Amyotrophic Lateral Sclerosis (ALS)

written by Amanda Li, Dal med student class of 2010
reviewed by Ian Grant, MD, neurologist, March 2009

Introduction

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gherig's disease, is a neurological disease characterized by progressive degeneration of both upper and lower motor neurons. It affects 5/100,000, with average age of onset in the late 50's and early 60's. Men are affected slightly more often than females. While ALS is frequently a devestating disease, with a median survival of 3 years following diagnosis, many people with this disease show incredible courage. Here is one patient's thoughts:

"I am not my body. I am my presence or spirit. I am paralyzed from the neck down, need help with the most basic bodily functions, and can't speak. In spite of this, I have not lost one ounce of my dignity. No one can take that away from you. You have to surrender it. I have pride in who I have become, and exist with an ere of confidence."

mikebougher.com

Causes and Risk Factors

90% of cases of ALS are idiopathic. Viral infection, autoimmune response, toxicity, and excitotoxicity/free radical damage, leading to accumulation of intracellular calcium have all be suggested to be associated with ALS. However, there is no conclusive evidence for any one of these factors in the studies completed to date.

Ten per cent of cases are familial, and of these, <20% carry a mutation in the superoxide dismutase 1 (SOD1) gene. Other, even less common gene mutations, have been identified in certain families.

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Pathophysiology

ALS affects both upper motor neurons (UMN) and lower motor neurons (LMN).

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Signs and Symptoms

Diagnosis of ALS requires three types of findings:

Evidence of LMN degeneration by clinical, electrophysiological, or neuropathological exam
Evidence of UMN degeneration by clinical exam
Progressive spread of signs/symptoms within or between regions by history or clinical exam

There must not be evidence of other pathological process (by electrophysiology, pathology, or imaging) that could explain these symptoms.

history
physical exam

History

Progressive weakness is the cardinal symptom of ALS. Weakness often starts in the hands, upper or lower limbs, and in the face, but can also begin at other sites. Limbs can initially be affected segmentally and asymmetrically. Patients often notice difficulty fastening buttons or opening jars.

Cranial nerve involvement can be substantial, especially in people with progressive bulbar disease. Symptoms can include dysphagia, dysarthria, and drooling.
Bulbar findings: mixed dysarthria (spastic + flaccid) characteristic in ALS:

slowed, strained speech (spastic dysarthria)
slurred, nasal speech (flaccid dysarthria)

Dysphagia can manifest as coughing or spluttering while eating, or with choking. Tongue atrophy and fasciculations may also be present.

Emotional Incontinence, Anxiety: Emotional lability such as abrupt onset of inappropriate laughter or crying triggered by minor or insignificant events. Patients are usually well aware, but cannot help it.
Anxiety often triggers and/or accompanies other ALS symptoms such as choking spells and dyspnea

Weakness of the respiratory muscles: leads to hypoxia, orthopnea, and high risk of aspiration pneumonia.

Physical Exam

Muscle weakness should be thoroughly assessed.

Signs of UMN degeneration

Spasticity
Hyperreflexia
Babinski’s sign positive

Signs of LMN degeneration

Atrophy
Flaccid tone
Hyporeflexia
Fasciculations

The following are NORMAL in ALS:

Eye movements
Bladder and bowel function
Sensation
Cognitive function
No cerebellar or extrapyramidal disease

Up to 1/2 of patients will develop some type of frontotemporal dysfunction. This can include executive and language dysfunction, as well as personality changes.

The tongue below shows evidence of atrophy:
(photo provided by Dr Ian Grant, Dalhousie University Faculty of Medicine, Division of Neurology)

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Investigations

lab investigations
diagnostic imaging

Lab Investigations

Bloodwork

essentially normal
creatine kinase (CK) may be mildly elevated

Muscle Biopsy (helpful but unnecessary for diagnosis) & Pathology:

small angulated fibres (denervation)
fibre type grouping
degeneration and loss of motor neurons with astrocytic gliosis
Bunina bodies (eosinophilic hyaline intracytoplasmic inclusions) in 70% of patients

Diagnostic Imaging

EMG

evidence of denervation in 3 limbs and paraspinal muscles: fibrillations, complex repetitive discharges
evidence of reinnervation: increased amplitude and duration of motor units
fasciculations

CT/MRI: to rule out cervical cord disease

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Differential Diagnosis

Progressive Muscle Atrophy / Progressive Bulbar Palsy
Spinal Muscle Atrophy
Primary Lateral Sclerosis / Progressive Pseudobulbar Palsy
Post-polio syndrome
Spinal cord disease: spondylosis
muscle disease: myositis
NMJ disorder: rare but myesthenia gravis
neuropathy

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Treatments

Disease Specific Therapy

Currently, there is only one drug that is indicated for treatment of ALS. Riluzole acts by blocking glutamate/excitotoxicity. Studies to date have shown a modest increase in median lifespan (3-6 months).

Symptom Management

Muscle cramping and spasticity– hydration, calcium/magnesium, baclofen, quinine, phenytoin
Sialorrhea (drooling) – anticholinergics, botox injections of parotid and submandibular glands
Emotional Incontinence – tricyclic antidepressants. New evidence for dextromethorphan & quinidine
anxiety and depression: treat accordingly
Dyspnea/Respiratory weakness – ventilatory support (non-invasive ventilation such as BIPAP, invasive ventilation, tracheostomy). Respiratory education (ie breath stacking) can be helpful
Swallowing and nutrition: important to keep nutritional intake adequate to maintain strength. Soft diets, high calorie nutrition thickened liquids, PEG (percutaneous endoscopic gastrostomy) tube insertion and feeding
Dysarthria: breath support, palatal lifts, voice amplification, augmentative communication