Phenotypic Variability in ALS

Transcription

1 Phenotypic Variability in ALS Michael A. Elliott, MD, FAAN Medical Director, ALS Clinic Swedish Neuroscience Institute 1

2 Outline ALS Background Description Typical Presentation Clinical Phenotype Motor Level (UMN, LMN) Region (Bulbar, Spinal) Non-motor FTD Other Genetic Phenotypic Correlations 2

3 Amyotrophic Lateral Sclerosis A-myo-trophic Lateral Sclerosis (also known as Lou Gehrig s Disease) Originally described by Jean-Martin Charcot in 1874 Progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord Early symptoms of ALS often include increasing muscle weakness involving the arms and legs, speech, swallowing or breathing Significant genotypic and phenotypic variability not one disease 3 3

4 Epidemiology M>F (1.5:1) Incidence 2/100,000 30,000 in the U.S., 5,000 new cases/year Onset 40 70, average age 55 Average life span 2-5 years Most cases are sporadic 5-10 % of ALS is inherited, familial ALS (FALS) 4

5 Age of Onset Histogram of age$age Frequency age$age 5 5

6 Anatomy 6 6

7 Clinical Signs UMN Spasticity (increased muscle tone) Increased reflexes (DTRs hyper-reactive) Muscle tightness/spasms Difficulty with smooth coordinated movement, jerky movements 7

8 Clinical Signs LMN Weakness Decreased muscle tone Decreased reflexes (DTRs hypo-reactive) Muscle atrophy Fasciculations 8 8

9 Disease Progression Variables Body region onset Mix of UMN and LMN involvement Rate of progression UMN and LMN deficits spread over contiguous anatomic regions Progression is linear and non-accelerating Ravits JM and LaSpada AR, 2009 Sep 8; 73(10):

10 ALS level of motor involvement Primary Lateral Sclerosis (PLS) UMN Predominant Classic Limb Onset LMN Predominant Progressive Muscular Atrophy (PMA) PLS UMN Classic LMN PMA Spectrum of Disease 10 10

11 Classic ALS Mean age of onset early 60s M>F (1.65:1) Painless weakness Usually begins in a limb Mixed UMN and LMN signs FTD reported in 4% Survival 2-5 years J Neurol Neurosurg Psychiatry 2011;82:740e746 11

12 Primary Lateral Sclerosis (PLS) 5% of all MND Pure UMN involvement The age of onset ranges from years, with a median age of 50.5 >50% symptoms begin in LEs Onset is usually symmetric (asymmetric = Mills Variant ) Pseudobulbar Affect seen in 2/3 of patients Long survival If no LMN signs after 4 years diagnosis more certain and not likely to convert to ALS (77% of patients develop LMN signs within 4 years; 90% in 6 years) Swinnen, B and Roberecht. W Nat. Rev. Neurol. 10, (2014) Ravits J, Appel S, Baloh R et al, Amyotrophic Lateral Scler Frontotemporal Degener., 14 (01): 5-18 (2013) Gordon PH et al. Neurology, 66, (2006) 12

13 Mills Variant (hemiplegic ALS) Originally described in 1900, CK Mills reported 8 cases Begins with unilateral UMN involvement Usually ascends from the leg or descends from the arm Variant of PLS One case reported with aphasia* Neurology 82, , February 4,

14 Progressive Muscular Atrophy (PMA) Adult-onset pure LMN disorder (distinct from adult onset SMA) Onset is usually asymmetric Distal and or proximal onset Progresses faster than SMA 5% of all patients with MND 30% will develop UMN signs w/in 18 months M>F Later age of onset c/w Classic ALS SOD1 mutations can give rise to this phenotype and lack UMN involvement (i.e. A4V) Swinnen, B and Roberecht. W Nat. Rev. Neurol. 10, (2014) Ravits J, Appel S, Baloh R et al, Amyotrophic Lateral Scler Frontotemporal Degener., 14 (01): 5-18 (2013) 14

15 LMN Regional Patterns of Involvement Bulbar Spinal Regional Variant Upper extremity - Flail Arm Lower extremity - Flail Leg Pseudopolyneuritic Axial Respiratory Swinnen, B and Roberecht. W Nat. Rev. Neurol. 10, (2014) Ravits J, Appel S, Baloh R et al, Amyotrophic Lateral Scler Frontotemporal Degener., 14 (01): 5-18 (2013) 15

16 Bulbar ALS Bulbar-onset reported in 20% of ALS patients Originally considered to be a different disease than ALS progressive bulbar palsy Poor prognosis mean survival 2 years F>M Older age of onset Highest prevalence of FTD 9% Swinnen, B and Roberecht. W Nat. Rev. Neurol. 10, (2014) Ravits J, Appel S, Baloh R et al, Amyotrophic Lateral Scler Frontotemporal Degener., 14 (01): 5-18 (2013) J Neurol Neurosurg Psychiatry 2011;82:740e746 16

17 Upper Extremity Regional Variant Also known as: Flail Arm Syndrome or Vulpian-Bernart Syndrome or hanging arm syndrome or neurogenic man-inthe-barrel or brachial amyotrophic diplegia (BAD) Proximal arm weakness Can begin asymmetrically Confined to 1 spinal region mos Diminished DTRs (LMN) Mean age of onset Male > Female Average survival 5 years Swinnen, B and Roberecht. W Nat. Rev. Neurol. 10, (2014) Ravits J, Appel S, Baloh R et al, Amyotrophic Lateral Scler Frontotemporal Degener., 14 (01): 5-18 (2013) Journal of Neurology, Neurosurgery & Psychiatry. 78(6):629-31, 2007 June ALS Regional Variants, Neurologic Clinics, Nov 2015, 33 (4):

18 Monomelic Amyotrophy Unilateral, less common bilateral 2 nd -3 rd decade onset M>F Sporadic Slow progression Benign outcome In some cases, compression of lower cervical spine Arterial compression Hirayama Disease Li, Y and Remmel, K. J Clin Neuromusc Dis. 2012;13;

19 Lower Extremity Regional Variant Also known as: Flail Leg Syndrome or Marie-Patrikios Form (1918) or Pseudopolyneuritic variant or Peroneal Form or Leg Amyotrophic Diplegia (LAD) 50% with pelviperoneal distribution 50% with asymmetric onset Confined to 1 spinal region mos Diminished DTRs (LMN) 3-3.5% of all MND Mean age of onset yrs Male = Female Mean survival 6-8 years Swinnen, B and Roberecht. W Nat. Rev. Neurol. 10, (2014) Ravits J, Appel S, Baloh R et al, Amyotrophic Lateral Scler Frontotemporal Degener., 14 (01): 5-18 (2013) Journal of Neurology, Neurosurgery & Psychiatry. 78(6):629-31, 2007 June ALS Regional Variants, Neurologic Clinics, Nov 2015, 33 (4):

20 Axial Onset in thoracoabdominal muscles Involvement of thoracic, abdominal and posterior neck muscles Head drop Inability to extend trunk Abdominal protuberance Axial onset predicts the early onset of respiratory failure and a poor prognosis. Amyotrophic Lateral Sclerosis. 2007; 8:

21 Respiratory < 3% of ALS cases. Clinical features: male predominance (76%)* frequent camptocormia or dropped head frequent widespread fasciculations limb mobility fairly well preserved significant weight loss in the early stages can present acutely (14%)* Poor prognosis: Onset to death 14.9 months* Amyotroph Lateral Scler Aug;11(4): Journal of Neurology, Neurosurgery & Psychiatry. 78(6):629-31, 2007 Jun* 21

22 Pattern of Motor Involvement Swinnen, B and Roberecht. W Nat. Rev. Neurol. 10, (2014) 22

23 Phenotypic Heterogeneity Chio et al 1332 patients with ALS divided by phenotype J Neurol Neurosurg Psychiatry 2011;82:740e746 23

24 J Neurol Neurosurg Psychiatry 2011;82:740e746 24

25 ALS phenotypes and prognosis Figure 3 Tracheostomy free survival, according to amyotrophic lateral sclerosis (ALS) phenotype. Yellow, PUMN; red, PLMN; light blue, pyramidal ALS; grey, flail arm; violet, classic ALS; green, flail leg; blue, bulbar; cyan, respiratory. Crosses are censored patients. PLMN, pure lower motor neuron phenotype; PUMN, pure upper motor neuron phenotype J Neurol Neurosurg Psychiatry 2011;82:740e

26 Spectrums of ALS Swinnen, B and Roberecht. W Nat. Rev. Neurol. 10, (2014) 26

27 ALS other system involvement ALS-FTD ALS with PBA ALS-Parkinsonism ALS-cerebellar degeneration ALS with sensory involvement ALS with autonomic involvement ALS with ophthalmoplegia ALS with deafness 27

28 FTD Progressive behavioral changes and frontal executive deficits and/or selective language difficulties Behavioral variant FTD (bvftd) Apathy Disinhibition Executive dysfunction Language variant FTD (PPA) Semantic Dementia (SD) - difficulty naming, single word comprehension, and object knowledge Progressive Non-fluent Aphasia (PNFA) apraxia of speech and/or expressive agrammatism bvftd SD PNFA J Neurol Neurosurg Psychiatry 2011;82:476e

29 Pseudobulbar Affect (PBA) Pseudobulbar affect (PBA) is a syndrome of involuntary emotional expression dissociated from one s true emotional experience. Occurs in ½ of patients with ALS and ⅔ of patients with PLS Impacts QOL, social, and occupational functioning 29 29

30 Impaired corticopontocerebellar tracts underlie pseudobulbar affect in motor neuron disorders PBA due to disruption of corticopontocerebellar pathways dysmetria of emotional expression Floeter, MK et al. Neurology 83 August 12,

31 ALS with Parkinsonism ALS-Parkinson dementia syndrome of Guam ALS associated with Parkinson disease Brait-Fahn- Schwartz syndrome Responsive to levodopa ALS-Parkinsonism Not responsive to levodopa Mild parkinsonism reported in 5-15% of patients with ALS Swinnen, B and Roberecht. W Nat. Rev. Neurol. 10, (2014) 31

32 Genetics 32

33 Phenotypic-Genotypic Correlation Familial and sporadic ALS cases are clinically indistinguishable Clinical phenotypic variability of FALS, even with the same mutation Trends SOD1 and FUS cause LMN syndromes TARDBP begins in UE, slow progression C9ORF72 assoc. with ALS, FTD, or FTD-MND SOD1 A4V mutation rapid progression SOD1 D90A mutation slow progression Ravits J, Appel S, Baloh R et al, Amyotrophic Lateral Scler Frontotemporal Degener., 14 (01): 5-18 (2013) 33

34 Genetic testing Commercially available genetic tests: ALS2, ANG, C9orf72, CHMP2B, DCTN1, FIG4, FUS, OPTN, PFN1, SETX, SIGMAR1, SOD1, SQSTM1, TARDBP, UBQLN2, VAPB, VCP 60-70% sensitivity for FALS Rational genetic testing: C9orf72 (30-40%) SOD 1 (20%) TARDBP (5%) FUS (5%) 34

35 Summary of Phenotypic Patterns UMN Bulbar Pseudobulbar Palsy Cortical (Motor) Symmetric PLS Asymmetric Mills Variant or Hemiplegic Non-motor FTD, Pseudobulbar Affect, Extrapyramidal, Cerebellar, Sensory LMN Bulbar Spinal Variants Upper extremity Lower extremity Pseudopolyneuritic Axial Respiratory Flail arm Flail leg 35