65 year old female with subacute onset of limbs weakness

1. 65 year old female with subacute onset of limbs weakness Cecile L. Phan, M.D. Eugene Lai, M.D. Yadollah Harati, M.D.

2. 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.

3. 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

4. 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

5. 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

6. 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.

7. 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

8. Examination • Areflexic • Stocking pattern of reduced pin prick and vibratory sense up to ankles • No cerebellar abnormalities • Gait could not be assessed.

9. 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?

10. 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

11. 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

12. 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.

13. Left biceps muscle biopsy: H&E ATPase 9.4 ATPase 4.6 Non-specific esterase

14. 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

15. SOD1 Familial ALS • 12%-23% of FALS • Most are AD, with a few cases of AR and sporadic mutations • Penetrance – 85% by age 85

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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”.