ALSAmyotrophic Lateral Sclerosis

Enrico Bonnì - 45881 - Erasmus

Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s or Charcot’s disease, is a neurodegenerative disease characterized by progressive degeneration of upper (UMN) and lower (LMN) motor neurons, in the brain and spinal cord.

They are the cells that control voluntary muscle activity such as skeletal muscle movement, breathing, speaking and swallowing.

Definition

It was described for the first time by Jean-Martin Charcot in the 1860s.

It is the most common Motor Neuron Disease, a group of diseases characterized by the progressive degeneration and loss of motor neurons (cortical, cranial nerves’ motor nuclei, anterior horn cells), accompanied by gliosis.

• Incidence: 20-30 per 1 million/year

• Sporadic form: 95% Familial form: 5%, about 10-20% of them are associated with mutation in

the Cu Zn Superoxide dismutase 1 (chromosome 21)

Epidemiology

• Age of onset: Mean age of onset of sporadic ALS is 65 years; mean age of onset of familial ALS ranges from 46-55 years

• M:F 3:2

• 93% of patients in the database are caucasian

• Isolated areas of increased incidence: Kii peninsula of Japan, Chamorro natives of Guam

• Age• Family History• Smoking is the only environmental

risk factor identified that may be considered “established”

Risk factors

• A possible increased risk of ALS in Italian professional soccer players and NFL players was reported, but it needs to be confirmed by other studies. The balance of the evidence supports that head trauma in general, including repetitive head trauma, is not a risk factor for ALS.

• The Etiology of ALS is still unknown.

Etiopathology

Cell death's pathway in ALS:•Oxidative damage

Copper/zinc superoxide dismutase 1 (SOD1) gene encodes an important antioxidant protein. His mutation has been seen in 10-20% of familial ALS patients.

•Defects in axonal transport•Glutamate excitotoxicity•Aggregation of abnormal proteins•Mitochondrial dysfunction•Caspase-mediated cell death (apoptosis)•Abnormal levels of VE growth factor

affects the capillary density in the spinal cord, meaning that the nerves and surrounding cells are less irrigated. The major cause of low VEGF is a mutation of what is now know as the ALS2 gene.

•Glial cell pathology

• Motor nerve degeneration is triggered by the death of the neuron cell body.

• Death of cell body leads to the degeneration of the axon (Wallerian degeneration)

• As the axon breaks down, surrounding Schwann cells catabolize the axon's myelin sheath and engulf the axon, breaking it into fragments. This forms myelin ovoid, containing axonal debris and surrounding myelin. They are phagocytized by macrophages.

• On muscle biopsy, various stages of atrophy are noted from this pattern of denervation and subsequent reinnervation of muscle fibers.

• In typical ALS, certain motor neurons are spared until very late in the disease process:• In the brain stem: oculomotor, trochlear, and

abducens nerves• In the spinal cord: the posterior columns,

spinocerebellar tracts, nucleus of Onuf (which controls bowel and bladder function), and the Clarke column generally are spared, (Clarke column can be affected in the familial form of the disease)

The clinical hallmark of ALS is the mix of these upper and lower motor neuron signs.

•Upper motor neuron signs: Spasticity, hyperreflexia, weakness

•Lower motor neuron signs: Weakness, muscle wasting, fasciculations, hyporeflexia, muscle cramps

Sensory neurons are not affected.minority of patients complains of some numbness and paresthesias

Clinical Features

• AMYOTROPHIC: weakness, atrophy, fasiculation due to denervation of muscles

• LATERAL SCLEROSIS: hyperreflexia, spasticity due to lateral corticospinal tract degeneration

• Asymmetric Weakness is most common sign: Upper limbs > Lower limbs Hands > Shoulder girdle muscles

• Bulbar symptoms is the second most common presentation: dysarthria or dysphagiae.g. slurred speech and difficulty chewing and swallowing

• Upper limbs signs and symptomsdifficulty in washing, dropping things, tripping, writing, pinching

• Lower limbs signs and symptomsLower extremity: foot dropProximal leg weakness: difficulty climbing stairs and difficulty arising from chairs

• Babinski’s sign positive

• Later signs and symptomsProgressing muscle weaknessParalysisWeight lossShortness of breath and Respiratory failureDementia (10%)

• Since the nucleus of Onuf is spared, sphincteric control is normal

The clinical standard for diagnosis is the Revised El Escorial World Federation of Neurology criteria:•Evidence of LMN degeneration by clinical, electrophysiological, or neuropathological examination •Evidence of UMN degeneration by clinical examination •Progressive spread of symptoms or signs within a region or to other regions (The body is divided into four regions: cranial, cervical, thoracic and lumbosacral) •Absence of electrophysiological, pathological or neuroimaging evidence of other disease processes.

Diagnosis

LAB studies•Nerve conduction studies (NCS): axonal involvement

•Electromyography (EMG):

mix of acute and chronic denervation features

•MRI

• Clinically definite ALS: UMN and LMN signs in at least 3 body segments

• Clinically probable ALS: UMN and LMN signs in at least 2 body segments with some UMN signs in a segment above the LMN signs

• Clinically probable, laboratory-supported ALS: UMN and LMN signs in 1 segment or UMN signs in 1 region coupled with LMN signs by electromyography (EMG) in at least 2 limbs

• Clinically possible ALS: UMN and LMN signs in 1 body segment, UMN signs alone in at least 2 segments, or LMN signs in segments above UMN signs

• Clinically suspected ALS (carried forward from the original El Escorial criteria): Pure LMN syndrome with other causes of LMN disease adequately excluded

Even with all this technology ALS is extremely difficult to diagnose. This is because many diseases mimic signs of ALS.

Physicians must exclude all treatable disease before to diagnose ALS.

Differential Diagnosis

• Other Motor Neuron Diseases• Primary lateral sclerosis

(UMN only)• Progressive muscular

atrophy (LMN only)• Progressive bulbar palsy

• Neuropathies• GB, CIDP

• Myopathies• PM, inclusion body myositis

• NM Junction• Myasthenia gravis

• Neurodegenerative Diseases• Parkinson’s, Progressive

Supranuclear Palsy, MS

• Malignancy• Primary/mets CNS• Motor neuron syndromes

with MM, Lymphoma, lung, breast

• Toxic Exposure• EtOH, heavy metals

• Endocrine• TSH, adrenal, pituitary

• Infectious• HIV, CMV

• ALS is a progressive disorder with a linear clinical course: no remissions or exacerbations

• The life-threatening aspects of ALS are neuromuscular respiratory failure and aspiration pneumonia

• Survival: about 5 years after diagnose but it’s variable: 50% live 3-4 or more years, 20% live 5 or more years, 10% live 10 or more years

Progression and Prognosis

TreatmentRILUZOLE•The only available medications for the treatment•Glutamate Inhibitor•Compared with placebo, riluzole may prolong median tracheostomy-free survival by 2-3 months in patients younger than 75 years with definite or probable ALS who have had the disease for less than 5 years and who have a forced vital capacity (FVC) of greater than 60%.

• The principal clinical side effects some patients with riluzole may experience are stomach upset and asthenia (lack of energy). These problems resolve if the medication is discontinued.

• Some patients on riluzole develop abnormal liver function test results or neutropenia. Serum levels of aminotransferases should be measured before and during riluzole therapy, with ALT levels being evaluated every month during the first 3 months of treatment, every 3 months during the remainder of the first year, and periodically thereafter.

SUPPORTIVE TREATMENT

TRIHEXYPHENIDYL or AMITRIPTYLINE may be prescribed for people with problems swallowing their own saliva (sialorrhea)

Limb stiffness can be treated with the antispasticity agents BACLOFEN (Lioresal) and TIZANIDINE (Zanaflex).

For treatment of depression, selective serotonin reuptake inhibitors (SSRIs)

Dysphagia poses a risk for aspiration of food, liquids or secretions with resultant pneumonia and may also leads to malnutrition and dehydration.

Symptoms can be minimized in patients who choose gastrostomy tube insertion with aggressive management of secretions.

Progressive neuromuscular respiratory failure is the most common cause of death in ALS. Noninvasive positive pressure ventilation can prolong survival up to 20 months.

Some patients choose tracheostomy and permanent ventilation – it is possible to maintain patient alive for years (in locked-in syndrome).

Ice Bucket Challenge is an activity involving dumping a bucket of ice water on someone's head to promote awareness of the disease amyotrophic lateral sclerosis and encourage donations to research. It went viral on social media during July–August 2014.

On August 29, the ALS Association announced that their total donations since July 29 had exceeded $100 million.

Ice Bucket Challenge

• Harrison's Principles of Internal Medicine, 19th Edition

• “Motor Neuron Diseases” presentation Department of Developmental Neurology, Chair of Neurology, Medical University of Gdansk (MUG)

• www.emedicine.medscape.com/article/1170097• www.en.wikipedia.org/wiki/

Ice_Bucket_Challenge• “Amyotrophic Lateral Sclerosis ” presentation

Anthony El Khoury, Student Trainer at GC LAU Model United Nations

References

Dziękuje za uwagę

Zingaro Nature Reserve, Sicily