Transcript 65 year old female with subacute onset of limbs weakness

65 year old female with subacute
onset of limbs weakness
Cecile L. Phan, M.D.
Eugene Lai, M.D.
Yadollah Harati, M.D.
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.
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
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
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
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.
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
Examination
Proximal
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.
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?
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
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
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.
• Left biceps muscle biopsy:
H&E
ATPase 9.4
Non-specific esterase
ATPase 4.6
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
SOD1 Familial ALS
• 12%-23% of FALS
• Most are AD, with a few cases of AR and
sporadic mutations
• Penetrance – 85% by age 85
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
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
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
– 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
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
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”.