Patient Summary Recent Advances in Neurology 2018 71 year-old - - PowerPoint PPT Presentation

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2/16/2018 1

Recent Advances in Neurology 2018

Difficult Diagnosis: A Polyneuropathy That Made a Turn for the Worse

Jeffrey W. Ralph, MD

Patient Summary



71 year-old right-handed man with HTN and hyperlipidemia referred for progressive numbness



Had bilateral CTS  underwent bilateral releases with success



In the last 18-months:

 Numbness in the soles of the feet  When it reached the ankles, he noticed numbness in the lateral right

hand and forearm

 In time, the numbness extended up to the knees  He then developed mirror symptoms in the left hand and forearm  15-20 lbs. weight loss over the past year



Negatives:

 No pain or radicular symptoms  No bowel or bladder control problems  No fevers, chills, or night sweats  Up to date on cancer screening

Testing

 HgbA1c: 5.4; SPEP/IFE: Normal; ESR: 2;

RPR: NR; GM-1AB: Negative; TSH .98

 EMG 1/2016:

IMPRESSION:

1) a moderate distal axonal sensorimotor polyneuropathy 2) a severe right median neuropathy at the wrist (carpal tunnel syndrome). Similar to those obtained by Dr. R. Stephens on 7/8/2015.

From Care Everywhere

• Dr. Raymond Stephens

“Suspicion of _________ given the sequence of events to date.”

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2/16/2018 2

Six Months Later…

 Speech now slurred; numbness up to the

thighs; numbness in the anus and perianal region; could not open bottles.

 CN: moderate lingual dysarthria; tip of

tongue numb; tongue-scalloped appearance w/ fasciculations

 Fasciculations seen in the shoulders and

quadriceps

 Atrophy of the hand and leg muscles

Recent Exam cont.

 Moderate weakness in proximal muscle groups in UEs +

LEs; severe weakness of distal muscles in UEs + LEs

 No reflexes; flexor plantar responses bilat  LT and pain sensation diffusely, severely impaired in the

limbs

 Vibration sensation intact at fingers; absent in RLE;

absent distal to knee in LLE

 JPS very impaired at toes  HKS clumsy with eyes closed  Wide based gait; could not walk on heels or toes;

Romberg-moderate sway

What would you do next?

A.

Repeat EMG/NCS

B.

Nerve Biopsy

C.

Lumbar Puncture

D.

Genetic testing

E.

No more testing… time for IVIG trial.

R e p e a t E M G / N C S N e r v e B i

• p

s y L u m b a r P u n c t u r e G e n e t i c t e s t i n g N

• m
• r

e t e s t i n g … t i m e f

• .

. .

21% 17% 4% 3% 55%

Which of the following genetic neurological disorders has an effective medical treatment?

A.

Pompe disease

B.

Familial amyloidosis

• C. Spinal Muscular Atrophy
• D. All of the above

P

• m

p e d i s e a s e F a m i l i a l a m y l

• i

d

• s

i s S p i n a l M u s c u l a r A t r

• p

h y A l l

• f

t h e a b

• v

e

55% 32% 8% 5%

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2/16/2018 3

Back to the patient…

 Left gastrocnemius and sural nerve

biopsies: Congo red: deposits of salmon- pink material that demonstrate apple- green birefringence on polarization

 Transthyretin stain is positive; amyloid A,

kappa, and lambda stains negative.

 Dx: amyloid myopathy; amyloid

neuropathy

Genetic testing

 TTR gene  c.250T>C heterozygous  p.Phe84Leu  MUTATION

Amyloidosis

 Extracellular deposition of soluble precursor

protein that aggregates in the form of insoluble fibrils

 Molecular β-pleated sheet structure with peptides

in antiparallel configuration

 Serum amyloid P, a glycoprotein, is a constituent

• f all amyloid

 Damage mainly secondary to tissue infiltration

and swelling

Transthyretin: the transporter for thyroxine and retinol

 Binds: Thyroxine (20%); Retinol binding protein  4 exons & 127 amino acids  Normal configuration: tetramer  Amyloidogenesis: tetramer  dimers 

monomers dissociate & may fold aberrantly aberrantly folded monomers aggregate to form amyloid

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Both Wild-Type and Mutant TTR Cause Amyloidosis

Wild-type TTR (no mutation); ATTRWT AND Age > 70 Mutant TTR; ATTRM AND Age > 30

Familial Transthyretin Amyloidosis

TTR amyloid neuropathy (TTR-FAP) TTR cardiac amyloidosis TTR leptomeningeal/CNS amyloidosis

Senile Amyloidosis

Cardiac Amyloidosis

Carpal tunnel syndrome Poly- neuropathy (?)

Familial Transthyretrin Amyloidosis

>150 mutations

Almost all missense point mutations

Autosomal dominant de novo mutations occur, but

frequency not known

True or false: The absence of a family history makes transthyretin familial amyloid polyneuropathy unlikely.

A.

TRUE

B.

FALSE

T R U E F A L S E

94% 6% DISEASE PHENOTYPE DEPENDS ON TTR MUTATION, GEOGRAPHIC REGION, AND GENETIC MILLEAU

 Penetrance and age of onset is variable

 Val30Met mutation

 In Portugal, 80% by age 50, and 91% by age 70  In French, 13% by age 30, 50% by age 70  In Sweden, 1.7% by age 30, 5% by age 40, 11%

by age 50, 22% by age 60, 36% by age 70, 52% by age 80, and 69% by age 90.

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TTR-Familial Amyloid Polyneuropathhy

 In the US

 Late onset is common and family history often

negative (50%)

 21 % have Val30Met variant (In Portugal, 90-100%)

 Epidemiology-Prevalence

 Worldwide

 TTR-FAP prevalence 0.87-1.1 / 1,000,000

 Endemic areas

 Portugal , 1:909 people  Japan, Nagano prefecture, 1:1108 people

TTR Familial Amyloid Neuropathy

 Neuropathy

 Usually starts in the lower extremities  Sensory symptoms—burning, shooting pains

 Loss of small > large fibers (but sometimes small and large

fiber dropout are =)

 Motor symptoms—Foot drop, wrist drop, and

disability of the hands and fingers common

 Autonomic neuropathy—Constipation, constipation

altering with diarrhea, delayed gastric emptying, anhidrosis, and urinary incontinence

Diagnosis: Tissue is the Issue

Abdominal fat Gastric or rectal mucosa Sural nerve Cardiac Peritendinous fat

Deposition of Amyloid – Congo Red Staining Immuno- histochemistry

If TTR  Sequence the gene

OR Mass Spectrometry- Based Proteomics

Management

 Neurologist

 Clinical examination  Disability scores

 Cardiologist – early diastolic dysfunction and

later systolic failure

 Interventions

 Carpal tunnel release for CTS  Pacemaker implantation for second-degree or third-

degree AV block

Van Selby, MD

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Treatments for Slowing Progression

• f TTR-FAP

 Liver transplantation  TTR Stabilizers

 Tafamadis (Europe only)  Diflunisal (US)

 TTR Gene Silencing

 Antisense Oligonucleotides (ASOs) – Inotersen  Small Interfering RNA (siRNA) – Patisiran

 Immune-Mediated Amyloid Clearance

 Anti-SAP Monoclonal Antibodies (hu-SAPMab)

Liver Transplantation

 Purpose: Removes the source of mutant TTR 

Stabilizes polyneuropathy – little objective improvement

 Until recently, the “Standard of Care” treatment for TTR-

FAP

 OLTX for early onset V30M-ATTR: 10 year survival

100% vs. 56% for nontransplanted patients (Yamashita et al. Neurology 78:637-643)

Liver Transplantation II

 Eligibility  Age younger than 60 years  Disease duration less than 5 years  Either polyneuropathy that is restricted to the

lower extremities or autonomic neuropathy alone

 No significant cardiac or renal dysfunction

 OLTX not effective in non-neuropathic TTR amyloidosis

 Cardiac amyloidosis – may progress; even accelerate after

OLTX in non Val30Met patients

TTR Stabilizer: Tafamidis

 Function

 Inhibits dissociation of TTR tetramers in vitro  Safe and well tolerated

 Pivotal study*

 Intention to treat analysis – benefit not significant  87/128 patients evaluated – benefit significant

 Regulatory Status

 2012 – Approved in Europe for stage I ATTR polyneuropathy

 Must be biopsy proven

 Not approved in the US Coelho T et al., Neurology 2012;79:785–792

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TTR Stabilizer: Diflunisal

 NSAID, 250mg twice daily  Randomized, double blind study of 130 patients

 Patients had different mutations  Endpoint – difference in neuropathy progression as

measured by Neuropathy Impairment Score + 7 nerve tests

 87 patients completed year 1 and 68 completed year 2

 Results:

 NIS+7 Score difference 6.1 @ 1 year (p

0.02) and 16.3 @ 2 yrs (<0.001)

 Adverse events

 4 stopped treatment (GI bleeding, CHF, glaucoma, and

nausea)

 Promising drug for TTR-FAP, and it’s cheap.

Formation of Disease-Causing Proteins

26

RNA

TRANSCRIPTION

Gene

TRANSLATION

Disease-Causing Protein

Courtesy of Ionis

Small Molecules & Biologics Target Proteins

27

RNA

DISEASE

TRANSCRIPTION

Gene

DISEASE MODIFICATION

TRANSLATION

Disease-Causing Protein

DISEASE MODIFICATION

SMALL MOLECULES TRADITIONAL MEDICINE

BIOLOGICS ANTIBODIES

Courtesy of Ionis

Inotersen Addresses the Underlying Cause of All Forms of ATTR

28

Less RNA = Less PROTEIN

Designed to Cause Destruction of RNA

mRNA

(Mutant and wild-type)

Blocks Translation

ANTISENSE DRUG Inotersen

TRANSCRIPTION

Gene

Prevents Formation of All Types of TTR Protein

Courtesy of Ionis

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Inotersen Produced Robust and Sustained Lowering of TTR Levels in hATTR Patients

29

Percent TTR Reduction from Baseline

10 20 30 40 50 60 70

• 80
• 70
• 60
• 50
• 40
• 30
• 20
• 10

Study Week TTR

% Change from Baseline LSM (± SE)

Placebo Inotersen

TTR Reduction (nadir) : -79% (median), -74% (mean)

Courtesy of Ionis

What are we doing?

 Now: Diflunisal  Near Future: ASO (Inotersen) -

Expanded Access Program

 Symptomatic therapies:

 Florinef

30

Genetic Counseling

 50% chance of getting the mutation  But the risk of getting the disease lowish  What would you recommend if his

daughter has the mutation:

 Surveillance  Start diflunisal?

FREE GENETIC TESTING IS AVAILABLE INVITAE COMPREHENSIVE NEUROPATHIES PANEL – 79 GENES INCLUDING TTR www.invitae.com/alnylam-act

Final Points

 Include TTR-FAP in your differential for

axonal polyneuropathy, particularly if there is autonomic involvement or heart failure

 Put this on your list of potentially treatable

neuropathies

 Stabilization of multimers using small

molecules

 ASOs and siRNA approaches to reduce TTR

expression

THANKS FOR YOUR ATTENTION