124. Evidence for respiratory chain abnormalities in the peripheral nerves of patients with MELAS
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122. Voltage-gated Potassium Channel Autoimmunity Mimicking Creutzfeldt-Jakob Disease K Meng Tan a , Michael D. Geschwind b , Vanda A. Lennon a , Sean J. Pittock a a Mayo Clinic College of Medicine, United States b University of California, San Francisco, United States Manifestations of voltage-gated potassium channel (VGKC) auto- immunity may mimic Creutzfeldt-Jakob disease (CJD), especially in cases of subacute cognitive impairment and myoclonus. We describe 15 patients provisionally diagnosed with (CJD), prior to serological detection of (VGKC) autoantibodies, and favorable therapeutic responses in 12 of 13 cases. In service serological evaluation for paraneoplastic autoantibod- ies, 2001-2007, the Mayo Clinic Neuroimmunology Laboratory iden- tified 15 patients with a provisional diagnosis of CJD and high-titer VGKC autoantibodies. Clinical information was obtained by review- ing medical records. Seven patients were women, median age at onset was 70 years (range, 58–84). Median follow-up was 11 months (range, 1–78). Median VGKC autoantibody titer by RIA was 1.53 nmol/L (range 0.16-51.9). Symptom onset was subacute (median 5 months; range, 0-13). All had cognitive impairment, 12 myoclonus, 12 seizures, 10 behavioral disturbance, 7 dysomnia, 6 tremor/parkinsonism, 6 dys- autonomia, 5 ataxia, 5 hallucinations, 7 hyponatraemia, and 2 hyper- phagia. Brain MRI was abnormal in 9 of 13; one had widespread cortical restricted diffusion. EEG revealed diffuse slowing in 9 of 13. CSF 14-3-3 protein or neuron-specific enolase were elevated in 6 of 8 patients. Active neoplasia was confirmed or suspected in 8 patients. Of 13 patients receiving immunomodulatory therapy (cor- ticosteroids, plasmapheresis, IVIG), 12 showed improvement (5 marked, 6 moderate, 1 mild). Seven had relapses requiring ongoing immunotherapy. VGKC autoantibody testing is justified in the evaluation of sus- pected CJD. Positive serology may obviate brain biopsy. Patients with VGKC autoimmunity generally have a beneficial response to anti- body-depleting therapy. doi:10.1016/j.jocn.2008.07.021 123. The clinical spectrum of X-Linked charcot-marie tooth dis- ease in childhood Eppie M. Yiu a , Nimeshan Geevasinga b , Garth A. Nicholson c , Robert A. Ouvrier b , Monique M. Ryan a a Royal Children’s Hospital Melbourne b The Children’s Hospital at Westmead c Concord Hospital Sydney Objectives: X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT, is most commonly caused by mutations in GJB1, (designated CMTX1). CMTX is rarely recognised in childhood, and the clinical features in this age group are not well described. We reviewed clinical, neurophysiologic and pathological findings on a cohort of paediatric patients with CMTX. Methods: A retrospective review of patients with CMTX treated at the Children’s Hospital at Westmead Sydney, and The Royal Chil- dren’s Hospital Melbourne. The diagnosis of CMTX was based on an identifiable GJB1 mutation (CMTX1), or a consistent pedigree and/or neurophysiological features in children without a GJB1 mutation (non-CMTX1). Results: Seventeen patients (14 male and three female) were identified. Five males and two females had CMTX1, and nine males and one female non-CMTX1. Age of onset was six months to 13 years, mean 6.3 years. At least one patient was symptomatic from early infancy. Clinical features included pes cavus, gait abnormali- ties, length dependent wasting and weakness, and distal areflexia. Less common features included sensorineural hearing loss, tremor, pathologic fractures and transient central nervous system distur- bances. Intermediate median motor nerve conduction velocities in children above age two years (male and female) were seen (ranging from 30–54 m/sec), with lower amplitude motor responses in the lower extremities. Temporal dispersion was present in two patients. Conclusions: The clinical phenotype of CMTX is broader than pre- viously reported, with some cases presenting early in life and with symptoms being apparent in some carrier females, even in childhood. doi:10.1016/j.jocn.2008.07.022 124. Evidence for respiratory chain abnormalities in the periph- eral nerves of patients with MELAS Karl Ng a , Susanne Winter b , Carolyn Sue c , David Burke d a Royal North Shore Hospital and Institute of Clinical Neurosciences, Royal Prince Alfred Hospital and University of Sydney b Royal North Shore Hospital c Royal North Shore Hospital and University of Sydney d Institute of Clinical Neurosciences, Royal Prince Alfred Hospital and University of Sydney Background: Disorders arising from primary mitochondrial genetic defects are known to be associated with peripheral neurop- athy. The mechanisms underlying this are poorly understood, and may be secondary to disordered oxidative phosphorylation and reduced energy-dependent maintenance of ionic gradients necessary for impulse propagation and neuronal cell integrity. Methods: Fifteen patients with mitochondrial disorders (MELAS 6, CPEO 5, MERRF 1, Pearson’s 1, undetermined 2) either confirmed by genetic characterisation or suspected on muscle biopsy were evaluated clinically and electrophysiologically. Axonal excitability was assessed in median motor nerves at the wrist and compared with 50 normal controls. Results: As a group, there was no significant difference in excit- ability parameters. However, the MELAS subgroup (4 genetically confirmed) showed significant changes in 5 threshold electrotonus parameters that could result from membrane depolarisation (TEd peak and at 10–20ms, TEh at 10–20, 20–40, 90–100ms; p = 0.02- 0.03). In support of this interpretation, there were trends for appro- priate changes in the relative refractory period, refractoriness and superexcitability. These trends were not significant, possibly because of the small sample size. Half the MELAS patients in the subgroup had diabetes or impaired glucose tolerance, and one had an axonal neuropathy on standard nerve conduction. None of the 15 had abnormal autonomic studies (RR interval with deep breathing, standing and Valsalva; SSR). Conclusion: Even with these small numbers, the suggestive evi- dence for axonal depolarisation in patients with MELAS accords with the a priori hypothesis of respiratory chain abnormalities. The man- ifestations appear to be subclinical in most patients. doi:10.1016/j.jocn.2008.07.024 125. Conduction failure and fatigue in diabetic neuropathy Arun V. Krishnan, Cindy S. Lin, Matthew C. Kiernan Prince of Wales Medical Research Institute 468 Abstracts / Journal of Clinical Neuroscience 16 (2009) 462–481
Transcript of 124. Evidence for respiratory chain abnormalities in the peripheral nerves of patients with MELAS
122. Voltage-gated Potassium Channel Autoimmunity MimickingCreutzfeldt-Jakob Disease
K Meng Tan a, Michael D. Geschwind b, Vanda A. Lennon a,Sean J. Pittock a
a Mayo Clinic College of Medicine, United Statesb University of California, San Francisco, United States
Manifestations of voltage-gated potassium channel (VGKC) auto-immunity may mimic Creutzfeldt-Jakob disease (CJD), especially incases of subacute cognitive impairment and myoclonus. We describe15 patients provisionally diagnosed with (CJD), prior to serologicaldetection of (VGKC) autoantibodies, and favorable therapeuticresponses in 12 of 13 cases.
In service serological evaluation for paraneoplastic autoantibod-ies, 2001-2007, the Mayo Clinic Neuroimmunology Laboratory iden-tified 15 patients with a provisional diagnosis of CJD and high-titerVGKC autoantibodies. Clinical information was obtained by review-ing medical records.
Seven patients were women, median age at onset was 70 years(range, 58–84). Median follow-up was 11 months (range, 1–78).Median VGKC autoantibody titer by RIA was 1.53 nmol/L (range0.16-51.9). Symptom onset was subacute (median 5 months; range,0-13). All had cognitive impairment, 12 myoclonus, 12 seizures, 10behavioral disturbance, 7 dysomnia, 6 tremor/parkinsonism, 6 dys-autonomia, 5 ataxia, 5 hallucinations, 7 hyponatraemia, and 2 hyper-phagia. Brain MRI was abnormal in 9 of 13; one had widespreadcortical restricted diffusion. EEG revealed diffuse slowing in 9 of13. CSF 14-3-3 protein or neuron-specific enolase were elevated in6 of 8 patients. Active neoplasia was confirmed or suspected in 8patients. Of 13 patients receiving immunomodulatory therapy (cor-ticosteroids, plasmapheresis, IVIG), 12 showed improvement (5marked, 6 moderate, 1 mild). Seven had relapses requiring ongoingimmunotherapy.
VGKC autoantibody testing is justified in the evaluation of sus-pected CJD. Positive serology may obviate brain biopsy. Patients withVGKC autoimmunity generally have a beneficial response to anti-body-depleting therapy.
doi:10.1016/j.jocn.2008.07.021
123. The clinical spectrum of X-Linked charcot-marie tooth dis-ease in childhoodEppie M. Yiu a, Nimeshan Geevasinga b, Garth A. Nicholson c,Robert A. Ouvrier b, Monique M. Ryan a
a Royal Children’s Hospital Melbourneb The Children’s Hospital at Westmeadc Concord Hospital Sydney
Objectives: X-linked Charcot-Marie-Tooth disease (CMTX), thesecond most common form of CMT, is most commonly caused bymutations in GJB1, (designated CMTX1). CMTX is rarely recognisedin childhood, and the clinical features in this age group are not welldescribed. We reviewed clinical, neurophysiologic and pathologicalfindings on a cohort of paediatric patients with CMTX.
Methods: A retrospective review of patients with CMTX treatedat the Children’s Hospital at Westmead Sydney, and The Royal Chil-dren’s Hospital Melbourne. The diagnosis of CMTX was based on anidentifiable GJB1 mutation (CMTX1), or a consistent pedigree and/orneurophysiological features in children without a GJB1 mutation(non-CMTX1).
Results: Seventeen patients (14 male and three female) wereidentified. Five males and two females had CMTX1, and nine males
and one female non-CMTX1. Age of onset was six months to 13years, mean 6.3 years. At least one patient was symptomatic fromearly infancy. Clinical features included pes cavus, gait abnormali-ties, length dependent wasting and weakness, and distal areflexia.Less common features included sensorineural hearing loss, tremor,pathologic fractures and transient central nervous system distur-bances. Intermediate median motor nerve conduction velocities inchildren above age two years (male and female) were seen (rangingfrom 30–54 m/sec), with lower amplitude motor responses in thelower extremities. Temporal dispersion was present in two patients.
Conclusions: The clinical phenotype of CMTX is broader than pre-viously reported, with some cases presenting early in life and withsymptoms being apparent in some carrier females, even in childhood.
doi:10.1016/j.jocn.2008.07.022
124. Evidence for respiratory chain abnormalities in the periph-eral nerves of patients with MELASKarl Ng a, Susanne Winter b, Carolyn Sue c, David Burke d
a Royal North Shore Hospital and Institute of Clinical Neurosciences,Royal Prince Alfred Hospital and University of Sydneyb Royal North Shore Hospitalc Royal North Shore Hospital and University of Sydneyd Institute of Clinical Neurosciences, Royal Prince Alfred Hospital andUniversity of Sydney
Background: Disorders arising from primary mitochondrialgenetic defects are known to be associated with peripheral neurop-athy. The mechanisms underlying this are poorly understood, andmay be secondary to disordered oxidative phosphorylation andreduced energy-dependent maintenance of ionic gradients necessaryfor impulse propagation and neuronal cell integrity.
Methods: Fifteen patients with mitochondrial disorders (MELAS6, CPEO 5, MERRF 1, Pearson’s 1, undetermined 2) either confirmedby genetic characterisation or suspected on muscle biopsy wereevaluated clinically and electrophysiologically. Axonal excitabilitywas assessed in median motor nerves at the wrist and comparedwith 50 normal controls.
Results: As a group, there was no significant difference in excit-ability parameters. However, the MELAS subgroup (4 geneticallyconfirmed) showed significant changes in 5 threshold electrotonusparameters that could result from membrane depolarisation (TEdpeak and at 10–20ms, TEh at 10–20, 20–40, 90–100ms; p = 0.02-0.03). In support of this interpretation, there were trends for appro-priate changes in the relative refractory period, refractoriness andsuperexcitability. These trends were not significant, possibly becauseof the small sample size. Half the MELAS patients in the subgrouphad diabetes or impaired glucose tolerance, and one had an axonalneuropathy on standard nerve conduction. None of the 15 hadabnormal autonomic studies (RR interval with deep breathing,standing and Valsalva; SSR).
Conclusion: Even with these small numbers, the suggestive evi-dence for axonal depolarisation in patients with MELAS accords withthe a priori hypothesis of respiratory chain abnormalities. The man-ifestations appear to be subclinical in most patients.
doi:10.1016/j.jocn.2008.07.024
125. Conduction failure and fatigue in diabetic neuropathyArun V. Krishnan, Cindy S. Lin, Matthew C. Kiernan
Prince of Wales Medical Research Institute
468 Abstracts / Journal of Clinical Neuroscience 16 (2009) 462–481
