: a focal form of stiff-man syndrome. Ann Neurol 1998;43400- 403
PubMedArticle
10.
Dinkel  KMeinck  HMJury  KMKarges  WRichter  W Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol 1998;44194- 201
PubMedArticle
11.
Dalakas  MCFujii  MLi  MLutfi  BKyhos  JMcElroy  B High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 2001;3451870- 1876
PubMedArticle
12.
Dalakas  MCLi  MFujii  MJacobowitz  DM Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology 2001;57780- 784
PubMedArticle
13.
Molloy  FMDalakas  MCFloeter  MK Increased brainstem excitability in stiff-person syndrome. Neurology 2002;59449- 451
PubMedArticle
14.
Levy  LMHallett  M Impaired brain GABA in focal dystonia. Ann Neurol 2002;5193- 101
PubMedArticle
15.
Levy  LMZiemann  UChen  RCohen  LG Rapid modulation of GABA in sensorimotor cortex induced by acute deafferentation. Ann Neurol 2002;52755- 761
PubMedArticle
16.
Lee  HKYaman  ANalcioglu  O Homonuclear J-refocused spectral editing technique for quantification of glutamine and glutamate by 1H NMR spectroscopy. Magn Reson Med 1995;34253- 259
PubMedArticle
17.
Rothman  DLPetroff  OABehar  KLMattson  RH Localized 1H NMR measurements of γ-aminobutyric acid in human brain in vivo. Proc Natl Acad Sci U S A 1993;905662- 5666
PubMedArticle
18.
Bottomley  PA Human in vivo NMR spectroscopy in diagnostic medicine: clinical tool or research probe? Radiology 1989;1701- 15
PubMedArticle
19.
Ryner  LNSorenson  JAThomas  MA Localized 2D J-resolved 1H MR spectroscopy: strong coupling effects in vitro and in vivo. Magn Reson Imaging199513853869 [published correction appears in Magn Reson Imaging. 1995;13:1043]
PubMed
20.
Behar  KLOgino  T Assignment of resonance in the 1H spectrum of rat brain by two-dimensional shift correlated and J-resolved NMR spectroscopy. Magn Reson Med 1991;17285- 303
PubMedArticle
21.
Thomas  MARyner  LNMehta  MPTurski  PASorenson  JA Localized 2D J-resolved 1H MR spectroscopy of human brain tumors in vivo. J Magn Reson Imaging 1996;6453- 459
PubMedArticle
22.
Moffett  JRNamboodiri  MACangro  CBNeale  JH Immunohistochemical localization of N-acetylaspartate in rat brain. Neuroreport 1991;2131- 134
PubMedArticle
23.
Simmons  MLFrondoza  CGCoyle  JT Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies. Neuroscience 1991;4537- 45
PubMedArticle
24.
Cendes  FStanley  JADubeau  FAndermann  FArnold  DL Proton magnetic resonance spectroscopic imaging for discrimination of absence and complex partial seizures. Ann Neurol 1997;4174- 81
PubMedArticle
25.
Vion-Dury  JNicoli  FSalvan  AMConfort-Gouny  SDhiver  CCozzone  PJ Reversal of brain metabolic alterations with zidovudine detected by proton localised magnetic resonance spectroscopy. Lancet 1995;34560- 61
PubMedArticle
26.
Videen  JSMichaelis  TPinto  PRoss  BD Human cerebral osmolytes during chronic hyponatremia: a proton magnetic resonance spectroscopy study. J Clin Invest 1995;95788- 793
PubMedArticle
27.
Miller  BLChang  LBooth  R  et al.  In vivo 1H MRS choline: correlation with in vitro chemistry/histology. Life Sci 1996;581929- 1935
PubMedArticle
28.
Tedeschi  GLundbom  NRaman  R  et al.  Increased choline signal coinciding with malignant degeneration of cerebral gliomas: a serial proton magnetic resonance spectroscopy imaging study. J Neurosurg 1997;87516- 524
PubMedArticle
29.
Tillakaratne  NJMedina-Kauwe  LGibson  KM γ-Aminobutyric acid (GABA) metabolism in mammalian neural and nonneural tissues. Comp Biochem Physiol A Physiol 1995;112247- 263
PubMedArticle
30.
Erecinska  MSilver  IA Metabolism and role of glutamate in mammalian brain. Prog Neurobiol 1990;35245- 296
PubMedArticle
31.
Urenjak  JWilliams  SRGadian  DGNoble  M Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 1992;5955- 61
PubMedArticle
32.
Holtzman  D Brain creatine kinases and phosphocreatine: an update. Dev Neurosci 1996;18522- 523
PubMedArticle
33.
Tedeschi  GBertolino  ARighini  A  et al.  Brain regional distribution pattern of metabolite signal intensities in young adults by proton magnetic resonance spectroscopic imaging. Neurology 1995;451384- 1391
PubMedArticle
34.
Solimena  MFolli  FAparisi  RPozza  GDe Camilli  P Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990;3221555- 1560
PubMedArticle
35.
Voiculescu  VCalcaianu  GStanescu  A Abnormal reflexes in the “stiff-man” syndrome. Rev Roum Neurol 1970;7221- 226
PubMed
36.
Howard  FM A new and effective treatment for stiff-man syndrome: preliminary report. Mayo Clin Proc 1963;38203- 212
PubMed
37.
Stayer  CTronnier  VDressnandt  J  et al.  Intrathecal baclofen therapy for stiff-man syndrome and progressive encephalomyelopathy with rigidity and myoclonus. Neurology 1997;491591- 1597
PubMedArticle
38.
Seitz  RJBlank  BKiwit  JCBenecke  R Stiff-person syndrome with anti-glutamic acid decarboxylase autoantibodies: complete remission of symptoms after intrathecal baclofen administration. J Neurol 1995;242618- 622
PubMedArticle
39.
Silbert  PLMatsumoto  JYMcManis  PGStolp-Smith  KAElliott  BAMcEvoy  KM Intrathecal baclofen therapy in stiff-man syndrome: a double-blind, placebo-controlled trial. Neurology 1995;451893- 1897
PubMedArticle
40.
Vasconcelos  OMDalakas  MC Stiff-person syndrome. Curr Treat Options Neurol 2003;579- 90
PubMedArticle
41.
Jonas  PBischofberger  JSandkuhler  J Corelease of two fast neurotransmitters at a central synapse. Science 1998;281419- 424
PubMedArticle
42.
Solimena  MButler  MHDe Camilli  P GAD, diabetes, and stiff-man syndrome: some progress and more questions. J Endocrinol Invest 1994;17509- 520
PubMedArticle
43.
Ziegler  BAugstein  PSchroder  D  et al.  Glutamate decarboxylase (GAD) is not detectable on the surface of rat islet cells examined by cytofluorometry and complement-dependent antibody-mediated cytotoxicity of monoclonal GAD antibodies. Horm Metab Res 1996;2811- 15
PubMedArticle
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