BRIEF COMMUNICATION
Apraxia in Anti-Glutamic Acid Decarboxylase–Associated Stiff Person Syndrome: Link to Corticobasal Degeneration? Lauren N. Bowen, MD, S.H. Subramony, MD, and Kenneth M. Heilman, MD Corticobasal syndrome (CBS) is associated with asymmetrical rigidity as well as asymmetrical limb-kinetic and ideomotor apraxia. Stiff person syndrome (SPS) is characterized by muscle stiffness and gait difficulties. Whereas patients with CBS have several forms of pathology, many patients with SPS have glutamic acid decarboxylase antibodies (GAD-ab), but these 2 disorders have not been reported to coexist. We report 2 patients with GAD-ab–positive SPS who also had signs suggestive of CBS, including asymmetrical limb rigidity associated with both asymmetrical limb-kinetic and ideomotor apraxia. Future studies should evaluate patients with CBS for GAD-ab and people with SPS for signs of CBS. ANN NEUROL 2014;00:000–000
R
ebeiz et al reported 3 individuals with severe impairments in the control of movements, abnormalities in posture, and involuntary motor activity, a disorder they called “corticodentatonigral degeneration with neuronal achromasia.”1 Since this initial report of this disorder, now often called corticobasal syndrome (CBS), there have been a variety of clinical descriptions of the symptoms associated with this disease. One pathological study of patients who met criteria for CBS including asymmetrical rigidity and asymmetrical apraxia found that there was pathological heterogeneity in these patients.2 Subsequently, pathological studies found that CBS may entail several different underlying pathological changes, including changes associated with Pick disease, Alzheimer diseases, and progressive supranuclear palsy.3,4 Recently, an international consortium developed criteria for 4 phenotypes of this disease, and according to this consensus report, asymmetrical ideomotor apraxia (IMA) has been a core element of all diagnostic criteria for CBS.5 This report also mentions that asymmetrical limb-kinetic apraxia can be associated with CBS. Additional signs associated with CBS include
asymmetrical limb rigidity, an alien hand, cortical sensory loss, and myoclonus.5 Stiff person syndrome (SPS) is characterized by stiffness and spasms in axial and limb muscles with difficulty in gait in the absence of clinical or imaging evidence for involvement of upper motor neuron or extrapyramidal pathways. There is a close association between the presence of antibodies to glutamic acid decarboxylase (GAD-ab) and SPS; however, other neurological syndromes are also associated with GAD-ab.6 To our knowledge, there have been no prior reports of patients with GAD-ab SPS who also had the signs of CBS. Recently, we evaluated 2 patients with SPS who revealed asymmetrical upper limb plastic rigidity as well as asymmetrical ideomotor, limb-kinetic apraxia and an apraxic agraphia.
Case Reports Patient 1 In October 2013, a 49-year-old African American woman was admitted to the inpatient Neurology Service at the University of Florida Health Hospital for progressive stiffness and muscle spasms of her back and neck. Two years prior to admission, she developed lower back pain and underwent L5 discectomy with fixation for presumed disk disease. In July of 2013, she had worsening of her lower back pain and spasms, with impairment of her ability to walk as well as falls. If touched unexpectedly, her spasms increased. While in clinic, her MiniMental Status Examination was normal (29 of 30), but on Montreal Cognitive Assessment she had a score of 24 of 30, with errors in visuospatial and executive domains, letter fluency tasks, and delayed recall. To test for the presence of IMA, she was verbally asked to perform, with each upper limb, several transitive pantomimes to verbal command, which is the most sensitive test for IMA.7 The errors associated with IMA are often postural, such as using a body part as the tool or holding the hand and arm in the incorrect position, as well as movement errors, with incorrect joint movements.7 On this praxis testing, she frequently made From the Department of Neurology, University of Florida College of Medicine, Gainesville, FL. Address correspondence to Dr Bowen, University of Florida Department of Neurology, MBI 1149 Newell Drive, Room L3-100, Gainesville, FL 32611. E-mail: [email protected] Received May 30, 2014, and in revised form Jul 12, 2014. Accepted for publication Aug 2, 2014. View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana. 24245
C 2014 American Neurological Association V 1
ANNALS
of Neurology
postural and movement errors, revealing that she had an IMA that was more severe in her right than left upper limb. For example, she was asked to make believe she was holding a pair of scissors in her hand and to show how she would cut a piece of paper in half. She was also told to not use her fingers as blades. When she attempted to perform this pantomime she made a postural error, keeping her index finger fully extended. She also made a movement error. When pantomiming the use of scissors, rather than moving her thumb toward and away from her index finger, she moved it sideways, so that the thumb’s movement was parallel to her index finger. Patients who have limb-kinetic apraxia have a loss of finger–hand deftness, with a loss of the ability to perform precise, independent but coordinated finger movements.7 To test for limb-kinetic apraxia, she was assessed with the coin rotation test, where patients attempt to rotate a nickel as rapidly as possible between their thumb, index, and middle finger for 20 rotations.8 Rotating a coin requires precise, independent but coordinated finger movements. She was unable to make any successful rotations with her right hand. She was able to perform a few rotations with her left hand, but had so much difficulty we terminated this test. When asked to write with her right hand she demonstrated an impaired ability to move the pen in the spatial directions needed to correctly form the letters of the words she wanted to write, a sign of apraxic agraphia. Cranial nerve examination was normal. On motor examination her strength was normal, but she had prominent axial rigidity and increased rigidity when startled. She also had moderate plastic rigidity of her upper limbs, the right being more rigid than the left. Although no dystonia, myoclonus, or alien hand was observed, when asked about these symptoms she stated that her right arm would occasionally appear to spontaneously elevate. Her sensory and her cerebellar examinations were normal, but her gait was abnormal, with a wide base, stiff legs, and small steps (marche a petits pas). Magnetic resonance imaging (MRI) of her head revealed no significant abnormalities. MRI of her cervical, thoracic, and lumbosacral spine without contrast showed edema of the paraspinous muscles, most prominently in the right lumbar spine, but there was no abnormality of the spinal cord. An analysis of her cerebrospinal fluid (CSF) was positive for oligoclonal bands. Her CSF GADab count was 210nmol/l (normal < 0.02 nmol/L), and serum GAD-ab count was 2449.1U/ml (normal < 1U/ml). Patient 2 In January 2013, a 68-year-old Caucasian woman with a past medical history of type II diabetes was admitted to the inpatient Neurology Service at the University of 2
Florida Health Hospital with a complaint of falling. Seven years prior to admission, she developed gradual difficulty walking. She started to use a cane 51=2 years prior to presentation and a walker 2 years prior to admission when her right leg became stiff. Occasionally, she felt a sense of her lower extremities being alien limbs, with an inability to control their movements. During the same time, she noticed increasing difficulty writing and using utensils with her right hand. Two years prior to presentation she underwent cervical laminectomy for stiffness in her neck and pain radiating down her right arm. Her neurological examination on admission revealed several abnormalities. Except for defective crossed response inhibition, her mental status and cranial nerve examinations were normal. There was no ataxia or adiadochokinesia. Muscle tone was normal in both upper extremities, but increased in her lower extremities, the right lower being more rigid than the left. Her back muscles showed paraspinous muscle hypertrophy in the lumbar spine. She was not able to stand without assistance and used a rolling walker to ambulate. Her gait appeared rigid. She had limb-kinetic apraxia with her right hand during the coin rotation test,8 as well as bilateral IMA with mild bilateral agraphesthesia and constructional apraxia as tested by having her attempt to copy a drawing of intersecting pentagons. The patient’s handwriting was small, with some evidence of apraxic agraphia with the right hand. Although handwriting with the left hand was unsteady, it was not clearly agraphic. Imaging studies revealed no spinal cord abnormalities, and she had mild cerebellar atrophy on brain MRI. An analysis of her CSF was positive for oligoclonal bands. Her GAD-ab were elevated (2,560U/ml). In February 2014, she was seen for a 1-year followup after intravenous immunoglobulin treatment. She had bilateral lower extremity rigidity, greatest in the right leg. In addition, she now demonstrated rigidity of her upper extremities, with more rigidity on the right than the left. She also had axial rigidity. She had positive Myerson sign, but no other cranial nerve abnormalities including vertical eye movements. She was tested for IMA by being asked to pantomime, with each upper limb, several transitive actions to verbal command.7 On this testing, she revealed spatial postural and movement errors that were worse when using her right than left upper extremity. For example, when asked to pantomime using a pair of scissors with her right hand, but not to use her fingers as the blades, she held her forefinger in a fully extended position and moved her hand at her wrist making ulnar and radial Volume 00, No. 00
Bowen et al: Apraxia in Anti-GAD SPS
deviations. This was also seen in the left hand, but was less pronounced. When asked to scramble eggs in a bowel on her lap with a fork held in her right hand, she demonstrated some flexion–extension motions at her wrist, but no rotation of her wrist so that her imaginary fork would rotate. She performed this pantomime normally with her left hand. She was also tested with the coin rotation task for limb-kinetic apraxia, and she revealed bilateral limb-kinetic apraxia that was more severe in her right than left hand, but when compared to her prior testing this appeared as less severe.8
Discussion SPS, originally described by Moersch and Woltman, is characterized by progressive axial and limbic rigidity lacking extrapyramidal features, with associated triggered muscle spasms.9 Subsequent work divided SPS into several subtypes, including stiff limb and progressive encephalomyelitis with rigidity.10 Diagnosis originally was made by clinical presentation and electromyography demonstrating involuntary firing of motor units with absent reciprocal firing.11 The association between GADab and SPS was first described in 1990, with 60% of SPS patients testing positive for GAD-ab.12 GAD is the rate-limiting enzyme in the synthesis of c-aminobutyric acid (GABA), the major inhibitory neurotransmitter of the nervous system. Since then other antibodies such as antiamphiphysin, antigephyrin, and anti-GABAA receptor–associated protein have also been noted in SPS seen as a paraneoplastic syndrome; nearly 80% of patients with SPS test positive for an autoantibody.11–13 Both of the patients described above had symptoms and signs of SPS and were anti-GAD positive. In addition, both patients also had an asymmetrical ideomotor and limb-kinetic apraxia, asymmetrical rigidity, and an asymmetrical apraxic agraphia. In addition, Patient 1 even described an alien limb. All are signs of possible CBS.5 In regard to the loci of the pathological changes that may have induced the asymmetrical (right greater than left) ideomotor and limb-kinetic apraxia observed in these 2 patients, we could find no article that described focal cortical atrophy with SPS. The 2 patients being reported, like many other patients with CBS, have an asymmetrical ideomotor and limb-kinetic apraxia; however, the reason this disorder is asymmetrical is not known. If these patients had a loss of their left parietal visuospatial–kinesthetic movement representations, then both upper limbs should be equally apraxic. Therefore, this asymmetry suggests that their deficit is more anterior and perhaps involves the lateral or medial premotor cortex or the connections between the premotor cortex and the primary motor cortex. A study of patients with CBS who had Month 2014
undergone MRI during life and came to autopsy revealed that all CBS pathologic groups showed gray matter loss in premotor cortices and supplemental motor area.14 As mentioned, CBS can have several forms of underlying pathology, but in the absence of pathology we cannot determine whether these 2 patients may have had 1 of these diseases in addition to SPS. To our knowledge, however, SPS and CBS have not been previously reported to co-occur. There are several symptoms and signs that do occur in both CBS and GAD-ab–positive SPS, including upper limb rigidity, myoclonus, gait disorders, and even cognitive disorders.5,15 Thus, it is possible that these 2 disorders share some pathogenic mechanisms, and it is even possible that some patients who have been diagnosed as having CBS have GAD-ab–positive SPS and some of the people with SPS who are GAD-ab negative have some of the pathological changes frequently associated with CBS. Thus, it may be worthwhile to treat patients with CBS who do test positive for GAD-ab with autoimmune therapy; however, future research will have to further test these hypotheses.
Potential Conflicts of Interest S.H.S.: speaker bureau, Athena Diagnostics. K.M.H.: funding, NIH, VAMC, Florida Department of Elder Affairs.
References 1.
Rebeiz JJ, Kolodny EH, Richardson EP Jr. Corticodentatonigral degeneration with neuronal achromasia: a progressive disorder of late adult life. Trans Am Neurol Assoc 1967;92:23–26.
2.
Boeve BF, Maraganore DM, Parisi JE, et al. Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 1999;53:795–800.
3.
Tokuda T. Biomarkers for the differential diagnosis of corticobasal syndrome [in Japanese]. Brain Nerve 2013;65:55–64.
4.
Ouchi H, Toyoshima Y, Tada M, et al. Pathology and sensitivity of current clinical criteria in corticobasal syndrome. Mov Disord 2014;29:238–244.
5.
Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013;80:496–503.
6.
Saiz A, Blanco Y, Sabater L, et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 2008;131(pt 10):2553–2563.
7.
Heilman KM, Coenen A, Kluger B. Progressive asymmetric apraxic agraphia. Cogn Behav Neurol 2008;21:14–17.
8.
Hanna-Pladdy B, Mendoza JE, Apostolos GT, Heilman KM. Lateralised motor control: hemispheric damage and the loss of deftness. J Neurol Neurosurg Psychiatry 2002;73:574–577.
9.
Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm ("stiff-man" syndrome); report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin 1956; 31:421–427.
10.
Barker RA, Revesz T, Thom M, et al. Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff
3
ANNALS
of Neurology
trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 1998;65:633–640.
13.
Dalakas MC, Fujii M, Li M, McElroy B. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 2000;55:1531–1535.
11.
Alexopoulos H, Dalakas MC. A critical update on the immunopathogenesis of stiff person syndrome. Eur J Clin Invest 2010;40: 1018–1025.
14.
Whitwell JL, Jack CR Jr, Boeve BF, et al. Imaging correlates of pathology in corticobasal syndrome. Neurology 2010;75:1879– 1887.
12.
Solimena M, Folli F, Aparisi R, et al. Autoantibodies to GABAergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990;322:1555–1560.
15.
McKeon A, Robinson MT, McEvoy KM, et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 2012;69:230–238.
4
Volume 00, No. 00
Apraxia in Anti-Glutamic Acid Decarboxylase–Associated Stiff Person Syndrome: Link to Corticobasal Degeneration? Lauren N. Bowen, MD, S.H. Subramony, MD, and Kenneth M. Heilman, MD Corticobasal syndrome (CBS) is associated with asymmetrical rigidity as well as asymmetrical limb-kinetic and ideomotor apraxia. Stiff person syndrome (SPS) is characterized by muscle stiffness and gait difficulties. Whereas patients with CBS have several forms of pathology, many patients with SPS have glutamic acid decarboxylase antibodies (GAD-ab), but these 2 disorders have not been reported to coexist. We report 2 patients with GAD-ab–positive SPS who also had signs suggestive of CBS, including asymmetrical limb rigidity associated with both asymmetrical limb-kinetic and ideomotor apraxia. Future studies should evaluate patients with CBS for GAD-ab and people with SPS for signs of CBS. ANN NEUROL 2014;00:000–000
R
ebeiz et al reported 3 individuals with severe impairments in the control of movements, abnormalities in posture, and involuntary motor activity, a disorder they called “corticodentatonigral degeneration with neuronal achromasia.”1 Since this initial report of this disorder, now often called corticobasal syndrome (CBS), there have been a variety of clinical descriptions of the symptoms associated with this disease. One pathological study of patients who met criteria for CBS including asymmetrical rigidity and asymmetrical apraxia found that there was pathological heterogeneity in these patients.2 Subsequently, pathological studies found that CBS may entail several different underlying pathological changes, including changes associated with Pick disease, Alzheimer diseases, and progressive supranuclear palsy.3,4 Recently, an international consortium developed criteria for 4 phenotypes of this disease, and according to this consensus report, asymmetrical ideomotor apraxia (IMA) has been a core element of all diagnostic criteria for CBS.5 This report also mentions that asymmetrical limb-kinetic apraxia can be associated with CBS. Additional signs associated with CBS include
asymmetrical limb rigidity, an alien hand, cortical sensory loss, and myoclonus.5 Stiff person syndrome (SPS) is characterized by stiffness and spasms in axial and limb muscles with difficulty in gait in the absence of clinical or imaging evidence for involvement of upper motor neuron or extrapyramidal pathways. There is a close association between the presence of antibodies to glutamic acid decarboxylase (GAD-ab) and SPS; however, other neurological syndromes are also associated with GAD-ab.6 To our knowledge, there have been no prior reports of patients with GAD-ab SPS who also had the signs of CBS. Recently, we evaluated 2 patients with SPS who revealed asymmetrical upper limb plastic rigidity as well as asymmetrical ideomotor, limb-kinetic apraxia and an apraxic agraphia.
Case Reports Patient 1 In October 2013, a 49-year-old African American woman was admitted to the inpatient Neurology Service at the University of Florida Health Hospital for progressive stiffness and muscle spasms of her back and neck. Two years prior to admission, she developed lower back pain and underwent L5 discectomy with fixation for presumed disk disease. In July of 2013, she had worsening of her lower back pain and spasms, with impairment of her ability to walk as well as falls. If touched unexpectedly, her spasms increased. While in clinic, her MiniMental Status Examination was normal (29 of 30), but on Montreal Cognitive Assessment she had a score of 24 of 30, with errors in visuospatial and executive domains, letter fluency tasks, and delayed recall. To test for the presence of IMA, she was verbally asked to perform, with each upper limb, several transitive pantomimes to verbal command, which is the most sensitive test for IMA.7 The errors associated with IMA are often postural, such as using a body part as the tool or holding the hand and arm in the incorrect position, as well as movement errors, with incorrect joint movements.7 On this praxis testing, she frequently made From the Department of Neurology, University of Florida College of Medicine, Gainesville, FL. Address correspondence to Dr Bowen, University of Florida Department of Neurology, MBI 1149 Newell Drive, Room L3-100, Gainesville, FL 32611. E-mail: [email protected] Received May 30, 2014, and in revised form Jul 12, 2014. Accepted for publication Aug 2, 2014. View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana. 24245
C 2014 American Neurological Association V 1
ANNALS
of Neurology
postural and movement errors, revealing that she had an IMA that was more severe in her right than left upper limb. For example, she was asked to make believe she was holding a pair of scissors in her hand and to show how she would cut a piece of paper in half. She was also told to not use her fingers as blades. When she attempted to perform this pantomime she made a postural error, keeping her index finger fully extended. She also made a movement error. When pantomiming the use of scissors, rather than moving her thumb toward and away from her index finger, she moved it sideways, so that the thumb’s movement was parallel to her index finger. Patients who have limb-kinetic apraxia have a loss of finger–hand deftness, with a loss of the ability to perform precise, independent but coordinated finger movements.7 To test for limb-kinetic apraxia, she was assessed with the coin rotation test, where patients attempt to rotate a nickel as rapidly as possible between their thumb, index, and middle finger for 20 rotations.8 Rotating a coin requires precise, independent but coordinated finger movements. She was unable to make any successful rotations with her right hand. She was able to perform a few rotations with her left hand, but had so much difficulty we terminated this test. When asked to write with her right hand she demonstrated an impaired ability to move the pen in the spatial directions needed to correctly form the letters of the words she wanted to write, a sign of apraxic agraphia. Cranial nerve examination was normal. On motor examination her strength was normal, but she had prominent axial rigidity and increased rigidity when startled. She also had moderate plastic rigidity of her upper limbs, the right being more rigid than the left. Although no dystonia, myoclonus, or alien hand was observed, when asked about these symptoms she stated that her right arm would occasionally appear to spontaneously elevate. Her sensory and her cerebellar examinations were normal, but her gait was abnormal, with a wide base, stiff legs, and small steps (marche a petits pas). Magnetic resonance imaging (MRI) of her head revealed no significant abnormalities. MRI of her cervical, thoracic, and lumbosacral spine without contrast showed edema of the paraspinous muscles, most prominently in the right lumbar spine, but there was no abnormality of the spinal cord. An analysis of her cerebrospinal fluid (CSF) was positive for oligoclonal bands. Her CSF GADab count was 210nmol/l (normal < 0.02 nmol/L), and serum GAD-ab count was 2449.1U/ml (normal < 1U/ml). Patient 2 In January 2013, a 68-year-old Caucasian woman with a past medical history of type II diabetes was admitted to the inpatient Neurology Service at the University of 2
Florida Health Hospital with a complaint of falling. Seven years prior to admission, she developed gradual difficulty walking. She started to use a cane 51=2 years prior to presentation and a walker 2 years prior to admission when her right leg became stiff. Occasionally, she felt a sense of her lower extremities being alien limbs, with an inability to control their movements. During the same time, she noticed increasing difficulty writing and using utensils with her right hand. Two years prior to presentation she underwent cervical laminectomy for stiffness in her neck and pain radiating down her right arm. Her neurological examination on admission revealed several abnormalities. Except for defective crossed response inhibition, her mental status and cranial nerve examinations were normal. There was no ataxia or adiadochokinesia. Muscle tone was normal in both upper extremities, but increased in her lower extremities, the right lower being more rigid than the left. Her back muscles showed paraspinous muscle hypertrophy in the lumbar spine. She was not able to stand without assistance and used a rolling walker to ambulate. Her gait appeared rigid. She had limb-kinetic apraxia with her right hand during the coin rotation test,8 as well as bilateral IMA with mild bilateral agraphesthesia and constructional apraxia as tested by having her attempt to copy a drawing of intersecting pentagons. The patient’s handwriting was small, with some evidence of apraxic agraphia with the right hand. Although handwriting with the left hand was unsteady, it was not clearly agraphic. Imaging studies revealed no spinal cord abnormalities, and she had mild cerebellar atrophy on brain MRI. An analysis of her CSF was positive for oligoclonal bands. Her GAD-ab were elevated (2,560U/ml). In February 2014, she was seen for a 1-year followup after intravenous immunoglobulin treatment. She had bilateral lower extremity rigidity, greatest in the right leg. In addition, she now demonstrated rigidity of her upper extremities, with more rigidity on the right than the left. She also had axial rigidity. She had positive Myerson sign, but no other cranial nerve abnormalities including vertical eye movements. She was tested for IMA by being asked to pantomime, with each upper limb, several transitive actions to verbal command.7 On this testing, she revealed spatial postural and movement errors that were worse when using her right than left upper extremity. For example, when asked to pantomime using a pair of scissors with her right hand, but not to use her fingers as the blades, she held her forefinger in a fully extended position and moved her hand at her wrist making ulnar and radial Volume 00, No. 00
Bowen et al: Apraxia in Anti-GAD SPS
deviations. This was also seen in the left hand, but was less pronounced. When asked to scramble eggs in a bowel on her lap with a fork held in her right hand, she demonstrated some flexion–extension motions at her wrist, but no rotation of her wrist so that her imaginary fork would rotate. She performed this pantomime normally with her left hand. She was also tested with the coin rotation task for limb-kinetic apraxia, and she revealed bilateral limb-kinetic apraxia that was more severe in her right than left hand, but when compared to her prior testing this appeared as less severe.8
Discussion SPS, originally described by Moersch and Woltman, is characterized by progressive axial and limbic rigidity lacking extrapyramidal features, with associated triggered muscle spasms.9 Subsequent work divided SPS into several subtypes, including stiff limb and progressive encephalomyelitis with rigidity.10 Diagnosis originally was made by clinical presentation and electromyography demonstrating involuntary firing of motor units with absent reciprocal firing.11 The association between GADab and SPS was first described in 1990, with 60% of SPS patients testing positive for GAD-ab.12 GAD is the rate-limiting enzyme in the synthesis of c-aminobutyric acid (GABA), the major inhibitory neurotransmitter of the nervous system. Since then other antibodies such as antiamphiphysin, antigephyrin, and anti-GABAA receptor–associated protein have also been noted in SPS seen as a paraneoplastic syndrome; nearly 80% of patients with SPS test positive for an autoantibody.11–13 Both of the patients described above had symptoms and signs of SPS and were anti-GAD positive. In addition, both patients also had an asymmetrical ideomotor and limb-kinetic apraxia, asymmetrical rigidity, and an asymmetrical apraxic agraphia. In addition, Patient 1 even described an alien limb. All are signs of possible CBS.5 In regard to the loci of the pathological changes that may have induced the asymmetrical (right greater than left) ideomotor and limb-kinetic apraxia observed in these 2 patients, we could find no article that described focal cortical atrophy with SPS. The 2 patients being reported, like many other patients with CBS, have an asymmetrical ideomotor and limb-kinetic apraxia; however, the reason this disorder is asymmetrical is not known. If these patients had a loss of their left parietal visuospatial–kinesthetic movement representations, then both upper limbs should be equally apraxic. Therefore, this asymmetry suggests that their deficit is more anterior and perhaps involves the lateral or medial premotor cortex or the connections between the premotor cortex and the primary motor cortex. A study of patients with CBS who had Month 2014
undergone MRI during life and came to autopsy revealed that all CBS pathologic groups showed gray matter loss in premotor cortices and supplemental motor area.14 As mentioned, CBS can have several forms of underlying pathology, but in the absence of pathology we cannot determine whether these 2 patients may have had 1 of these diseases in addition to SPS. To our knowledge, however, SPS and CBS have not been previously reported to co-occur. There are several symptoms and signs that do occur in both CBS and GAD-ab–positive SPS, including upper limb rigidity, myoclonus, gait disorders, and even cognitive disorders.5,15 Thus, it is possible that these 2 disorders share some pathogenic mechanisms, and it is even possible that some patients who have been diagnosed as having CBS have GAD-ab–positive SPS and some of the people with SPS who are GAD-ab negative have some of the pathological changes frequently associated with CBS. Thus, it may be worthwhile to treat patients with CBS who do test positive for GAD-ab with autoimmune therapy; however, future research will have to further test these hypotheses.
Potential Conflicts of Interest S.H.S.: speaker bureau, Athena Diagnostics. K.M.H.: funding, NIH, VAMC, Florida Department of Elder Affairs.
References 1.
Rebeiz JJ, Kolodny EH, Richardson EP Jr. Corticodentatonigral degeneration with neuronal achromasia: a progressive disorder of late adult life. Trans Am Neurol Assoc 1967;92:23–26.
2.
Boeve BF, Maraganore DM, Parisi JE, et al. Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 1999;53:795–800.
3.
Tokuda T. Biomarkers for the differential diagnosis of corticobasal syndrome [in Japanese]. Brain Nerve 2013;65:55–64.
4.
Ouchi H, Toyoshima Y, Tada M, et al. Pathology and sensitivity of current clinical criteria in corticobasal syndrome. Mov Disord 2014;29:238–244.
5.
Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013;80:496–503.
6.
Saiz A, Blanco Y, Sabater L, et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 2008;131(pt 10):2553–2563.
7.
Heilman KM, Coenen A, Kluger B. Progressive asymmetric apraxic agraphia. Cogn Behav Neurol 2008;21:14–17.
8.
Hanna-Pladdy B, Mendoza JE, Apostolos GT, Heilman KM. Lateralised motor control: hemispheric damage and the loss of deftness. J Neurol Neurosurg Psychiatry 2002;73:574–577.
9.
Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm ("stiff-man" syndrome); report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin 1956; 31:421–427.
10.
Barker RA, Revesz T, Thom M, et al. Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff
3
ANNALS
of Neurology
trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 1998;65:633–640.
13.
Dalakas MC, Fujii M, Li M, McElroy B. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 2000;55:1531–1535.
11.
Alexopoulos H, Dalakas MC. A critical update on the immunopathogenesis of stiff person syndrome. Eur J Clin Invest 2010;40: 1018–1025.
14.
Whitwell JL, Jack CR Jr, Boeve BF, et al. Imaging correlates of pathology in corticobasal syndrome. Neurology 2010;75:1879– 1887.
12.
Solimena M, Folli F, Aparisi R, et al. Autoantibodies to GABAergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990;322:1555–1560.
15.
McKeon A, Robinson MT, McEvoy KM, et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 2012;69:230–238.
4
Volume 00, No. 00
