Mrs P

Matt Silsby

Con Yiannikas

The Case

• 49 year old right handed lady

• Knee pain on climbing stairs 4 years ago

• GP assessment: concerns re intermittent leg heaviness, referred to Neurologist

New Symptoms

• 1 year ago (mid 2015)
• Intermittent diplopia, noted most in bright settings
• Significant fatigue
• Difficulty taking a deep breath
• Blocked ears
• No dysphagia, dysarthria, dysphonia
• Re-reviewed by Neurologist:

Further Progress

• šNoted softening of voice, no slurring, no dysphagia
• šOngoing difficulty with dyspnoea
• šIntermittent headaches
• šNo longer complaining of diplopia
• šNo vertigo
• šNo bladder or bowel symptoms
• šNo rash or arthralgia
• šNo recent systemic illness

    Further Progress

• šEnd of last year (Dec 2015)
• šProgression of weakness, felt things were declining quickly
• šSummer months, felt her symptoms were worse with hot weather
• šNow weak lower > upper limbs, proximal > distal
• šDifficulty sit-to-stand, couldn’t ascend a slight incline, stairs without handrails
• šUnable to safely drive due to arm weakness
• šImpaired balance causing three falls on turning, without significant injury

    Examination

• šCranial nerves normal. No ptosis
• š4+/5 shoulder abduction
• š4+/5 elbow flex, 4/5 elbow ext
• š4/5 intrinsic hand muscles/APB
• šHip flexion 3-4/5, hip extension 4/5
• šKnee ext 3-4/5, knee flex 4-4+/5
• šAnkle DF, PF 5/5
• šReflexes absent
• šCerebellar + sensory normal

Motor Conduction Studies

Sensory Conduction Studies

    EMG Vastus Lateralis

Investigations

• šVasculitis/Immunological screen negative
• šVGKC negative
• šAntineuronal antibodies negative
• šAntiganglioside antibodies: GM1 IgG and GQ1B IgG antibodies positive
• šMRI whole spine: NAD

Reflexes

    Ulnar CMAP

Pre-Exercise

Post-Exercise

    Repetitive Stimulation

Pre-Exercise

3 min Post-Exercise

30 sec Post-Exercise

Progress

• šVGCC antibodies positive – 281pM  {< 30}
• š20 kg weight loss over the preceding 2 years
• šNo change in appetite, no night sweats
• šCT CAP – NAD
• šPET scan:

Management

• šPlasmapheresis daily for 3 days
• šWeekly since then
• šApplication with TGA for 3,4-DAP
• š
• šMaking some improvements

    LEMS ¹

• šRare disorder affecting 3 per 1 million described by Lambert, Eaton and Rooke 1956
• šParaneoplastic in 50-60%
• šSCLC most commonly, median age of onset is 60 and majority (65%) are men
• šNon-tumour LEMS of autoimmune aetiology also described, peak incidence at 35 and 60 years old, 52% female
   
• šOther implicated tumours incl NSCLC, prostate cancer, thymoma, lymphoproliferative
  • šHowever few reports only, statistical chance rather than correlation?

1: Titulaer et al, Lancet Neurol 2011; 10: 1098–107

    Pathophysiology

    Clinical Features

• Triad typically consisting of proximal muscle weakness, areflexia and autonomic features
• Proximal leg weakness is usually the first symptom noted by the patient (in 80%)
• Weakness of the arms is present on initial assessment or develops quickly
• Weakness normally spreads proximally to distally, involving feet and hands, and caudally to cranially, finally reaching the oculobulbar region
• The speed of progression is much more pronounced in SCLC-LEMS than in NT-LEMS
• Occurrence of ocular symptoms ranges from 0–80%, and bulbar symptoms from 5–80%
• By contrast with MG, isolated ocular symptoms is rare

LEMS

NT-LEMS

SCLC-LEMS

NCS

• šRepetitive stimulation is the electrophysiological study of choice
• šThe first CMAP amplitude is already low, and becomes even lower at low stimulating frequencies (2–5 Hz)
• šDecrement can be present at frequencies as low as 0·1 Hz and 94-98% of patients have at least 10% decrement
• šTo discriminate between LEMS and MG, high frequency stimulation (50 Hz) or, preferably, post-exercise stimulation is done
• šAn increment in CMAP amplitude higher than 100% is considered abnormal
• šPost-exercise stimulation has a sensitivity of 84–96% and specificity 100% for LEMS

Management

• šFind the SCLC
• šIf present, treating the malignancy can improve symptoms
• šIf this is not present, or symptoms are not improving, add pharmacotherapy:
  • š3,4 DAP
  • šPrednisone + Azathioprine + above
  • šIVIG or plasmapheresis + above

Prognosis

• š2008 series of 100 patients with biopsy-proven SCLC
  • šMedian survival of LEMS patients was 19.6 months vs. antibody negative patients, 8.9 months
     
• š2001 series of 47 patients with NT-LEMS, 45% of patients in remission at 10 years
  • šOnly 14% were not taking Prednisone at final follow up
    • š50% taking 3,4-DAP alone
    • š25% on AZA and 3,4-DAP
    • š25% on no treatment

SCLC Screening

• šScreening may not find a tumour
   
• šSabata, et al (2008) in Barcelona isolated antibodies to SOX1, anti-glial nuclear antibody
• šSOX1 present in 64% of SCLC-LEMS vs 0% patients with NT-LEMS (p  0.0001)
• šPresent in 22% of patients with SCLC without LEMS 

    Novel therapy

• Tarr, et al, 2014, Philadelphia
• Developed a novel Ca2+ channel agonist, GV-58, that selectively affects P/Q- and N-type, but not L-type, Ca2+ channels as a possible alternative treatment strategy for LEMS
• 3,4-DAP plus GV-58 combination was tested using a mouse passive transfer model of LEMS
   
• Supra-additive effect that completely reversed the deficit in neurotransmitter release
• There was less significant improvement observed with either compound alone
   
• Combination 3,4-DAP and GV-58 a future treatment option for LEMS?