- Email: [email protected]
Rituximab for treatment of refractory childhood chronic inflammatory demyelinating polyneuropathy
Australian and New Zealand Association of Neurologists / Clinical Neurophysiology 119 (2008) e17–e26
strongly positive with blood testing indicating acute intermittent porphyria.
doi:10.1016/j.clinph.2007.10.032
Abnormalities in peripheral motor axon excitability in patients with acute spinal injury—R.A. Boland 1,4, C.S.-Y. Lin 1, A.V. Krishnan 1, S. Engel 3, M.C. Kiernan 1,2 (1 Spinal Injuries Research Centre, Prince of Wales Medical Research Institute, Sydney, Australia, 2 Prince of Wales Clinical School, University of New South Wales, Sydney, Australia, 3 Spinal Injuries Unit, Prince of Wales Hospital, Sydney, Australia, 4 Discipline of Physiotherapy, Faculty of Health Sciences, University of Sydney, Australia) Objective: To investigate peripheral motor nerve excitability in patients within 14 days of spinal cord injury (SCI). Methods: Eight patients with lesions at T8/9 or above were studied and compared with 25 control subjects. Nerve excitability was formally assessed using threshold tracking techniques to measure axonal excitability parameters (stimulus-response curves, strength-duration properties, threshold electrotonus, a current– threshold relationship and recovery cycle) of motor axons in the common peroneal nerve to tibialis anterior. Results: In three patients with low thoracic lesions, lower limb axons were completely inexcitable. Relative to control data, latency and amplitudes of compound muscle action potentials in the remaining patients were preserved. However, responses for threshold electrotonus were significantly ‘‘fanned in’’ (p < 0.01), consistent with increased refractoriness (SCI 79.61 ± 21.6%, controls 37.13 ± 3.83%; p < 0.005) and reduced superexcitability (SCI 11.23 ± 2.15%, controls 19.31 ± 1.31%; p < 0.005) recorded during the recovery cycle. These changes were suggestive of depolarization. Preliminary mathematical modeling did not support a focal abnormality of axonal membrane ion channels as the underlying cause. Conclusions: Decentralisation and inactivity appear to underlie these complex changes in excitability. Significance: There is a need to investigate methods for preserving peripheral nerve function in the acute stages of injury. doi:10.1016/j.clinph.2007.10.033
MRI of peripheral nerves and selected peripheral neuropathies—A.S. Robertson 1, C. Yiannikas 2 (1 Pittwater Radiology, Sydney, NSW, Australia, 2 Concord Hospital, Sydney, NSW, Australia) MRI is an exciting and emerging field in the characterisation of peripheral neuropathies and underlying causes. We present selected cases of common peripheral neuropathies and their MRI features. Background: Neurophysiology of peripheral nerves has been the mainstay of identification, characterisation and localisation of peripheral neuropathies. MRI of peripheral nerves is an emerging field which is an important adjunct in the identification and
e19
localisation of the specific level of many acquired peripheral neuropathies, as well as the underlying pathological causes. Imaging findings: MRI of selected peripheral nerves in mononeuropathies and peripheral neuropathies and underlying pathological causes are presented, including common neuropathies of radial, ulnar, median, common peroneal and posterior tibial nerves. Primary features of entrapment syndromes are: (1) Abnormal high signal in the neuropathic nerve on T2-weighted or ‘water weighted’ images. (2) Abnormal calibre of the entrapped nerve which includes thickening (the most common appearance) or thinning, kinking or ‘bowstringing’. (3) The underlying pathology such as tumour, fibrous bands, synovial cysts for example, causing the entrapment. Secondary features such as muscle denervation changes are subcategorised into acute and chronic changes, both of which may be visible on MRI simultaneously depending on the time course of the neuropathy. Active denervation change in muscles is principally high signal in the muscle bellies on T2weighted, Proton Density fat saturated, or ‘water weighted’ images. Chronic denervation change in muscle includes high signal in T1-weighted or Proton Density images, with a feather-like pattern of internal striations (‘feathering’),similar to the fatty pattern within Wagyu beef. Chronic denervation change includes loss of muscle bulk. Many of following cases have neurophysiological and surgical correlation. Conclusion: MRI of the peripheral nerves should be considered as an important adjunct to conventional electrophysiology in the diagnosis and management of many common acquired peripheral neuropathies. MRI can characterise the neuropathic nerve, localise exact site of entrapment, as well as the underlying pathological cause. It is particularly useful in characterisation of ulnar neuropathy where electrophysiology is inconclusive and fails to localise the site of the neuropathy, and in fact in this situation MRI is the most sensitive test. Both the primary and secondary MRI features of peripheral mononeuropathies can significantly impact treatment and management of peripheral neuropathies, particularly entrapment neuropathies. doi:10.1016/j.clinph.2007.10.034
Rituximab for treatment of refractory childhood chronic inflammatory demyelinating polyneuropathy—Eppie M. Yiu 1, Lloyd K. Shield 1, Chiara Tewierik 2, Monique M. Ryan 1,3 (1 Neurosciences Department, Royal Children’s Hospital, Melbourne, Australia, 2 Physiotherapy Department, Royal Children’s Hospital, Melbourne, Australia, 3 Murdoch Children’s Research Institute, Melbourne, Australia) Objective: Childhood chronic inflammatory demyelinating polyneuropathy (CIDP) is rare, with most children having a favourable long term outcome. However, refractory cases have been described. We describe our experience of a case of refractory paediatric CIDP in whom rituximab was trialed. Methods: We present the case of a 14-year-old patient with refractory CIDP on combination steroid, methotrexate and immunoglobulin therapy. This patient also has multiple sclerosis. Rituximab was administered at a dose of 375 mg/m2 once weekly for four weeks, with continued maintenance therapy with prednisone, methotrexate and intravenous immunoglobulin.
e20
Australian and New Zealand Association of Neurologists / Clinical Neurophysiology 119 (2008) e17–e26
Results: Rituximab was well-tolerated other than a mild infusion reaction during the first dose. Early follow-up data at 3 months showed clinical improvement in functional speed during walking and speed on arising from the floor. Formal muscle testing also showed improvement in most muscle groups. Nerve conduction studies showed mild improvement in distal latencies and amplitude of compound motor action potentials. Conclusions: Rituximab has potential as a second-line agent for refractory adult and paediatric CIDP. doi:10.1016/j.clinph.2007.10.035
Early-onset severe axonal neuropathy associated with optic atrophy and vocal cord paresis due to a mitofusin 2 mutation—Eppie M. Yiu 1, Lloyd K. Shield 1, Leslie J. Roberts 2, Desire´e du Sart 3, Belinda Chong 3, Justin O’Day 4, Monique M. Ryan 1,3 (1 Neurosciences Department, Royal Children’s Hospital, Melbourne, Australia, 2 Neurology Department, St. Vincent’s Hospital, Melbourne, Australia, 3 Murdoch Children’s Research Institute, Melbourne, Australia, 4 Department of Ophthalmology, University of Melbourne, Australia) Objective: Mutations in the mitofusin 2 (MFN2) gene have been described in Charcot–Marie-Tooth disease Type 2A (CMT 2A), hereditary motor and sensory neuropathy Type VI (HMSN VI), and the Ouvrier form of axonal neuropathy of early childhood onset. The R364W mutation has been reported in five kindreds with an early-onset autosomal dominant severe axonal neuropathy, and associated with variable optic atrophy and vocal cord paresis. We describe the clinical phenotype of a pedigree with the R364W mutation. Methods: We describe the clinical and electrophysiological features of a severe early-onset axonal neuropathy in a 53year-old woman and her 24-year-old daughter with the R364W mutation. Results: Both patients developed gait abnormalities at age three. Features include severe length dependent weakness and wasting, areflexia, optic atrophy and vocal cord paresis. Progression over time to severe disability has occurred in both patients. Conclusions: The R364W mutation in the MFN2 gene is associated with a severe early-onset axonal neuropathy with variable additional features of optic atrophy and vocal cord paresis. doi:10.1016/j.clinph.2007.10.036
The agrin – MuSK pathway as the second messenger at the neuromuscular junction—S.W. Reddel, R.N. Cole, M.J. Thurtell, W.D. Phillips (Faculty of Medicine, University of Sydney, Australia) The neuromuscular junction has traditionally been understood as a single messenger synapse. This paradigm may need to be revised with the demonstration of an in vivo role for the agrin – MuSK (muscle specific tyrosine kinase receptor) signalling pathway. Experimental and clinical evidence suggests that this pathway is constitutively active and upregulates the expression of acetyl-
choline receptors. Acetylcholine, the primary transmitter, may down regulate the expression of acetylcholine receptors, and the balance may be critical. There also appear to be two rates at which synapses can form – fast and slow. The fast synapsing receptors may be more sensitive to the disruption of the agrin – MuSK second messenger pathway, possibly explaining the clinical selectivity of weakness in patients with anti-MuSK antibodies. The clinical cohort of Australian patients with anti-MuSK antibodies will be discussed with particular attention to deviations from standard acetylcholine receptor antibody myasthenia, pitfalls in diagnosis and treatment, and pathological and experimental data obtained from the cohort. doi:10.1016/j.clinph.2007.10.037
Physiological evidence for up-regulation of KCNQ2 channel activity in human motor axons—Karl Ng, James Howells, John Pollard, David Burke (Institute of Clinical Neurosciences, The University of Sydney and Royal Prince Alfred Hospital, Sydney, Australia) Comprehensive studies of axonal excitability have revealed increased accommodation to depolarizing currents in peripheral nerves of multiple sclerosis patients who had no evidence of peripheral nerve disease. In a computer model the data were best explained by an 11% increase in slow K+ channel activity, implying increased expression of KCNQ2 (Kv7.2) channels. We suggest that the spinal lesions of MS result in plastic changes in motoneurons remote from the primary pathology, and that these peripheral nerve changes provide a ‘‘window’’ into the adaptive responses of the motoneuron pool to altered inputs. doi:10.1016/j.clinph.2007.10.038
Cortical hyperexcitability is an early feature of motor neuron disease—Steve Vucic 1, Garth A. Nicholson 2, Matthew C. Kiernan 1 (1 Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, Australia, 2 ANZAC Research Institute, University of Sydney, Concord Hospital, Australia) Background: Motor neuron disease (MND) is a neurodegenerative disorder of motor neurons. Although 10–15% of cases are attributed to mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the mechanisms underlying neurodegeneration remains unknown. Anterograde excitotoxicity, mediated via corticomotoneurons, has been proposed as a potential mechanism of neurodegeneration. Consequently, novel threshold tracking transcranial magnetic stimulation (TMS) techniques were applied in familial MND (FMND) subjects to investigate this potential mechanism. Methods: Seventeen SOD-1 mutation carriers were followed longitudinally for 3-years. Results were compared to 6 SOD-1 FMND patients, 50 sporadic MND patients and 55 normal controls. Threshold tracking TMS was performed using a 90 mm circular coil with responses recorded from the abductor pollicis brevis.
strongly positive with blood testing indicating acute intermittent porphyria.
doi:10.1016/j.clinph.2007.10.032
Abnormalities in peripheral motor axon excitability in patients with acute spinal injury—R.A. Boland 1,4, C.S.-Y. Lin 1, A.V. Krishnan 1, S. Engel 3, M.C. Kiernan 1,2 (1 Spinal Injuries Research Centre, Prince of Wales Medical Research Institute, Sydney, Australia, 2 Prince of Wales Clinical School, University of New South Wales, Sydney, Australia, 3 Spinal Injuries Unit, Prince of Wales Hospital, Sydney, Australia, 4 Discipline of Physiotherapy, Faculty of Health Sciences, University of Sydney, Australia) Objective: To investigate peripheral motor nerve excitability in patients within 14 days of spinal cord injury (SCI). Methods: Eight patients with lesions at T8/9 or above were studied and compared with 25 control subjects. Nerve excitability was formally assessed using threshold tracking techniques to measure axonal excitability parameters (stimulus-response curves, strength-duration properties, threshold electrotonus, a current– threshold relationship and recovery cycle) of motor axons in the common peroneal nerve to tibialis anterior. Results: In three patients with low thoracic lesions, lower limb axons were completely inexcitable. Relative to control data, latency and amplitudes of compound muscle action potentials in the remaining patients were preserved. However, responses for threshold electrotonus were significantly ‘‘fanned in’’ (p < 0.01), consistent with increased refractoriness (SCI 79.61 ± 21.6%, controls 37.13 ± 3.83%; p < 0.005) and reduced superexcitability (SCI 11.23 ± 2.15%, controls 19.31 ± 1.31%; p < 0.005) recorded during the recovery cycle. These changes were suggestive of depolarization. Preliminary mathematical modeling did not support a focal abnormality of axonal membrane ion channels as the underlying cause. Conclusions: Decentralisation and inactivity appear to underlie these complex changes in excitability. Significance: There is a need to investigate methods for preserving peripheral nerve function in the acute stages of injury. doi:10.1016/j.clinph.2007.10.033
MRI of peripheral nerves and selected peripheral neuropathies—A.S. Robertson 1, C. Yiannikas 2 (1 Pittwater Radiology, Sydney, NSW, Australia, 2 Concord Hospital, Sydney, NSW, Australia) MRI is an exciting and emerging field in the characterisation of peripheral neuropathies and underlying causes. We present selected cases of common peripheral neuropathies and their MRI features. Background: Neurophysiology of peripheral nerves has been the mainstay of identification, characterisation and localisation of peripheral neuropathies. MRI of peripheral nerves is an emerging field which is an important adjunct in the identification and
e19
localisation of the specific level of many acquired peripheral neuropathies, as well as the underlying pathological causes. Imaging findings: MRI of selected peripheral nerves in mononeuropathies and peripheral neuropathies and underlying pathological causes are presented, including common neuropathies of radial, ulnar, median, common peroneal and posterior tibial nerves. Primary features of entrapment syndromes are: (1) Abnormal high signal in the neuropathic nerve on T2-weighted or ‘water weighted’ images. (2) Abnormal calibre of the entrapped nerve which includes thickening (the most common appearance) or thinning, kinking or ‘bowstringing’. (3) The underlying pathology such as tumour, fibrous bands, synovial cysts for example, causing the entrapment. Secondary features such as muscle denervation changes are subcategorised into acute and chronic changes, both of which may be visible on MRI simultaneously depending on the time course of the neuropathy. Active denervation change in muscles is principally high signal in the muscle bellies on T2weighted, Proton Density fat saturated, or ‘water weighted’ images. Chronic denervation change in muscle includes high signal in T1-weighted or Proton Density images, with a feather-like pattern of internal striations (‘feathering’),similar to the fatty pattern within Wagyu beef. Chronic denervation change includes loss of muscle bulk. Many of following cases have neurophysiological and surgical correlation. Conclusion: MRI of the peripheral nerves should be considered as an important adjunct to conventional electrophysiology in the diagnosis and management of many common acquired peripheral neuropathies. MRI can characterise the neuropathic nerve, localise exact site of entrapment, as well as the underlying pathological cause. It is particularly useful in characterisation of ulnar neuropathy where electrophysiology is inconclusive and fails to localise the site of the neuropathy, and in fact in this situation MRI is the most sensitive test. Both the primary and secondary MRI features of peripheral mononeuropathies can significantly impact treatment and management of peripheral neuropathies, particularly entrapment neuropathies. doi:10.1016/j.clinph.2007.10.034
Rituximab for treatment of refractory childhood chronic inflammatory demyelinating polyneuropathy—Eppie M. Yiu 1, Lloyd K. Shield 1, Chiara Tewierik 2, Monique M. Ryan 1,3 (1 Neurosciences Department, Royal Children’s Hospital, Melbourne, Australia, 2 Physiotherapy Department, Royal Children’s Hospital, Melbourne, Australia, 3 Murdoch Children’s Research Institute, Melbourne, Australia) Objective: Childhood chronic inflammatory demyelinating polyneuropathy (CIDP) is rare, with most children having a favourable long term outcome. However, refractory cases have been described. We describe our experience of a case of refractory paediatric CIDP in whom rituximab was trialed. Methods: We present the case of a 14-year-old patient with refractory CIDP on combination steroid, methotrexate and immunoglobulin therapy. This patient also has multiple sclerosis. Rituximab was administered at a dose of 375 mg/m2 once weekly for four weeks, with continued maintenance therapy with prednisone, methotrexate and intravenous immunoglobulin.
e20
Australian and New Zealand Association of Neurologists / Clinical Neurophysiology 119 (2008) e17–e26
Results: Rituximab was well-tolerated other than a mild infusion reaction during the first dose. Early follow-up data at 3 months showed clinical improvement in functional speed during walking and speed on arising from the floor. Formal muscle testing also showed improvement in most muscle groups. Nerve conduction studies showed mild improvement in distal latencies and amplitude of compound motor action potentials. Conclusions: Rituximab has potential as a second-line agent for refractory adult and paediatric CIDP. doi:10.1016/j.clinph.2007.10.035
Early-onset severe axonal neuropathy associated with optic atrophy and vocal cord paresis due to a mitofusin 2 mutation—Eppie M. Yiu 1, Lloyd K. Shield 1, Leslie J. Roberts 2, Desire´e du Sart 3, Belinda Chong 3, Justin O’Day 4, Monique M. Ryan 1,3 (1 Neurosciences Department, Royal Children’s Hospital, Melbourne, Australia, 2 Neurology Department, St. Vincent’s Hospital, Melbourne, Australia, 3 Murdoch Children’s Research Institute, Melbourne, Australia, 4 Department of Ophthalmology, University of Melbourne, Australia) Objective: Mutations in the mitofusin 2 (MFN2) gene have been described in Charcot–Marie-Tooth disease Type 2A (CMT 2A), hereditary motor and sensory neuropathy Type VI (HMSN VI), and the Ouvrier form of axonal neuropathy of early childhood onset. The R364W mutation has been reported in five kindreds with an early-onset autosomal dominant severe axonal neuropathy, and associated with variable optic atrophy and vocal cord paresis. We describe the clinical phenotype of a pedigree with the R364W mutation. Methods: We describe the clinical and electrophysiological features of a severe early-onset axonal neuropathy in a 53year-old woman and her 24-year-old daughter with the R364W mutation. Results: Both patients developed gait abnormalities at age three. Features include severe length dependent weakness and wasting, areflexia, optic atrophy and vocal cord paresis. Progression over time to severe disability has occurred in both patients. Conclusions: The R364W mutation in the MFN2 gene is associated with a severe early-onset axonal neuropathy with variable additional features of optic atrophy and vocal cord paresis. doi:10.1016/j.clinph.2007.10.036
The agrin – MuSK pathway as the second messenger at the neuromuscular junction—S.W. Reddel, R.N. Cole, M.J. Thurtell, W.D. Phillips (Faculty of Medicine, University of Sydney, Australia) The neuromuscular junction has traditionally been understood as a single messenger synapse. This paradigm may need to be revised with the demonstration of an in vivo role for the agrin – MuSK (muscle specific tyrosine kinase receptor) signalling pathway. Experimental and clinical evidence suggests that this pathway is constitutively active and upregulates the expression of acetyl-
choline receptors. Acetylcholine, the primary transmitter, may down regulate the expression of acetylcholine receptors, and the balance may be critical. There also appear to be two rates at which synapses can form – fast and slow. The fast synapsing receptors may be more sensitive to the disruption of the agrin – MuSK second messenger pathway, possibly explaining the clinical selectivity of weakness in patients with anti-MuSK antibodies. The clinical cohort of Australian patients with anti-MuSK antibodies will be discussed with particular attention to deviations from standard acetylcholine receptor antibody myasthenia, pitfalls in diagnosis and treatment, and pathological and experimental data obtained from the cohort. doi:10.1016/j.clinph.2007.10.037
Physiological evidence for up-regulation of KCNQ2 channel activity in human motor axons—Karl Ng, James Howells, John Pollard, David Burke (Institute of Clinical Neurosciences, The University of Sydney and Royal Prince Alfred Hospital, Sydney, Australia) Comprehensive studies of axonal excitability have revealed increased accommodation to depolarizing currents in peripheral nerves of multiple sclerosis patients who had no evidence of peripheral nerve disease. In a computer model the data were best explained by an 11% increase in slow K+ channel activity, implying increased expression of KCNQ2 (Kv7.2) channels. We suggest that the spinal lesions of MS result in plastic changes in motoneurons remote from the primary pathology, and that these peripheral nerve changes provide a ‘‘window’’ into the adaptive responses of the motoneuron pool to altered inputs. doi:10.1016/j.clinph.2007.10.038
Cortical hyperexcitability is an early feature of motor neuron disease—Steve Vucic 1, Garth A. Nicholson 2, Matthew C. Kiernan 1 (1 Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, Australia, 2 ANZAC Research Institute, University of Sydney, Concord Hospital, Australia) Background: Motor neuron disease (MND) is a neurodegenerative disorder of motor neurons. Although 10–15% of cases are attributed to mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the mechanisms underlying neurodegeneration remains unknown. Anterograde excitotoxicity, mediated via corticomotoneurons, has been proposed as a potential mechanism of neurodegeneration. Consequently, novel threshold tracking transcranial magnetic stimulation (TMS) techniques were applied in familial MND (FMND) subjects to investigate this potential mechanism. Methods: Seventeen SOD-1 mutation carriers were followed longitudinally for 3-years. Results were compared to 6 SOD-1 FMND patients, 50 sporadic MND patients and 55 normal controls. Threshold tracking TMS was performed using a 90 mm circular coil with responses recorded from the abductor pollicis brevis.