Journal of the Neurological Sciences 337 (2014) 235–237
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Evidence of T-cell mediated neuronal injury in stiff-person syndrome with anti-amphiphysin antibodies Mervyn Q.W. Poh a,⁎, Neil G. Simon b,c, Michael E. Buckland d, Elizabeth Salisbury e, Shaun Watson a,b,c a
Department of Neurology, Prince of Wales Hospital, Barker St., Randwick, Australia Neuroscience Research Australia, Barker St., Randwick, Australia Prince of Wales Clinical School, University of New South Wales, Barker St., Randwick, Australia d Neuropathology Department, Royal Prince Alfred Hospital and the University of Sydney, Sydney, Australia e Department of Anatomical Pathology, Prince of Wales Hospital, Barker St., Randwick, Australia b c
a r t i c l e
i n f o
Article history: Received 16 June 2013 Received in revised form 9 November 2013 Accepted 5 December 2013 Available online 15 December 2013 Keywords: Stiff-person syndrome Amphiphysin Paraneoplastic Neuronophagia Cytotoxic T-cell Amphiphysin antibodies
a b s t r a c t Paraneoplastic stiff-person syndrome (SPS) has been associated with antibodies against amphiphysin. Current evidence supports a pathogenic role for anti-amphiphysin antibodies. A 74-year-old female was diagnosed with amphiphysin-associated paraneoplastic stiff-person syndrome and associated encephalomyelitis. She had initial response to IVIG, however her symptoms worsened after two months and were resistant to further treatment. Subsequently the patient died and a post-mortem was performed. Neuropathology revealed perivascular and parenchymal lymphocytic infiltrates, with neuronophagia mediated by CD8 + T cells and microglia in brainstem, spinal cord, and mesial temporal lobe structures. These findings suggest a pathogenic role of cytotoxic CD8+ T-cells, with potential implication for therapy of future patients. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Stiff-person syndrome (SPS) is a disorder characterised by muscle rigidity and painful spasms with sensitivity to sensory or emotional stimulation. It can arise as a paraneoplastic disorder, most frequently associated with breast cancer, or more commonly as an idiopathic form. A number of auto-antibodies have been associated with SPS. Antibodies against glutamic acid decarboxylase (GAD) are most prevalent in idiopathic forms, while paraneoplastic forms have been associated with other antibodies, predominantly anti-amphiphysin antibody [1]. Amphiphysin, a 128 kDa intracellular protein, is highly expressed in neurons with intensive synaptic activity and mediates vesicle endocytosis [2]. Although it is expressed at low levels outside the brain, it has been proposed that the enhanced expression of amphiphysin by breast cancer tissue and an immune response against these tumour cells promote the formation of amphiphysin antibody [3]. There is evidence for a dose-dependent, pathogenic role of anti-amphiphysin antibodies in the generation of muscle stiffness and spasms in SPS [2,4]. Cytotoxic T-cells may also play a role in the pathogenesis of SPS, although this has not previously been confirmed by the clear demonstration of T-cell neuronophagia [5,6].
⁎ Corresponding author at: 83 Jalan Pergam, 488359, Singapore. E-mail address: [email protected] (M.Q.W. Poh). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.12.015
The present study provides histopathological evidence of T-cell mediated neuronal injury in a patient with SPS associated with antiamphiphysin antibodies and breast cancer. 2. Methods 2.1. Case report A 74-year-old woman presented with widespread parasthesiae and episodic vertigo. She then developed spasm and stiffness of her left arm, right leg, neck and jaw muscles with associated diplopia. During the admission a malignant breast lump was discovered and left mastectomy performed. Histologic investigation of mammary tissue revealed a grade 3 invasive ductal carcinoma with metastatic invasion of 1 of the 17 axillary lymph nodes. Contrast-enhanced MRI of brain and spine were considered unremarkable for age. Cerebrospinal fluid analysis demonstrated a lymphocytic pleocytosis (8 cells/mm3) and raised protein concentration (0.66 g/L). Serum was positive for anti-amphiphysin antibodies but negative for anti-GAD antibodies. Serologic testing for infective and other autoimmune and vasculitic diseases was negative. Despite the commencement of intravenous (IV) methylprednisolone, continued deterioration was noted with increased muscle stiffness, slow saccadic eye movements and development of confusion.
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M.Q.W. Poh et al. / Journal of the Neurological Sciences 337 (2014) 235–237
Methylprednisolone therapy was replaced by diazepam and IV immunoglobulin, which resulted in temporary improvement in muscle stiffness and spasms. However, two months later the limb stiffness worsened. At this stage there was no clinical response to immunoglobulin or intrathecal baclofen and chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil did not produce significant improvement. Plasmaphoresis was subsequently considered but was not feasible because of cardiovascular and respiratory instability. The patient continued to deteriorate and she developed severe stridor and type two respiratory failure largely due to chest wall restriction. Her condition progressed until death from respiratory failure 7 months after disease onset, after the decision was taken to withdraw active treatment. She underwent full autopsy examination. 3. Results 3.1. Neuropathology The brain and spinal cord were examined. The brain fresh weight was 1266 g. There was mild ventriculomegaly noted; the macroscopic examination was otherwise unremarkable. Microscopic examination revealed prominent perivascular and parenchymal lymphocytic and microglial infiltration of grey matter, predominantly affecting the spinal cord and medulla symmetrically,
with lesser involvement of the amygdala (Fig. 1A, B), pons, hippocampus, and basal ganglia. The neocortex (including primary motor cortex), thalamus and cerebellum were uninvolved. There were associated and variable neuronal loss, microglial nodules, and gliosis. Brain white matter tracts were generally uninvolved, however moderate white matter loss and macrophage infiltration were seen in the spinal cord, including the anterior and lateral corticospinal tracts. Immunohistochemistry showed that the inflammatory infiltrate was a mix of activated CD68 positive microglia, CD20 positive B-cells and CD3 positive T-cells. The lymphocytes' cuffing vessels were predominantly B cells (Fig. 1C) with lesser numbers of CD4+ T cells (Fig. 1D) and CD8 + T cells (Fig. 1E). Infiltrating cells in the grey matter were predominantly CD8 + T-cells and CD68 + microglia. Areas showing neuronophagia had a preponderance of CD8 + T-cells (Fig. 1F, G), with these cells intimately juxtaposed against damaged neurons. In the brainstem and spinal cord, both motor and sensory neuronal regions were severely involved, including the dorsal and ventral horns of the spinal cord, inferior olives, hypoglossal nuclei (Fig. 1F, G), vestibular nuclei, and dorsal motor nuclei of the vagus. All these regions showed varying combinations of neuronal loss, neuronophagia, parenchymal and perivascular infiltrates of lymphocytes and microglia, and gliosis. In the hippocampus, there was patchy neuronal dropout in the CA2/CA3 region associated with inflammatory neuronophagia and gliosis.
Fig. 1. Histopathology of the temporal lobe (A–E) and brainstem lesions. (A) Haematoxylin and eosin (H&E) stained section of the amygdala reveals perivascular and intraparenchymal infiltrates of mononuclear inflammatory cells. The boxed area is shown at higher magnification in (B), where neuronophagia is evident, mediated by lymphocytes and some microglia. (C, D, E) shows the perivascular inflammatory infiltrate to contain a predominance of CD20+ B cells, with a lesser number of CD4 + and CD8 + T cells. (F) Neuronophagia in the hypoglossal nucleus, which is in part mediated by numerous CD8+ T cells (G; arrows indicate degenerating neuronal nuclei). Magnification: 200× (A), 630× (B, F, G), 400× (C, D, E).
M.Q.W. Poh et al. / Journal of the Neurological Sciences 337 (2014) 235–237
There was no evidence of residual or metastatic breast carcinoma or other malignancy.
237
Disclosure Statement No financial assistance was received for this case report.
4. Discussion References The present case provided histopathological evidence for cytotoxic T-cell mediated neuronal injury in a patient with SPS and encephalomyelitis associated with anti-amphiphysin antibodies and breast cancer. Strikingly region-specific neuronophagia by cytotoxic T-cells was seen centred on the spinal cord and brainstem, with lesser involvement of the basal ganglia and mesial temporal structures. The post-mortem findings in this case were in agreement with previous histopathological studies of SPS, which demonstrated neuronal loss and gliosis in the brain, brainstem and spinal cord. Furthermore, perivascular infiltrates are typically comprised of B lymphocytes and parenchymal infiltrates were predominantly CD8 + and CD4 + T-cells [5–8]. However, this report is the first demonstrating direct evidence of cytotoxic T cell-mediated neuronal injury in SPS. The nature and distribution of the histopathological features is not unique to paraneoplastic SPS. Perivascular lymphocytic infiltrates associated with T-cell mediated neuroaxonal injury have been identified in other autoimmune disorders [9]. In addition, perivascular inflammatory infiltrates, glial nodules, and neuronophagia have been reported in anti-Ma2 paraneoplastic encephalitis but in this condition, pathological changes are confined to the brain [10,11]. The occurrence of SPS in patients with anti-amphiphysin antibodies may relate to cellular injury in the spinal cord, including corticospinal tract injury, which is not as prominent in the other autoimmune disorders. However, it is noted that anti-amphiphysin antibodies are able to evoke SPS-like phenomena in passive transfer experiments, suggesting that there is also a humoral contribution to the pathogenesis of the disease [2,4]. Clinical features noted in the present report overlap with findings in progressive encephalomyelitis with rigidity and myoclonus (PERM), the severe and rapidly progressive end of the SPS clinical syndrome [12–14]. Anti-amphiphysin antibody in PERM has been reported in only one previous case report [15]. Similar neuropathological findings may be seen in both SPS and PERM, suggesting that the two diseases may also lie on a pathological spectrum [12]. While neuronophagia by microglial cells and direct apposition of CD 8 + cytotoxic T-cells to hippocampal neurones have been noted in previous PERM neuropathology findings, none have reported neuronophagia by CD8 + cytotoxic T cells [14,16–18].
[1] Murinson BB, Guarnaccia JB. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 2008;71:1955–8. [2] Geis C, Weishaupt A, Hallermann S, Grunewald B, Wessig C, Wultsch T, et al. Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 2010;133:3166–80. [3] Floyd S, Butler MH, Cremona O, David C, Freyberg Z, Zhang X, et al. Expression of amphiphysin I, an autoantigen of paraneoplastic neurological syndromes, in breast cancer. Mol Med 1998;4:29–39. [4] Sommer C, Weishaupt A, Brinkhoff J, Biko L, Wessig C, Gold R, et al. Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet 2005;365:1406–11. [5] Wessig C, Klein R, Schneider MF, Toyka KV, Naumann M, Sommer C. Neuropathology and binding studies in anti-amphiphysin-associated stiff-person syndrome. Neurology 2003;61:195–8. [6] Pittock SJ, Lucchinetti CF, Parisi JE, Benarroch EE, Mokri B, Stephan CL, et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol 2005;58:96–107. [7] Bateman DE, Weller RO, Kennedy P. Stiffman syndrome: a rare paraneoplastic disorder? J Neurol Neurosurg Psychiatry 1990;53:695–6. [8] Holmoy T, Skorstad G, Roste LS, Scheie D, Alvik K. Stiff person syndrome associated with lower motor neuron disease and infiltration of cytotoxic T cells in the spinal cord. Clin Neurol Neurosurg 2009;111:708–12. [9] Simon NG, Parratt JD, Barnett MH, Buckland ME, Gupta R, Hayes MW, et al. Expanding the clinical, radiological and neuropathological phenotype of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). J Neurol Neurosurg Psychiatry 2012;83:15–22. [10] Barnett M, Prosser J, Sutton I, Halmagyi GM, Davies L, Harper C, et al. Paraneoplastic brain stem encephalitis in a woman with anti-Ma2 antibody. J Neurol Neurosurg Psychiatry 2001;70:222–5. [11] Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004;127:1831–44. [12] Meinck HM, Thompson PD. Stiff man syndrome and related conditions. Mov Disord 2002;17:853–66. [13] McKeon A, Robinson MT, McEvoy KM, Matsumoto JY, Lennon VA, Ahlskog JE, et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 2012;69:230–8. [14] Barker RA, Revesz T, Thom M, Marsden CD, Brown P. Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 1998;65:633–40. [15] Ishii A, Hayashi A, Ohkoshi N, Matsuno S, Shoji S. Progressive encephalomyelitis with rigidity associated with anti-amphiphysin antibodies. J Neurol Neurosurg Psychiatry 2004;75:661–2. [16] Whiteley AM, Swash M, Urich H. Progressive encephalomyelitis with rigidity. Brain 1976;99:27–42. [17] Howell DA, Lees AJ, Toghill PJ. Spinal internuncial neurones in progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 1979;42:773–85. [18] Turner MR, Irani SR, Leite MI, Nithi K, Vincent A, Ansorge O. Progressive encephalomyelitis with rigidity and myoclonus: glycine and NMDA receptor antibodies. Neurology 2011;77:439–43.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Evidence of T-cell mediated neuronal injury in stiff-person syndrome with anti-amphiphysin antibodies Mervyn Q.W. Poh a,⁎, Neil G. Simon b,c, Michael E. Buckland d, Elizabeth Salisbury e, Shaun Watson a,b,c a
Department of Neurology, Prince of Wales Hospital, Barker St., Randwick, Australia Neuroscience Research Australia, Barker St., Randwick, Australia Prince of Wales Clinical School, University of New South Wales, Barker St., Randwick, Australia d Neuropathology Department, Royal Prince Alfred Hospital and the University of Sydney, Sydney, Australia e Department of Anatomical Pathology, Prince of Wales Hospital, Barker St., Randwick, Australia b c
a r t i c l e
i n f o
Article history: Received 16 June 2013 Received in revised form 9 November 2013 Accepted 5 December 2013 Available online 15 December 2013 Keywords: Stiff-person syndrome Amphiphysin Paraneoplastic Neuronophagia Cytotoxic T-cell Amphiphysin antibodies
a b s t r a c t Paraneoplastic stiff-person syndrome (SPS) has been associated with antibodies against amphiphysin. Current evidence supports a pathogenic role for anti-amphiphysin antibodies. A 74-year-old female was diagnosed with amphiphysin-associated paraneoplastic stiff-person syndrome and associated encephalomyelitis. She had initial response to IVIG, however her symptoms worsened after two months and were resistant to further treatment. Subsequently the patient died and a post-mortem was performed. Neuropathology revealed perivascular and parenchymal lymphocytic infiltrates, with neuronophagia mediated by CD8 + T cells and microglia in brainstem, spinal cord, and mesial temporal lobe structures. These findings suggest a pathogenic role of cytotoxic CD8+ T-cells, with potential implication for therapy of future patients. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Stiff-person syndrome (SPS) is a disorder characterised by muscle rigidity and painful spasms with sensitivity to sensory or emotional stimulation. It can arise as a paraneoplastic disorder, most frequently associated with breast cancer, or more commonly as an idiopathic form. A number of auto-antibodies have been associated with SPS. Antibodies against glutamic acid decarboxylase (GAD) are most prevalent in idiopathic forms, while paraneoplastic forms have been associated with other antibodies, predominantly anti-amphiphysin antibody [1]. Amphiphysin, a 128 kDa intracellular protein, is highly expressed in neurons with intensive synaptic activity and mediates vesicle endocytosis [2]. Although it is expressed at low levels outside the brain, it has been proposed that the enhanced expression of amphiphysin by breast cancer tissue and an immune response against these tumour cells promote the formation of amphiphysin antibody [3]. There is evidence for a dose-dependent, pathogenic role of anti-amphiphysin antibodies in the generation of muscle stiffness and spasms in SPS [2,4]. Cytotoxic T-cells may also play a role in the pathogenesis of SPS, although this has not previously been confirmed by the clear demonstration of T-cell neuronophagia [5,6].
⁎ Corresponding author at: 83 Jalan Pergam, 488359, Singapore. E-mail address: [email protected] (M.Q.W. Poh). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.12.015
The present study provides histopathological evidence of T-cell mediated neuronal injury in a patient with SPS associated with antiamphiphysin antibodies and breast cancer. 2. Methods 2.1. Case report A 74-year-old woman presented with widespread parasthesiae and episodic vertigo. She then developed spasm and stiffness of her left arm, right leg, neck and jaw muscles with associated diplopia. During the admission a malignant breast lump was discovered and left mastectomy performed. Histologic investigation of mammary tissue revealed a grade 3 invasive ductal carcinoma with metastatic invasion of 1 of the 17 axillary lymph nodes. Contrast-enhanced MRI of brain and spine were considered unremarkable for age. Cerebrospinal fluid analysis demonstrated a lymphocytic pleocytosis (8 cells/mm3) and raised protein concentration (0.66 g/L). Serum was positive for anti-amphiphysin antibodies but negative for anti-GAD antibodies. Serologic testing for infective and other autoimmune and vasculitic diseases was negative. Despite the commencement of intravenous (IV) methylprednisolone, continued deterioration was noted with increased muscle stiffness, slow saccadic eye movements and development of confusion.
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M.Q.W. Poh et al. / Journal of the Neurological Sciences 337 (2014) 235–237
Methylprednisolone therapy was replaced by diazepam and IV immunoglobulin, which resulted in temporary improvement in muscle stiffness and spasms. However, two months later the limb stiffness worsened. At this stage there was no clinical response to immunoglobulin or intrathecal baclofen and chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil did not produce significant improvement. Plasmaphoresis was subsequently considered but was not feasible because of cardiovascular and respiratory instability. The patient continued to deteriorate and she developed severe stridor and type two respiratory failure largely due to chest wall restriction. Her condition progressed until death from respiratory failure 7 months after disease onset, after the decision was taken to withdraw active treatment. She underwent full autopsy examination. 3. Results 3.1. Neuropathology The brain and spinal cord were examined. The brain fresh weight was 1266 g. There was mild ventriculomegaly noted; the macroscopic examination was otherwise unremarkable. Microscopic examination revealed prominent perivascular and parenchymal lymphocytic and microglial infiltration of grey matter, predominantly affecting the spinal cord and medulla symmetrically,
with lesser involvement of the amygdala (Fig. 1A, B), pons, hippocampus, and basal ganglia. The neocortex (including primary motor cortex), thalamus and cerebellum were uninvolved. There were associated and variable neuronal loss, microglial nodules, and gliosis. Brain white matter tracts were generally uninvolved, however moderate white matter loss and macrophage infiltration were seen in the spinal cord, including the anterior and lateral corticospinal tracts. Immunohistochemistry showed that the inflammatory infiltrate was a mix of activated CD68 positive microglia, CD20 positive B-cells and CD3 positive T-cells. The lymphocytes' cuffing vessels were predominantly B cells (Fig. 1C) with lesser numbers of CD4+ T cells (Fig. 1D) and CD8 + T cells (Fig. 1E). Infiltrating cells in the grey matter were predominantly CD8 + T-cells and CD68 + microglia. Areas showing neuronophagia had a preponderance of CD8 + T-cells (Fig. 1F, G), with these cells intimately juxtaposed against damaged neurons. In the brainstem and spinal cord, both motor and sensory neuronal regions were severely involved, including the dorsal and ventral horns of the spinal cord, inferior olives, hypoglossal nuclei (Fig. 1F, G), vestibular nuclei, and dorsal motor nuclei of the vagus. All these regions showed varying combinations of neuronal loss, neuronophagia, parenchymal and perivascular infiltrates of lymphocytes and microglia, and gliosis. In the hippocampus, there was patchy neuronal dropout in the CA2/CA3 region associated with inflammatory neuronophagia and gliosis.
Fig. 1. Histopathology of the temporal lobe (A–E) and brainstem lesions. (A) Haematoxylin and eosin (H&E) stained section of the amygdala reveals perivascular and intraparenchymal infiltrates of mononuclear inflammatory cells. The boxed area is shown at higher magnification in (B), where neuronophagia is evident, mediated by lymphocytes and some microglia. (C, D, E) shows the perivascular inflammatory infiltrate to contain a predominance of CD20+ B cells, with a lesser number of CD4 + and CD8 + T cells. (F) Neuronophagia in the hypoglossal nucleus, which is in part mediated by numerous CD8+ T cells (G; arrows indicate degenerating neuronal nuclei). Magnification: 200× (A), 630× (B, F, G), 400× (C, D, E).
M.Q.W. Poh et al. / Journal of the Neurological Sciences 337 (2014) 235–237
There was no evidence of residual or metastatic breast carcinoma or other malignancy.
237
Disclosure Statement No financial assistance was received for this case report.
4. Discussion References The present case provided histopathological evidence for cytotoxic T-cell mediated neuronal injury in a patient with SPS and encephalomyelitis associated with anti-amphiphysin antibodies and breast cancer. Strikingly region-specific neuronophagia by cytotoxic T-cells was seen centred on the spinal cord and brainstem, with lesser involvement of the basal ganglia and mesial temporal structures. The post-mortem findings in this case were in agreement with previous histopathological studies of SPS, which demonstrated neuronal loss and gliosis in the brain, brainstem and spinal cord. Furthermore, perivascular infiltrates are typically comprised of B lymphocytes and parenchymal infiltrates were predominantly CD8 + and CD4 + T-cells [5–8]. However, this report is the first demonstrating direct evidence of cytotoxic T cell-mediated neuronal injury in SPS. The nature and distribution of the histopathological features is not unique to paraneoplastic SPS. Perivascular lymphocytic infiltrates associated with T-cell mediated neuroaxonal injury have been identified in other autoimmune disorders [9]. In addition, perivascular inflammatory infiltrates, glial nodules, and neuronophagia have been reported in anti-Ma2 paraneoplastic encephalitis but in this condition, pathological changes are confined to the brain [10,11]. The occurrence of SPS in patients with anti-amphiphysin antibodies may relate to cellular injury in the spinal cord, including corticospinal tract injury, which is not as prominent in the other autoimmune disorders. However, it is noted that anti-amphiphysin antibodies are able to evoke SPS-like phenomena in passive transfer experiments, suggesting that there is also a humoral contribution to the pathogenesis of the disease [2,4]. Clinical features noted in the present report overlap with findings in progressive encephalomyelitis with rigidity and myoclonus (PERM), the severe and rapidly progressive end of the SPS clinical syndrome [12–14]. Anti-amphiphysin antibody in PERM has been reported in only one previous case report [15]. Similar neuropathological findings may be seen in both SPS and PERM, suggesting that the two diseases may also lie on a pathological spectrum [12]. While neuronophagia by microglial cells and direct apposition of CD 8 + cytotoxic T-cells to hippocampal neurones have been noted in previous PERM neuropathology findings, none have reported neuronophagia by CD8 + cytotoxic T cells [14,16–18].
[1] Murinson BB, Guarnaccia JB. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 2008;71:1955–8. [2] Geis C, Weishaupt A, Hallermann S, Grunewald B, Wessig C, Wultsch T, et al. Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 2010;133:3166–80. [3] Floyd S, Butler MH, Cremona O, David C, Freyberg Z, Zhang X, et al. Expression of amphiphysin I, an autoantigen of paraneoplastic neurological syndromes, in breast cancer. Mol Med 1998;4:29–39. [4] Sommer C, Weishaupt A, Brinkhoff J, Biko L, Wessig C, Gold R, et al. Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet 2005;365:1406–11. [5] Wessig C, Klein R, Schneider MF, Toyka KV, Naumann M, Sommer C. Neuropathology and binding studies in anti-amphiphysin-associated stiff-person syndrome. Neurology 2003;61:195–8. [6] Pittock SJ, Lucchinetti CF, Parisi JE, Benarroch EE, Mokri B, Stephan CL, et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol 2005;58:96–107. [7] Bateman DE, Weller RO, Kennedy P. Stiffman syndrome: a rare paraneoplastic disorder? J Neurol Neurosurg Psychiatry 1990;53:695–6. [8] Holmoy T, Skorstad G, Roste LS, Scheie D, Alvik K. Stiff person syndrome associated with lower motor neuron disease and infiltration of cytotoxic T cells in the spinal cord. Clin Neurol Neurosurg 2009;111:708–12. [9] Simon NG, Parratt JD, Barnett MH, Buckland ME, Gupta R, Hayes MW, et al. Expanding the clinical, radiological and neuropathological phenotype of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). J Neurol Neurosurg Psychiatry 2012;83:15–22. [10] Barnett M, Prosser J, Sutton I, Halmagyi GM, Davies L, Harper C, et al. Paraneoplastic brain stem encephalitis in a woman with anti-Ma2 antibody. J Neurol Neurosurg Psychiatry 2001;70:222–5. [11] Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004;127:1831–44. [12] Meinck HM, Thompson PD. Stiff man syndrome and related conditions. Mov Disord 2002;17:853–66. [13] McKeon A, Robinson MT, McEvoy KM, Matsumoto JY, Lennon VA, Ahlskog JE, et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 2012;69:230–8. [14] Barker RA, Revesz T, Thom M, Marsden CD, Brown P. Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 1998;65:633–40. [15] Ishii A, Hayashi A, Ohkoshi N, Matsuno S, Shoji S. Progressive encephalomyelitis with rigidity associated with anti-amphiphysin antibodies. J Neurol Neurosurg Psychiatry 2004;75:661–2. [16] Whiteley AM, Swash M, Urich H. Progressive encephalomyelitis with rigidity. Brain 1976;99:27–42. [17] Howell DA, Lees AJ, Toghill PJ. Spinal internuncial neurones in progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 1979;42:773–85. [18] Turner MR, Irani SR, Leite MI, Nithi K, Vincent A, Ansorge O. Progressive encephalomyelitis with rigidity and myoclonus: glycine and NMDA receptor antibodies. Neurology 2011;77:439–43.
