The penny drops

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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
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Objectives

• To review an approach to sensory neuronopathy
• To review the diagnostic features of Sjögrens
  Syndrome
• To highlight an important Quality Improvement
  issue

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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

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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

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Clinical course

• Spring, 2007
• Cant 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

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Further History

• Past History
• 65 pack year smoker
• COPD
• No EtOH x 5 years
• remote gastric ulcer surgery
• Meds
• Theophylline, tiotropium bromide, salbutamol,
  budenoside

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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

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On exam

• Higher cognitive function intact
• Cranial nerves intact
• Motor
• normal bulk, tone, power
• DTRs 1 in U/Es, 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

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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
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Dr. Lynne Noël de Tilley

• Department of Medical Imaging

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May 2007
T2
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May 2007
September 2007
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Working diagnosis

• Dorsal columnopathy

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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?

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Dr. Gyl Midroni

• Division of Neurology

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Dr. Midroni

• Why cant he walk?
• -not because hes 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)

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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

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• This patient almost certainly has a central
  sensory ataxia
• Reflexes are relatively preserved
• No neuropathic symptoms

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Differential DxVNIIMTGTCF

• AVM, posterior spinal artery infarct
• Tumor (intramed vs compressive)
• HIV, Syphilis
• MS, transverse myelitis, collagen disease
  associated (esp. SLE and Sjögrens)
• B12 deficiency, copper deficiency

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Differential DxVNIIMTGTCF

• Nitrous oxide abuse, pyridoxine excess
• Spinocerebellar degenerations , genetic B12
  resistance
• Spinal cord trauma, acute radiation myelopathy

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Peripheral sensory ataxia?

• sensory ganglionopathy
• Paraneoplastic
• Sjögrens associated
• Idiopathic
• Toxic (cis-Platinum, pyridoxine overdose)

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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

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NCS / EMG
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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)

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Course in Hospital

• Paraneoplastic workup
• Inflammatory (CTD) workup
• Studies to look for primary myelopathy/myelitis

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Investigations
123
81
137
103
241
5.3
3.8
25
6.6
MCV 90.1
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Investigations
ACE 23 SPEP negative RF negative ANA 9.6
(lt1.0)
Vitamin B12 283 Vitamin E 16 Homocysteine
12 Anti-IF negative
HIV negative Anti-Hu negative VDRL
negative Anti-Yo negative Hep B and C
negative Anti-Ri negative
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Investigations
Anti-dsDNA negative Anti-Sm negative Anti-Jo1 n
egative Anti-Scl70 negative Anti-Ro 219 Anti-La
44 C3 0.53 C4 0.10
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Questions

• How should we interpret these serological
  studies?
• What other tests are required to make a
  diagnosis?
• Is the patients presentation explained by these
  findings?

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Dr. Laurence Rubin

• Division of Rheumatology

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ANA 9.6 (lt1.0) Anti-dsDNA negative Anti-Sm ne
gative Anti-Jo1 negative Anti-Scl70 negative Ant
i-Ro 219 Anti-La 44 C3 0.53 C4 0.10
Autoantibody profile most consistent with either
SLE or Primary Sjögrens Syndrome (PSS)
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Further testing to confirm Primary Sjögrens
Syndrome

• Ocular findings
• Schirmers test
• Rose Bengal
• Histopathology
• Biopsy of minor salivary gland
• Salivary gland involvement
• parotid sialography
• salivary scintigraphy

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This patient

• Objective ocular signs
• Schirmers test positive
• Positive autoantibodies
• Histopathology
• Salivary gland showing multiple foci of
  lymphocytes (gt 50) in multiple lobules with focal
  infiltration of ductal epithelium
• Appearances in keeping with Sjögrens disease

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Primary Sjögrens Syndrome

• Diagnostic criteria
• Ocular symptoms
• Oral symptoms
• Ocular findings
• Schirmer's test, performed without anaesthesia (
  5 mm in 5 minutes)
• Rose bengal score or other ocular dye score
• Histopathology (minor salivary glands)
• focal lymphocytic sialoadenitis
• Salivary gland involvement (?salivary flow,
  parotid sialography, salivary scintigraphy)
• Autoantibodies (anti-Ro or anti-La)

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Primary Sjögrens Syndrome

• A diagnosis can be made with any of
• 4 of 6 criteria, including either salivary gland
  biopsy or autoantibodies
• Sens 97 Spec 90
• 3 of 4 objective criteria
• Sens 84 Spec 95
• Decision tree
• Sens 96 Spec 94

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Neurologic Manifestations of PSS
Reported to occur in 20-25 of cases of
PSS Previously thought to be PNS gtgt CNS
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Clinical course

• Diagnosed with Sjögrens syndrome complicated by
  sensory neuronopathy
• Treated with PLEX, IVIG, cyclophosphamide
• No clinical improvement
• Complications included pneumonia, atrial
  fibrillation, hematuria

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The penny drops
Serum copper 1.0 µmol/L (11-22.0 µmol/L)
Could this have been the etiology of this
patients problem?
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Hypocupremic Myelopathy

• Dr. Andrew Lim
• Chief Neurology Resident

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Neurological Features

• Similar to B12-related subacute combined
  degeneration

• May have SSx of concomitant sensorimotor
  neuropathy

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Hematological Features

• Not always present
• Anemia (micro, normo, or macro)
• Neutropenia

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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
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Electrophysiology

• SSEPs show central delay1
• NCS may show evidence of concomitant axonal
  sensorimotor neuropathy2

1Crum et al, Neurology, 2005 2Kumar, Mayo Clin
Proc, 2006
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Causes of Hypocupremic Myelopathy1

• 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
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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
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Copper Dependent CNS Enzymes

• Cytochrome C Oxidase
• Copper-Zinc Superoxide Dismutase
• Others...

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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
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Resolution of MR Changes with Copper Replacement1
1Kumar et al, AJNR, 2006
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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

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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

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Lessons

• Causes of sensory ataxia
• Utility of EMG/NCS
• Dx Sjögrens, neuro manifestations
• Cu deficiency
• QI and patient safety aspects of the case

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Discussion