J Neurol (2014) 261:238–239 DOI 10.1007/s00415-013-7197-3
LETTER TO THE EDITORS
Cortical dysfunction in cerebellar ataxia with antibodies to glutamic acid decarboxylase Neil G. Simon • Steve Vucic • Ronald Joffe Matthew C. Kiernan
•
Received: 12 November 2013 / Accepted: 15 November 2013 / Published online: 30 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Dear Sirs, Antibodies against glutamic acid decarboxylase (GAD) have been identified in a number of neurological disorders, including cerebellar ataxia [1] and stiff-person syndrome (SPS) [2]. Recent studies have suggested a role for glutamic acid decarboxylase antibodies (GAD-Ab) in producing cortical dysfunction in SPS [3], but the pathogenesis of other neurological disorders with GAD-Ab remains to be fully elucidated. In order to further define the pathogenic role of GAD-Ab in cerebellar ataxia, the cortical modulating effects of GAD-Ab were evaluated in a patient with cerebellar ataxia with GAD-Ab. A 52-year-old female, with a background of matureonset type 1 diabetes mellitus, presented with 12 months of progressive cerebellar dysfunction characterised by gait and truncal ataxia, dysarthria, complex nystagmus, and left N. G. Simon (&) S. Vucic Neuroscience Research Australia, Barker St, Randwick, NSW 2031, Australia e-mail: [email protected] N. G. Simon Prince of Wales Clinical School, University of New South Wales, Sydney, Australia S. Vucic Western Clinical School, University of Sydney, Sydney, Australia R. Joffe Department of Neurology, Royal North Shore Hospital, Reserve Rd, St Leonards, Australia M. C. Kiernan Brain and Mind Research Institute, The University of Sydney, Mallett St, Camperdown, Australia e-mail: [email protected]
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upper limb dysmetria and intention tremor. Cerebellar dysfunction was quantified using the Brief Ataxia Rating Scale, with a score of 14 out of a maximum of 30 [4]. The patient did not demonstrate features of SPS according to the heightened-sensitivity scale (HSS) [5]. On investigation, upper and lower limb nerve conduction studies, F-wave conduction and electromyography of axial and limb muscles were normal without evidence of continuous motor unit activity. Serial cerebral magnetic resonance imaging demonstrated progressive global cerebellar atrophy. GAD-Ab was detected by radioimmunoassay at high titres in both the serum (5,100 kIU/L) and CSF (1,840 kIU/L). The patient was treated with third weekly intravenous immunoglobulin (IVIG) and methylprednisolone, which did not produce significant clinical improvement. Partial clinical improvement was noted following the introduction of baclofen. Monthly IV rituximab infusions were trialled with a partial symptomatic improvement following the first treatment, but no benefit with subsequent infusions. Cortical excitability was assessed using the paired-pulse threshold tracking transcranial magnetic stimulation (TMS) technique [6], and results were compared with 32 agematched normal controls (Table 1). Testing was performed three days prior to monthly IVIG treatment and with baclofen withheld. Cortical excitability studies were abnormal with all parameters falling outside 95 % confidence intervals of control data (Fig. 1). Reductions were noted in resting motor threshold (RMT, 33 % of maximum output; control 61.4 ± 1.5 %), averaged short interval intracortical inhibition (SICI, 0.4 %; control 10.2 ± 1.0 %), peak SICI (10.4 %; control 15.6 ± 1.7 %), and intracortical facilitation (2.4 %; control -0.7 ± 1.2 %). The key finding of the present study was that cortical dysfunction was a feature of cerebellar ataxia associated with GAD antibodies. Cortical abnormalities have been
J Neurol (2014) 261:238–239
239
Table 1 GAD-Ab concentrations and cortical excitability measurements in a patient with progressive ataxia, and 32 age-matched control subjects Patient
Age
Serum GAD-Ab (kIU/L)
CSF GAD-Ab (kIU/L)
RMT (% output)
Mean SICI (%)
Peak SICI (%)
ICF (%)
Patient
53
5,100
1,840
33a
0.4a
10.4a
2.4a
Control
55.6 ± 1.5
–
–
61.4 ± 1.5
10.2 ± 1.0
15.6 ± 1.7
-0.7 ± 1.2
Values are presented as mean ± standard error of the mean GAD-Ab glutamic acid decarboxylase antibodies, RMT resting motor threshold, SICI short-interval intracortical inhibition, ICF intracortical facilitation a
Value outside 95 % confidence interval of control values
support the hypothesis that cerebellar dysfunction and cortical excitability are manifestations that lie on the spectrum of neurological disorders associated with GADAb, and may provide a pathophysiological link between cerebellar ataxia with GAD-Ab and SPS. Conflicts of interest Dr. Neil Simon received funding from the National Health and Medical Research Council of Australia and the Motor Neurone Disease Research Institute of Australia (grant #1039520). The study was supported by a National Health and Medical Research Council Program Grant (#1037746). The authors declare that they have no conflicts of interest. Ethical statement The study protocol was approved by the SouthEastern Sydney and Illawarra Area Health Service Human Research Ethics Committee. Written consent was obtained from each subject.
References
Fig. 1 a SICI (y axis, %) plotted against interstimulus interval (x axis) demonstrating reduction of SICI in the patient (filled squares) compared with controls (open squares). b Averaged SICI and Peak SICI in the patient compared with controls. Vertical bars indicate 95 % confidence interval
previously reported in stiff person syndrome [3], which correlate with intrathecal GAD-Ab titres [2]. A contribution from cerebellar disease could not be discounted, as reduction of intracortical facilitation has been reported in patients with cerebellar degeneration [7]. However, SICI and RMT are not affected in cerebellar degeneration; hence, the totality of the TMS findings could not be explained by cerebellar disease. Rather, the TMS findings
1. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, de Andres C, Maestre J, Fabien N, Vighetto A, Casamitjana R, Thivolet C, Tavolato B, Antoine J, Trouillas P, Graus F (2001) Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol 58:225–230 2. Koerner C, Wieland B, Richter W, Meinck HM (2004) Stiff-person syndromes: motor cortex hyperexcitability correlates with antiGAD autoimmunity. Neurology 62:1357–1362 3. Kim SD, Vucic S, Mahant N, Kiernan MC, Fung VS (2012) The relationship between cortical and spinal hyperexcitability and clinical disease severity in stiff-man syndrome. Parkinsonism Relat Disord 18:1045–1047 4. Schmahmann JD, Gardner R, MacMore J, Vangel MG (2009) Development of a brief ataxia rating scale (BARS) based on a modified form of the ICARS. Mov Disord 24:1820–1828 5. Dalakas MC, Fujii M, Li M, McElroy B (2000) The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 55:1531–1535 6. Vucic S, Howells J, Trevillion L, Kiernan MC (2006) Assessment of cortical excitability using threshold tracking techniques. Muscle Nerve 33:477–486 7. Wessel K, Tegenthoff M, Vorgerd M, Otto V, Nitschke MF, Malin JP (1996) Enhancement of inhibitory mechanisms in the motor cortex of patients with cerebellar degeneration: a study with transcranial magnetic brain stimulation. Electroencephalogr Clin Neurophysiol 101:273–280
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LETTER TO THE EDITORS
Cortical dysfunction in cerebellar ataxia with antibodies to glutamic acid decarboxylase Neil G. Simon • Steve Vucic • Ronald Joffe Matthew C. Kiernan
•
Received: 12 November 2013 / Accepted: 15 November 2013 / Published online: 30 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Dear Sirs, Antibodies against glutamic acid decarboxylase (GAD) have been identified in a number of neurological disorders, including cerebellar ataxia [1] and stiff-person syndrome (SPS) [2]. Recent studies have suggested a role for glutamic acid decarboxylase antibodies (GAD-Ab) in producing cortical dysfunction in SPS [3], but the pathogenesis of other neurological disorders with GAD-Ab remains to be fully elucidated. In order to further define the pathogenic role of GAD-Ab in cerebellar ataxia, the cortical modulating effects of GAD-Ab were evaluated in a patient with cerebellar ataxia with GAD-Ab. A 52-year-old female, with a background of matureonset type 1 diabetes mellitus, presented with 12 months of progressive cerebellar dysfunction characterised by gait and truncal ataxia, dysarthria, complex nystagmus, and left N. G. Simon (&) S. Vucic Neuroscience Research Australia, Barker St, Randwick, NSW 2031, Australia e-mail: [email protected] N. G. Simon Prince of Wales Clinical School, University of New South Wales, Sydney, Australia S. Vucic Western Clinical School, University of Sydney, Sydney, Australia R. Joffe Department of Neurology, Royal North Shore Hospital, Reserve Rd, St Leonards, Australia M. C. Kiernan Brain and Mind Research Institute, The University of Sydney, Mallett St, Camperdown, Australia e-mail: [email protected]
123
upper limb dysmetria and intention tremor. Cerebellar dysfunction was quantified using the Brief Ataxia Rating Scale, with a score of 14 out of a maximum of 30 [4]. The patient did not demonstrate features of SPS according to the heightened-sensitivity scale (HSS) [5]. On investigation, upper and lower limb nerve conduction studies, F-wave conduction and electromyography of axial and limb muscles were normal without evidence of continuous motor unit activity. Serial cerebral magnetic resonance imaging demonstrated progressive global cerebellar atrophy. GAD-Ab was detected by radioimmunoassay at high titres in both the serum (5,100 kIU/L) and CSF (1,840 kIU/L). The patient was treated with third weekly intravenous immunoglobulin (IVIG) and methylprednisolone, which did not produce significant clinical improvement. Partial clinical improvement was noted following the introduction of baclofen. Monthly IV rituximab infusions were trialled with a partial symptomatic improvement following the first treatment, but no benefit with subsequent infusions. Cortical excitability was assessed using the paired-pulse threshold tracking transcranial magnetic stimulation (TMS) technique [6], and results were compared with 32 agematched normal controls (Table 1). Testing was performed three days prior to monthly IVIG treatment and with baclofen withheld. Cortical excitability studies were abnormal with all parameters falling outside 95 % confidence intervals of control data (Fig. 1). Reductions were noted in resting motor threshold (RMT, 33 % of maximum output; control 61.4 ± 1.5 %), averaged short interval intracortical inhibition (SICI, 0.4 %; control 10.2 ± 1.0 %), peak SICI (10.4 %; control 15.6 ± 1.7 %), and intracortical facilitation (2.4 %; control -0.7 ± 1.2 %). The key finding of the present study was that cortical dysfunction was a feature of cerebellar ataxia associated with GAD antibodies. Cortical abnormalities have been
J Neurol (2014) 261:238–239
239
Table 1 GAD-Ab concentrations and cortical excitability measurements in a patient with progressive ataxia, and 32 age-matched control subjects Patient
Age
Serum GAD-Ab (kIU/L)
CSF GAD-Ab (kIU/L)
RMT (% output)
Mean SICI (%)
Peak SICI (%)
ICF (%)
Patient
53
5,100
1,840
33a
0.4a
10.4a
2.4a
Control
55.6 ± 1.5
–
–
61.4 ± 1.5
10.2 ± 1.0
15.6 ± 1.7
-0.7 ± 1.2
Values are presented as mean ± standard error of the mean GAD-Ab glutamic acid decarboxylase antibodies, RMT resting motor threshold, SICI short-interval intracortical inhibition, ICF intracortical facilitation a
Value outside 95 % confidence interval of control values
support the hypothesis that cerebellar dysfunction and cortical excitability are manifestations that lie on the spectrum of neurological disorders associated with GADAb, and may provide a pathophysiological link between cerebellar ataxia with GAD-Ab and SPS. Conflicts of interest Dr. Neil Simon received funding from the National Health and Medical Research Council of Australia and the Motor Neurone Disease Research Institute of Australia (grant #1039520). The study was supported by a National Health and Medical Research Council Program Grant (#1037746). The authors declare that they have no conflicts of interest. Ethical statement The study protocol was approved by the SouthEastern Sydney and Illawarra Area Health Service Human Research Ethics Committee. Written consent was obtained from each subject.
References
Fig. 1 a SICI (y axis, %) plotted against interstimulus interval (x axis) demonstrating reduction of SICI in the patient (filled squares) compared with controls (open squares). b Averaged SICI and Peak SICI in the patient compared with controls. Vertical bars indicate 95 % confidence interval
previously reported in stiff person syndrome [3], which correlate with intrathecal GAD-Ab titres [2]. A contribution from cerebellar disease could not be discounted, as reduction of intracortical facilitation has been reported in patients with cerebellar degeneration [7]. However, SICI and RMT are not affected in cerebellar degeneration; hence, the totality of the TMS findings could not be explained by cerebellar disease. Rather, the TMS findings
1. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, de Andres C, Maestre J, Fabien N, Vighetto A, Casamitjana R, Thivolet C, Tavolato B, Antoine J, Trouillas P, Graus F (2001) Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol 58:225–230 2. Koerner C, Wieland B, Richter W, Meinck HM (2004) Stiff-person syndromes: motor cortex hyperexcitability correlates with antiGAD autoimmunity. Neurology 62:1357–1362 3. Kim SD, Vucic S, Mahant N, Kiernan MC, Fung VS (2012) The relationship between cortical and spinal hyperexcitability and clinical disease severity in stiff-man syndrome. Parkinsonism Relat Disord 18:1045–1047 4. Schmahmann JD, Gardner R, MacMore J, Vangel MG (2009) Development of a brief ataxia rating scale (BARS) based on a modified form of the ICARS. Mov Disord 24:1820–1828 5. Dalakas MC, Fujii M, Li M, McElroy B (2000) The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 55:1531–1535 6. Vucic S, Howells J, Trevillion L, Kiernan MC (2006) Assessment of cortical excitability using threshold tracking techniques. Muscle Nerve 33:477–486 7. Wessel K, Tegenthoff M, Vorgerd M, Otto V, Nitschke MF, Malin JP (1996) Enhancement of inhibitory mechanisms in the motor cortex of patients with cerebellar degeneration: a study with transcranial magnetic brain stimulation. Electroencephalogr Clin Neurophysiol 101:273–280
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