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Motor Neuron Disease- Clinical Aspects -

Sanjay Kalra, MD, FRCPC Division of Neurology, Department of Medicine

Centre for Neuroscience Department of Biomedical Engineering

S Kalra, UofA

Case

A 53 year old man noticed progressive clumsiness in his right hand. He had difficulty writing and buttoning his shirt.

He was reassured by a physician that he probably had a pinched nerve in his neck.

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Case (cont)

6 months later he was unsteady when walking and was liable to trip.

On examination he had wasting and weakness of hand muscles (right worse than left). The legs were spastic and reflexes were increased in the legs.

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Case (cont)

MRI Cervical Spine – Normal

Electromyography – active lower motor neuron disease in the arms and legs

ALS was diagnosed – 9 months after his initial symptoms.

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Case (cont)

3 months later his speech became slurred and he started coughing when eating or drinking. Eventually a feeding tube (PEG) was inserted.

Physiotherapy and analgesics were required to control shoulder pain.

2 years after his symptoms began, he was restricted to a wheelchair with no functional strength remaining in his arms.

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Case (cont)

He slept poorly and fatigue worsened as respiratory muscle strength deteriorated. Non-invasive ventilation (NIV) alleviated this significantly. After several months he needed NIV and morphine during the day for shortness of breath.

Several episodes of pneumonia were treated successfully with antibiotics.

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Case (cont)

He had dodged the discussion of personal directives throughout his illness, but eventually made it clear that he did not want invasive measures (tracheostomy with mechanical ventilation).

Death was peaceful at home 3 years after his first symptoms (no choking, suffocating).

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Clinical Features - Overview

muscle wasting, weakness, fasciculations

spasticity, cramps

limb, bulbar, respiratory

spared: sensation, sphincter function, (cognition)

survival 3-5 yearsMitsumoto

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Clinical Features - Overview

Extreme heterogeneity in presentation and progression -- everyone is different

But, relentlessly progressive: a “moving target”• Mute• Quadriplegia• Can’t eat or breathe• Alert, competent

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Plan

Motor System and Nosology Pathology & Pathophysiology Diagnosis & Classification Clinical Features Management Clinical Research

S Kalra, UofAAdapted from Belsh and Schiffman, 1996

UMN

LMN

Corticobulbar tractCorticospinal tract

Motor System - Anatomy

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Corticobulbar tractCorticospinal tract

Terminology – Anatomic SyndromesUMN

PrimaryLateral

Sclerosis

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Corticobulbar tractCorticospinal tract

Terminology – Anatomic SyndromesUMN

PseudobulbarPalsy

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Terminology – Anatomic SyndromesLMN

ProgressiveBulbarPalsy

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Terminology – Anatomic SyndromesLMN

ProgressiveMuscularAtrophy

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Corticobulbar tractCorticospinal tract

Terminology – Anatomic SyndromesUMN + LMN

AmyotrophicLateral

Sclerosis

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Terminology

Motor Neuron Disorders• Any disease with motor neuron degeneration

Amyotrophic Lateral Sclerosis (ALS)• the most common idiopathic motor neuron disorder• Motor Neuron Disease (MND)• Lou Gehrig’s Disease

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ALS – some statisticsOnset anytime in adulthood; mean age ~ 55 years

Incidence, Prevalence [per 100,000]ALS 2, 6Multiple Sclerosis 4, 140

Male:Female 1.5:1

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Goodall 2006Goodall 2006

(10% familial)

What causes ALS? Pathophysiological mechanisms

Goodall 2006

Goodall 2006Goodall 2006

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Pathology – Neuronal atrophy and loss

“lateralsclerosis”

Loss of anterior horn cells(Hirano, in Mitsumoto 1998)

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Pathology – Neuronal Inclusions

Neurofilament aggregates

Immunoreactivity• Ubiquitin +ve• Tau –ve• Alpha-synuclein –ve

NF aggregates in cell body (left) & proximal axon (right) - note normal appearing cell body (Cleveland, 2001)

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Pathology – Astrogliosis

Ventral horn of spinal cord Cerebral

Frontal cortex, GFAP(Schiffer 2004)

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Pathology – Activated Microglia

Lipid-laden microgliawithin degeneratingcorticospinal tract

Ramified activatedmicroglia adjacentto spinal motor neuronsin spinal cord

Strong 2003

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Pathology – Cognitively impaired ALS

Superficial spongiform degeneration in layers II/III of frontal lobe

Higher density and distribution of dystrophic neurites and Tau+veinclusions (Yang, 2003)

Wilson 2001

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MR Volumetry: Motor and Extramotor Atrophy

Chang 2005

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Positron Emission Tomography (PET)

Lloyd 2000

GABAA receptor ligand: [C11]-Flumazenil

Motor and extra motor involvement also indicated by:-11CR-PK11195 (activated microglia)

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Spectrum: ALS FTD

Clinical Pathology / Imaging

Ubiquinated inclusions in FTD and ALS• both contain fragmented protein TDP-43 (Lee, Science,

2006)

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ALS is a multisystem disease

Neuronal and non-neuronal elements Motor cortex and extra-motor cortex

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Diagnosis

El Escorial Criteria• combined upper AND

lower motor neuron signs • progression

UMN

• Spasticity, hyperreflexia, Babinski sign

LMN

• Atrophy, fasciculations, hypotonia, hyporeflexia

• EMG

UMN

LMN

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EE Criteria - Regions

Bulbar

Cervical

Thoracic

Lumbosacral

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Classification according to EE Criteria

Sporadic ALS

Familial ALS

ALS-Plus Syndromes

ALS-Mimic Syndromes

ALS with Laboratory Abnormalities of Uncertain Significance

**these meet EE criteria for ALS

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Classification according to EE Criteria

ALS-Plus Syndromes• Geographic clustering

(Western Pacific, Guam, etc)• Extrapyramidal• Cerebellar• Dementia• Autonomic• Sensory• Ocular

ALS-Mimic Syndromes• Post Polio Syndrome• Multifocal motor

neuropathy• Endocrinopathies• Lead intoxication• Infections• Paraneoplastic

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Work up

EMG• Sub-clinical denervation• Staging• Rule out neuropathy

MRI Brain or Cervical Spine

Blood tests

Pulmonary Function Tests

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Diagnosis?

73 yo presumptive dxALS

Progressive gait difficulty

Exam• scissor gait• proximal arm weakness

Cervical Spondylosis

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Mitsumoto, 1998 S Kalra, UofA

Clinical Features

Limb Bulbar Respiratory Cognitive Indirect

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Clinical Features

Limb• Weakness• Cramps• Fasciculations• Fatigue• Stiffness

Bulbar• Dyasarthria• Dysphagia• Drooling• Laryngospasm• Labile affect

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Clinical Features - Respiratory

Dyspnea Orthopnea Sleep disordered breathing

• Frequent awakenings• Unrefreshing sleep• Fatigue• Poor concentration• Morning headache• Anxiety, depression• Anorexia, weight loss

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Clinical Features - Cognitive Impairment

Frontotemporal Lobar Degeneration (FTLD)• Executive dysfunction• Behavioural changes

Prevalence: upwards of 50% Frank dementia rare

impacts decision making capacity reduced survival

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Cognitive Impairment -Features and proposed criteria

ALS

ALS withoutFrontotemporal

Involvement

FrontotemporalInvolvement

Cognitive ImpairmentALSci

(attention, cognitive flexibility, word generation

spared visuospatial and memory)

Behavioural ImpairmentALSbi

(interpersonal skills, socialComportment

esp. apathy, irritability)

FrontotemporalDementia FTD

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UMN

LMN

Distribution of disease

Implications• pathogenesis• multisystem disease ?• multiple diseases ?• drug trials / treatment

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Clinical Features - Indirect

Constipation Dependent edemaPain Sleep disturbanceFrozen shoulder GERDThick mucous Nasal CongestionPsychological Sexuality

depression, anxiety

Caregiver Burden

Financial Burden

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Management – Overview

Breaking the newsSymptomatic treatment

RehabilitationNutrition management

Respiratory managementAdvanced Directives

Terminal phase and death

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It’s not hopeless

Symptomatic Treatment Disease Modifying Treatment Rehabilitation Education Counseling Research

The Players ClericalResearchPersonnel

Psychologist

PastoralCare

RadOnc

Gastro-enterologist

RTRespirol-

ogist F&SDietician

SWPhysiatry

OT

PT

SpeechLP

Neurologist

Home /Palliative

Care

GPALS

Society

RN /Coordinator

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Symptomatic Treatment: Medical Options

Sialorrhea Anticholinergics: Amitriptyline, glycopyrrolate, transdermal scopolamine, others “thick mucus”: propranolol metoprolol mucomyst guaifenesin manually assisted coughing suction devices parotid irradiation

Spasticity Baclofen Dantrolene Diazepam IT Baclofen Cramps Baclofen Gabapentin Phenytoin Carbamazepine Diazepam Fasciculations Lorazepam Gabapentin Pain Rx spasticity, NSAIDS, gabapentin, TCAs, “stepped-care”

Pseudobulbar symptoms Amitriptyline Fluvoxamine Fear & Anxiety Clonazepam Lorazepam Amitriptyline SSRI Insomnia Amitriptyline Benzodiazepines Depression SSRI TCA

Respiratory NIPPV Morphine Benzodiazepines Nutritional Support PEG

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Disease Modifying Treatment

Riluzole• Anti-glutamatergic• Prolongs survival 3-6 months

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Netter

Dysarthria

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Mobility

Clinical Research

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Clinical research – what’s hot

Cognitive impairment

Neuroprotective drugs

Effect of interventions on quality of life• Nutritional, respiratory, assistive devices

Surrogate Markers / Biomarkers

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Candidate drugs under human investigation

CoQ 10

Ceftriaxone, Memantine

Lithium

Combination Therapy• celecoxib / creatine• minocycline / creatine

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Ceftriaxone – in vitro and in vivo neuroprotection

Beta-lactam antibiotic

Identified through a screen of 1,040 FDA approved compounds – in vitro and in vivo neuroprotection

Stimulates glial glutamate transporter (GLT1) expression by increased GLT1 transcription

Clinical trial underway

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Getting closer – but a long way to go still

Stem Cell Therapy

Replacement of motor neurons

Replacement of supporting cells

Gene Therapy

Delivery of growth factors

Replacement of abnormal elements, eg. glutamate transporters

Copyright ©2007 by the National Academy of Sciences

Urushitani, Makoto et al. (2007) Proc. Natl. Acad. Sci. USA 104, 2495-2500

Delayed onset and extension of life span in G37R SOD1 mice vaccinated with recombinant mutant SOD1

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Still no effective treatment ! WHY?

Pathogenesis not completely understood Disease vs Syndrome Inadequate in vitro and animal models Insensitive clinical measures, no specific test

• delays in diagnosis→ delays in inclusion into clinical trials

• inadequate monitoring of disease progression

Clinical trial issuesRequired: an objective, sensitive and indirect measure of disease burden and drug efficacy

(surrogate marker)

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Biomarkers under investigation

Metabolomics / Proteomics – serum, CSF• CSF axonal markers: tau, NF (Brettschneider, 2006)

• CSF mass spectrometry proteomics: 3 proteins (Pasinetti, 2006)

Neuroimagingmagnetic resonance spectroscopydiffusion tensor imagingpositron emission tomography

Electrodiagnosticmotor unit number estimationtranscranial magnetic stimulation

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Magnetic Resonance Spectroscopy: Neurochemistry

N-acetylaspartate Glutamate GABA Glutamine Myo-Inositol Choline Creatine Lactate Aspartate Taurine

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Magnetic Resonance Spectroscopy: Motor and extramotor involvement

Primary motor ↓↓↓Parietal / Occipital ↔Frontal ↓ or ↔Cingulate ↓Brainstem ↓

Improved detection of cerebral degeneration using High Improved detection of cerebral degeneration using High Field Magnetic Resonance Spectroscopy: Field Magnetic Resonance Spectroscopy: MyoMyo--InositolInositol

Arch Neurol, 2006

ALSHealthy Control

1 1 1mI NAA/mINAA0

1

2

3

4

- 22%+ 18%- 10%

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mI, relevance to ALS

Precursor to phosphatidylinositol second messenger system

Findings could reflect altered signal transduction in ALS which is supported by ↑ PI-3 kinase activity, ↑ protein kinase C

Glutamate-mediated excitotoxicityPI cycle activation by stimulation of metabotropic receptors & cell

depolarizationup-regulation mI surface transporter

Glial marker

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Glutamate metabolism: neuron – astrocyte coupling

Hyder, 2006

High field,“Targeted”

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Cerebral degeneration predicts survival

JNNP 2006

NAA/Cho < 2.11

NAA/Cho > 2.11

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-0.30

-0.15

0.00

0.15

0.30

MotorCortex

∆ NAA/Cr

Riluzole Gabapentin IT-BDNF

Early Drug Effects (3-5 weeks)

Neuroreport,1998J Neurol, 2006AJNR, 2003ALSMND, 2003

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Diffusion Tensor Imaging: microarchitecture

J Neuroimag, 2007

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Phase II study of memantine: A multimodal approach

MMT FVC ALSFRS Cognitive

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Take Home Messages

Clinical / pathogenetic heterogeneity pose challenges to finding treatment

There is much to offer patients at all stages, from the point of revealing the diagnosis through to the terminal stages and death

Riluzole, BiPAP and PEG are important interventions

Maximizing QoL is the goal

Multidisciplinary care is mandatory

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Suggested reading and resources

Strong MJ. The basic aspects of therapeutics in amyotrophic lateral sclerosis. Pharmacology & Therapeutics 2003;98:379-414.

Goodall EF and Morrison E. Amyotrophic lateral sclerosis motor neuron disease): proposed mechanisms and pathways to treatment. Expert Reviews in Molecular Medicine 2006;9(11):1-22.

Miller RG, et al. The care of the patient with amyotrophic lateral sclerosis (an evidence-based review). Neurology 1999;52:1311-1323.

• A practice parameter published by the American Academy of Neurology

www.ualberta.ca/ALS