65 year old female with subacute onset of limbs weakness cecile l. phan, m.d. eugene lai, m.d....
TRANSCRIPT
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65 year old female with subacute onset of limbs weakness
Cecile L. Phan, M.D.
Eugene Lai, M.D.
Yadollah Harati, M.D.
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History
• 65 yo retired nurse with chronic lower back, neck, and knees pain:– April 2010 – started limping, attributed to left knee
although minimal knee pain. Cortisone and Synvisc injections did not help.
– August 2010 – began to fall, also noticed left arm weakness
– September 2010 – right side, especially arm, gradually becoming weaker over 2-3 weeks period. More falls. Required rolling walker. Admitted to hospital when required assistance to transfer.
– We were consulted to do a muscle biopsy.
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History
– Chronic back and neck pain not worse– Chronic numbness and tingling in the feet,
also not worse– No swallowing, speech, breathing difficulty.– No bowel or bladder dysfunction
– Started on Decadron 4 mg QID by local neurologist
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History
• Recurrent “TIA”:– Last one in Nov 2009 - Feb 2010– Episodes of slurred speech, mental confusion,
visual disturbance, generalized weakness lasting 1-2 hours.
– Hospital admission and full stroke investigation negative
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History
• PMHx:– Hypertension, obesity– Cervical and lumbar multilevel spondylotic
disease– Idiopathic peripheral neuropathy– Hypothyroidism– Depression
• Medications:– Aciphex, Celebrex, Levothyroxine, Metoprolol,
Allegra, Gabapentin, Buproprion, Pristiq, Risperdal• NKDA
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History
• Family history:– Father died, 72, CHF– Mother died, 72, lymphoma with CNS spread– 1 brother, 3 sisters:
• 1 sister died at age 56 of ALS.• 1 sister age 70 has “lifelong polio”
– 2 sons and one daughter well.
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Examination
• General exam – normal• Neurologic exam:
– Mental status – normal– CN’s – normal. – Tone ranges from normal to hypotonic with
significantly reduced muscle bulk especially proximal muscles.
– Diffuse weakness, upper and lower extremities, proximal > distal, left > right
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ExaminationProximal Distal
Left arm 2/3 3/5
Left leg 2/3 3/5
Right arm 3/5 4/5
Right leg 3+/5 4/5
•Areflexic
•Stocking pattern of reduced pin prick and vibratory sense up to ankles
•No cerebellar abnormalities
•Gait could not be assessed.
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Any thoughts?
65 year old female with subacute onset, rapidly progressive, painless, asymmetrical limbs weakness. Exam showed diffuse weakness, proximal > distal, left > right, areflexic, minimal sensory findings.•Localization?•Differential diagnosis?
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Investigations
• CSF – protein 58, glucose 63, 0 WBC, 1 RBC, normal protein electropheresis. Negative cytology
• SPEP, RF, ANA, ESR, CRP, TSH normal• CK 68• AChR Ab panel negative• Campylobacter Jejuni serology – negative• Anti GM1 negative• CEA, CA 125 negative
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Investigations
• MRI Cervical spine:– Multilevel spondylotic disk disease. – Mild canal stenosis C4-C5– Moderate canal and bilateral foraminal
stenosis with mild deformity of cord at C5-C6• MRI Lumbar spine:
– Moderate spinal stenosis with severe bilateral foraminal stenosis L2-3 and L3-4
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Investigations:
• EMG/NCS:– Motor conductions – diffusely low CMAP, normal F wave, distal
motor latencies and conduction velocities.– Sensory conductions – normal– EMG of limbs:
• diffuse 4+ fibrillation potentials and positive sharp waves. • MUAP – mixture of high amplitude, long duration polyphasic units
and small, short, polyphasic units (interpreted as “neuro-myositis”)• Severely reduced recruitment throughout
– EMG of thoracic paraspinals:• No fibs or PSW, mixture of long and short duration polyphasic units
– EMG of tongue normal
Diffuse involvement of motor roots or motor neurons with active and chronic denervation changes, sparing bulbar muscles.
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• Left biceps muscle biopsy:
H&E
ATPase 9.4 ATPase 4.6
Non-specific esterase
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Investigations
• A diagnostic test was performed• SOD 1 genetic testing sent:
– Transition C>T– Nucleotide position 14, codon 5– Alanine > Valine– Disease associated, heterozygous, AD
Genetially determined familial ALS
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SOD1 Familial ALS
• 12%-23% of FALS• Most are AD, with a few cases of AR and
sporadic mutations• Penetrance – 85% by age 85
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SOD1 genotype-phenotype relationship
• > 150 disease related SOD1mutations found. • Some SOD1 mutants showed uniform
phenotypes (D90A-homozygous), while others mutants have widely variable phenotypes (A4V, I113T).
• Phenotype-genotype variability seen between and within same pedigrees
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SOD1 phenotype• Clinically similar to sporadic ALS except
for:– Onset younger that SALS (mean age around
46) and non SOD 1 FALS– Preparetic phase– Limb onset >>> bulbar onset– LMN signs – common, predominant in
rapidly progressive case– Dominant UMN signs not reported– ? Extra motor involvement more common
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SOD1 phenotype-genotype
• Several syndromes correlate with specific SOD mutations:– LMN predominant
• A4V; G72C; Leu84Val; Gly93Cys; E100K; D101N; S134N
– Rapid progression:• Ala4Thr (1.5 yrs);
Asn86Ser Homozygous (5 mo);Leu106Val (1.2 yrs); Val148Gly (2 yrs); V148G
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– Slow progression:• Gly37Arg (18 yrs)
Gly41Asp (11 yrs) • Gly93Cys (13 yrs) • Leu144Phe (9 yrs)
– Late or early onset– Legs onset:
• G10V; H46R; L84F; D90A;Gly93Cys; Gly93Ser
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Back to patient
• Received empiric treatment with IV steroids before SOD1 results came back – no benefit.
• Underwent cervical decompression surgery in hospital – no benefit.
• Released to skilled nursing facility. • Clinical status:
– Able to sit with support.– Weaker– No bulbar or respiratory involvement
• Another cousin has SOD1 mutation
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Conclusion
• SOD1 FALS can have widely variable phenotypes
• High index of suspicion when there is family history of ALS, even when the clinical presentation is “atypical”.