Grand Rounds The penny drops

The penny drops… Medical Grand Rounds 21/11/07 D. Maslove - Chief Medical Resident L. Noël de Tilly - Medical Imaging G. Midroni - Division of Neurology L. Rubin - Division of Rheumatology A. Lim - Chief Neurology Resident Objectives • To review an approach to sensory neuronopathy • To review the diagnostic features of Sjögren’s Syndrome • To highlight an important Quality Improvement issue Case A 71 year-old man, retired welder • December, 2006 “...legs encased in sand” • Progressive worsening of symptoms • Spastic gait, began walking with a cane Clinical course • Presented to a peripheral hospital • Exam revealed: – wide-based gait – Heel-shin ataxia – Decreased vibration and joint position sense in lower extremities • Investigations – Vitamin B12 level 157 (133-675 pmol/L) – MR brain normal • Treated with B12 injections Clinical course • Spring, 2007 “Can’t tell where feet are…” • Worsening of gait impairment • Cognition intact, no changes in vision, no dysphagia, no weakness • Transferred to SMH in May ’07 for further investigation Further History • Past History – 65 pack year smoker – COPD – No EtOH x 5 years – remote gastric ulcer surgery • Meds – Theophylline, tiotropium bromide, salbutamol, budenoside Review of Systems • 80 lb. weight loss over 4 years • No fevers, chills, or night sweats • No GI upset, diarrhea, anorexia • No arthralgias, skin changes, sicca syndrome • No CV or respiratory symptoms • No infectious contacts or travel On exam… • Higher cognitive function intact • Cranial nerves intact • Motor – normal bulk, tone, power – DTR’s 1+ in U/E’s, 2+ patellar, absent at ankles. Toes downgoing. • Sensory – Absent vibration sense to knees and wrists – Absent proprioception to knees and wrists – Decreased light touch sensation to knees On exam… • Marked lower limb ataxia – Impaired heel-shin • Gait impairment – Only able to stand with support on either side • General examination unremarkable MRI of spine Dr. Lynne Noël de Tilley Department of Medical Imaging May 2007 T2 May 2007 September 2007 Working diagnosis “Dorsal columnopathy” Primary CNS disease Secondary to dorsal root ganglionopathy Questions • What type of neurologic disturbance does this patient have? • What are the diagnostic considerations? • What further tests are indicated at this time? – What is the role of EMG/NCS? Dr. Gyl Midroni Division of Neurology Dr. Midroni Why can’t he walk? -not because he’s weak -probably not because he has cerebellar failure (lack of other signs) -not because of a movement disorder Time course? -subacute to chronic (6 months) Sensory ataxia • Central – Lesion of sensory pathways anywhere from dorsal columns to cortex • Peripheral – Peripheral nerves subserving joint position and discriminative touch • In isolation (large fiber neuropathy) • As part of a diffuse sensory neuropathy affecting all fiber types • This patient almost certainly has a central sensory ataxia – Reflexes are relatively preserved – No neuropathic symptoms Differential Dx VNIIMTGTCF • AVM, posterior spinal artery infarct • Tumor (intramed vs compressive) • HIV, Syphilis • MS, transverse myelitis, collagen disease associated (esp. SLE and Sjögren’s) • B12 deficiency**, copper deficiency Differential Dx VNIIMTGTCF • Nitrous oxide abuse, pyridoxine excess • Spinocerebellar degenerations , genetic B12 resistance • Spinal cord trauma, acute radiation myelopathy Peripheral sensory ataxia? • sensory ganglionopathy – – – – Paraneoplastic Sjögren’s associated Idiopathic Toxic (cis-Platinum, pyridoxine overdose) Peripheral sensory ataxia? – Sensory CIDP – GBS (Miller Fisher) – Rare paraprotein-associated neuropathies with specific target antigens – Vit E deficiency, B vitamin deficiencies – Taxol, metronidazole, thalidomide… – Very rare genetic large fiber sensory neuropathies NCS / EMG Conclusion • This is a central cause of sensory ataxia. No caveats. – Not paraneoplastic, not any cause of neuropathy • Overall pattern in space and time favour a metabolic / toxic process, less likely inflammatory. (By all rights, this patient SHOULD have B12 deficiency) Course in Hospital • Paraneoplastic workup • Inflammatory (CTD) workup • Studies to look for primary myelopathy/myelitis Investigations 123 137 103 5.3 241 3.8 25 6.6 81 MCV 90.1 Investigations Vitamin B12 Vitamin E Homocysteine Anti-IF negative 283 16 12 ACE 23 SPEP RF ANA negative negative 9.6 (<1.0) HIV negative Anti-Hu negative VDRL negative Hep B and C negative Anti-Yo Anti-Ri negative negative Investigations Anti-dsDNA Anti-Sm Anti-Jo1 negative negative negative Anti-Scl70 Anti-Ro Anti-La C3 C4 negative 219 44 0.53 0.10 Questions • How should we interpret these serological studies? • What other tests are required to make a diagnosis? • Is the patient’s presentation explained by these findings? Dr. Laurence Rubin Division of Rheumatology ANA Anti-dsDNA Anti-Sm Anti-Jo1 9.6 (<1.0) negative negative negative Anti-Scl70 Anti-Ro Anti-La C3 C4 negative 219 44 0.53 0.10 Autoantibody profile most consistent with either SLE or Primary Sjögren’s Syndrome (PSS) Further testing to confirm Primary Sjögren’s Syndrome • Ocular findings – Schirmer’s test – Rose Bengal • Histopathology – Biopsy of minor salivary gland • Salivary gland involvement – parotid sialography – salivary scintigraphy This patient • Objective ocular signs – Schirmer’s test positive • Positive autoantibodies • Histopathology – Salivary gland showing multiple foci of lymphocytes (> 50) in multiple lobules with focal infiltration of ductal epithelium – Appearances in keeping with Sjögren’s disease Primary Sjögren’s Syndrome Diagnostic criteria: I. Ocular symptoms II. Oral symptoms III. Ocular findings – – Schirmer's test, performed without anaesthesia ( 5 mm in 5 minutes) Rose bengal score or other ocular dye score IV. – Histopathology (minor salivary glands) focal lymphocytic sialoadenitis V. VI. Salivary gland involvement (↓salivary flow, parotid sialography, salivary scintigraphy) Autoantibodies (anti-Ro or anti-La) Primary Sjögren’s Syndrome A diagnosis can be made with any of: I. 4 of 6 criteria, including either salivary gland biopsy or autoantibodies • Sens 97% Spec 90% II. • • 3 of 4 objective criteria Sens 84% Spec 95% Sens 96% Spec 94% III. Decision tree Neurologic Manifestations of PSS Reported to occur in 20-25% of cases of PSS Previously thought to be PNS >> CNS Clinical course • Diagnosed with Sjögren’s syndrome complicated by sensory neuronopathy • Treated with PLEX, IVIG, cyclophosphamide • No clinical improvement • Complications included pneumonia, atrial fibrillation, hematuria The penny drops Serum copper 1.0 μmol/L (11-22.0 μmol/L) Could this have been the etiology of this patient’s problem? Hypocupremic Myelopathy Dr. Andrew Lim Chief Neurology Resident Neurological Features Similar to B12-related subacute combined degeneration Corticospinal Tract Signs UMN weakness Spasticity / hyperreflexia Upgoing toes Dorsal Column Signs Loss of proprioception Loss of vibration sense Sensory ataxia Spastic bladder May have SSx of concomitant sensorimotor neuropathy Hematological Features • Not always present • Anemia (micro, normo, or macro) • Neutropenia Radiological Features 71F with sensory ataxia and history of remote peptic ulcer surgery; serum copper 0.16ug/ml (normal = 0.75-1.45ug/ml)1 1Kumar et al, AJNR, 2006 Electrophysiology • SSEPs show central delay1 • NCS may show evidence of concomitant axonal sensorimotor neuropathy2 1Crum et al, Neurology, 2005 2Kumar, Mayo Clin Proc, 2006 Causes of Hypocupremic 1 Myelopathy • • • • • • Prior gastric surgery (ulcer, bariatric surgery) Excessive zinc ingestion Excessive iron intake TPN or enteral feeding with insuficient copper Idiopathic RARELY dietary 1Kumar, Mayo Clin Proc, 2006 Pathology • No human autopsy studies • In hypocupremic myelopathy in animals – “swayback” - see vacuolation and degeneration of posterior and lateral columns of spinal cord as well as chromatolysis of grey matter nuclei 1Tan et al, J Neurol Sci, 1983 Copper Dependent CNS Enzymes • Cytochrome C Oxidase • Copper-Zinc Superoxide Dismutase • Others... Treatment • Oral or parenteral copper salts (copper gluconate, copper chloride) • Mayo Clinic regimen1 – 6mg/d po x1wk then 4mg/d x1wk then 2mg/d thereafter • Hematologic abnormalities resolve • Neurological deterioration arrests, but get only variable recovery 1Kumar, Mayo Clin Proc, 2006 Resolution of MR Changes with Copper Replacement1 1Kumar et al, AJNR, 2006 Follow up • Copper studies repeated – Copper 4.3 μmol/L – Ceruloplasmin 0.14 g/L (0.22 - 0.58 g/L) • Started on oral copper supplementation • Seen in follow up November 19th and 20th • Remains largely unchanged • Relieved to have a diagnosis How did this happen? • Initial copper studies sent off June 15, 2007 • Results in Soarain July 25, 2007 • New rotation, new housestaff, new attendings, new academic year… Lessons • Causes of sensory ataxia • Utility of EMG/NCS • Dx Sjögren’s, neuro manifestations • Cu deficiency • QI and patient safety aspects of the case Discussion