Motor neuron disease

62
MOTOR NEURON DISEASE: GLIMPSES INTO THE FUTURE DR.Rudrashis Samal JUNIOR RESIDENT P. G. Department of Medicine

description

MND glimpses into future.

Transcript of Motor neuron disease

Page 1: Motor neuron disease

MOTOR NEURON DISEASE:

GLIMPSES INTO THE FUTURE

DR.Rudrashis Samal

JUNIOR RESIDENT

P. G. Department of Medicine

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DEFINITION

Motor neuron disease (MND) refers to a heterogeneous group of conditions characterized by degeneration of lower motor neurons (those that have cell bodies in the cranial nerve nuclei or in the anterior horn of the spinal cord and synapse directly on muscle) and/or upper motor neurons (those that have cell bodies in the brain and synapse on lower motor neurons). [1]

1. ROWLAND LP , SCHNEIDER N : Amyotrophic lateral sclerosis . New. Engl J. Med. ( 2002) 344 ( 22 ) : 1691 - 1700

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 Amyotrophic lateral sclerosis (ALS) is one of multiple degenerative motor neuron diseases that are clinically defined, based on the involvement of upper and/or lower motor neurons

ALS is the most common form and includes upper motor neuron (UMN) and lower motor neuron (LMN) pathology

SPECTRUM OF MOTOR NEURON DISEASE

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UMN DISORDERS Primary Lateral sclerosis

Hereditary spastic paraplegia

HTLV-1 associated myelopathy

Adrenomyeloneuropathy

Lathyrism

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LMN DISORDERS Poliomyelitis Multifocal Motor Neuropathy Benign Focal Amyotrophy Hopkins’ syndrome: Acute post-

asthmatic amyotrophy Spinal Muscular Atrophy Bulbo-Spinal Muscular Atrophy

(BSMA; Kennedy's Syndrome; X-linked)

Primary Muscular Atrophy (PMA)

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ALS PLUS syndrome

ALS is considered a degenerative disorder of the upper and lower motor neurons.

However, some patients have all of the clinical features of ALS along with features of other disorders such as

• Frontotemporal dementia

• Autonomic insufficiency

• Parkinsonism, supranuclear gaze paresis and/or sensory loss.

Such patients are considered to have ALS plus syndrome

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ALS

Also known as LOU GEHRIG’S DISEASE

Degeneration of UMN and LMN

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HISTORY OF ALS

1869 - First described in publication by Dr. Jean-Martin Charcot, in Paris

1881 - Lectures translated into English

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A-myo-trophic Lateral Sclerosis

Amyotrophic: no muscle nourishment

Lateral: refers to the the areas in a person's spinal cord where portions of the nerve cells that signal and control the muscles are located

Sclerosis: scarring of the affected nerves

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INCIDENCE AND PREVALENCE

•Incidence rates for ALS in Europe and North America range between 1.5 and 2.7 per 100,000/year.[2]

•Prevalence rates range between 2.7 and 7.4 per 100,000 [2] .

•Incidence of ALS may be lower among African, Asian, and Hispanic ethnic groups than among Caucasians [3].

•The male to female ratio is about 1.3 to 1.5 for sporadic ALS, although the ratio becomes closer to unity in the age group over 70 years.

• ALS is most commonly sporadic. Genetic or familial ALS represents only 10 percent of all ALS

• In the United States, about 7000 new cases of ALS are diagnosed each year2. Worms, pm .the epidemiology of motor neuron disorder;a review of recent studies.j neuro sci

2001;191. 3. Cronin s, hardiman o,traynor BJ ethnic variation in the incidence of als ; a systemic review.neurology

2007;68;1002.

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High prevalence clusters of ALS are found in three regions of the western Pacific including Guam, West New Guinea, and the Kii Peninsula in Japan. The first cluster described was found in the indigenous people of Guam [5] .

The frequent association of ALS with parkinsonism and Alzheimer disease in this population has led to the designation of this entity as the amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC)

Neurotoxicity was mediated by the local dietary consumption of Cycad (Cycas circinalis) . Cycad is rich in beta-N-methylamino-L-alanine (BMAA), an excitatory amino acid .

GEOGRAPHIC CLUSTERS

5-Kurland, LT, Mulder, DW. Epidemiologic investigations of amyotrophic lateral sclerosis. I. Preliminary report on geographic distribution, with special reference to the Mariana Islands, including clinical and pathologic observations. Neurology 1954; 4:355

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•The only established risk factors for ALS are age and family history.

•Increased risk for developing ALS has been suggested for cigarette smokers, labourers engaged in agricultural work, factory work, heavy manual labour, exposure to welding or soldering, and work in the plastics industry .

•Repetitive muscle use, athleticism, playing professional soccer, trauma, and electrical shock have also been proposed as risk factors.

•A large case-control study found no association between physical activity and the risk of developing ALS, but did find that increased leisure time physical activity was associated with a younger age of onset in patients with ALS [4].

RISK FACTORS

4- Physical activity and the association with sporadic ALS. AU - Veldink JH; Kalmijn S; Groeneveld GJ; Titulaer MJ; Wokke JH; van den Berg LH SO - Neurology 2005 Jan 25;64(2):241-5.

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GENERAL: HEREDITARY VS SPORADIC ALS

Feature Hereditary ALS Sporadic ALS

Males:Females 1:1 1.7:1

Onset

  Age distribution More younger More older

  Mean age 46 years 56 to 63 years

  Juvenile ALS 2, 4, 5 Rare

  Bulbar features 20% to 30% Unusual

 Involvement of Legs Common Occasional

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The classical motor neuron disease seen in India is similar to that in the west in the clinical picture and frequency of occurrence. However, the onset of the illness is about a decade earlier and the proportion of patients below the age of 30 is considerably high.

In addition to these forms of motor neuron disease in the young, two specific types have been identified. Single limb involvement variously described as

•Juvenile muscular atrophy of upper extremity

•Monomelic amyotrophy

•Wasted leg syndrome

•Benign focal amyotrophy.

INDIAN SCENARIO

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The second type, the Madras pattern of motor neuron disease was first described by Meenakshisundaram et al from South India in 1970.

Essential features- • sensorineural deafness • Involvement of lower cranial nerve nuclei. • Persistent asymmetry in the distribution of weakness.

There was no positive family history, all being sporadic in occurrence A characteristic biochemical finding of persistently low citrate and elevated pyruvate level has been described in patients with MMND.

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•ALS is characterized by motor neuron degeneration and death with gliosis replacing lost neurons.

•Cortical motor cells (pyramidal and Betz cells) disappear leading to retrograde axonal loss and gliosis in the corticospinal tract.

• This gliosis results in the bilateral white matter changes sometimes seen in the brain magnetic resonance imaging (MRI) of patients with ALS.

• The spinal cord becomes atrophic. The ventral roots become thin, and there is a loss of large myelinated fibers in motor nerves.

• The affected muscles show denervation atrophy.

PATHOLOGY 

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•Intracellular inclusions — Intracellular inclusions in Degenerating neurons and glia are frequent neuropathological findings of ALS. Bunina bodies are unique to ALS and consist of eosinophilic aggregates that are positive for cystatin C, a cysteine protease inhibitor.

• Ubiquinated inclusions are seen in ALS .

TDP-43 protein — The TAR DNA binding protein 43 (TDP-43) has been identified as a major component of ubiquinated inclusions in sporadic ALS.

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PATHOGENESIS

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GENETICS OF ALS

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TOXIC MECHANISMS IN ALS

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SOD1-MEDIATED TOXICITY  • Superoxide dismutase type 1 (SOD1) is a metalloenzyme that catalyzes the conversion of toxic superoxide radicals to oxygen (O2) and hydrogen peroxide (H2O2).

• Mutations in the SOD1 gene are associated with some cases of familial ALS suggested that free radical toxicity may play a role in the process of neuronal cell death or apoptosis [6] .

• SOD1 mutations have been found in 0.7 to 4% patients with "sporadic" ALS [6] . • SOD1 has pro-oxidant as well as anti-oxidant activity, and mutated SOD1 could lead to oxidative injury by an increase in pro-oxidant pathways, including generation of hydroxyl radicals and nitration of tyrosine.6-ANDERSEN PM : Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene. Curr. Neurol. Neurosci. Rep. ( 2006 ) 6 ( 1 ) : 37 - 46 .

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THE MITOCHONDRION AS A TARGET OF MUTANT SOD1

Translocator Outer

Membrane Complex

Mitochondrial Permeability

Transition

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Protein misfolding — Another hypothesis is that mutant SOD1 induces protein aggregates that are potentially toxic to motor neurons [7].

Microglial activation — Microglia are immune-modulating cells of the CNS.Their presence was observed in ALS tissue .

•Once activated, microglia elaborate a host of factors, including nitric oxide, oxygen radicals, glutamate, and others that may play roles in part of the cascade leading to motor neuron cell death .

•Mutant SOD1 appears to increase the production of damaging reactive oxygen species by activated microglia , thereby accelerating motor neuron injury [8] .

7-WANG J , XU G , SLUNT HH : Coincident thresholds of mutant protein for paralytic disease and protein aggregation caused by restrictively expressed superoxide dismutase cDNA. Neurobiol. Dis. ( 2005 ) 20 :943 - 9528-MOISSE K , STRONG M : Innate immunity in amyotrophic lateral sclerosis. Biochimica et Biophysica Acta ( 2006 ) 1762: 1083 - 1093

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Excitotoxicity — The excitotoxicity hypothesis postulates that excessive levels of the excitatory neurotransmitter glutamate may initiate a cascade resulting in cellular death of motor neurons in ALS.[9].

Excessive activation of glutamate receptors may lead to increased entry of calcium into cells. In turn, intracellular calcium may trigger a cascade of events that causes neuronal cell death via

• Lipid peroxidation

• Nucleic acid damage

• and mitochondrial disruption.

9-VAN DEN BOSCH L , VAN DAMME P , BOGAERT E , ROBBERECHT W : The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. biochimica et Biophysica Acta ( 2006 ) 1762: 1068 - 1082

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•Deranged neurofilaments could disrupt axonal transport and Cause axonal strangulation .

•Mutations in the neurofilament gene peripherin have been found in sporadic and familial forms of ALS.

•Inhibition of axonal transport may be a cause of motor neuron degeneration.

•Defects in the dynein-dynactin complex, a molecular motor responsible for axonal transport along microtubules, have been linked with motor degeneration.[10]

Cytoskeletal and axonal transport defect

10-BOILLEE S , VANDE VELDE C , CLEVELAND D : ALS: a disease of motor neurons and their nonneuronal neighbors . Neuron ( 2006 ) 52 :39 - 59 .

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The cause of the mitochondrial dysfunction is accumulation of aggregated proteins (such as mSOD1) within the mitochondria where• they may clog protein translocation machinery.

• tie up antiapoptotic proteins such as Bcl-2 [11] .

. Dysfunctional mitochondria may result in

•Impaired calcium buffering within neurons.•Impaired energy production•Spillage of reactive oxygen species into the cytoplasm. •Release of cytohome C into the cytoplasm, which may activate the apoptosis cascade

Mitochondrial dysfunction

11-MANFREDI G , BEAL M : Mitochondrial dysfunction and energy metabolism in amyotrophic lateral sclerosis.In: Amyotrophic Lateral Sclerosis.Brown RH, Swash M, Pasinelli P (Eds) ,Informa Healthcare, London, UK( 2006 ); 323-331

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Apoptosis or programmed cell death cascades have been implicated in several studies . These reports have shown a number of the hallmarks of apoptosis including

•DNA fragmentation

•caspase activation

•altered expression of the antiapoptotic protein Bcl-2 [16]

Apoptosis

16-LI M , ONA VO , GUEGAN C et al. : Functional role of caspase 1 and 3 in ALS. Science ( 2000 ) 288 :335 - 339

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Loss of muscle strength Atrophy Fasciculations Muscle cramps Difficulty in chewing, swallowing &

movement of face and tongue

CLINICAL FEATURES: LOWER MOTOR SYMPTOMS

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Loss of dexterity Slowed movements Loss of muscle strength Stiffness Emotional lability

CLINICAL FEATURES:UPPER MOTOR SYMPTOMS

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PERCENTAGE OF 220 PATIENTS IN AN STUDY IN DEPARTMENT OF NEUROLOGY THE UNIVERSITY OF UTAH (1996-2005)

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DIAGNOSIS OF ALS• No biological marker has been identified yet.

• Series of clinical and neurological exams.

• MRI

• Myelogram of cervical spine (an x-ray analysis that allows the detection of lesions in selected area of the spinal cord)

• Muscle and/or nerve biopsy

• Electromyography (EMG) and nerve conduction velocity (NCV) to measure muscle response to nervous stimulation.

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EL ESCORIAL DIAGNOSTIC CRITERIA

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ALS: DIFFERENTIAL DIAGNOSIS

Other Motor Neuron Diseases Primary lateral sclerosis (UMN only)

Progressive muscular atrophy (LMN only)

Progressive bulbar palsy

Structural lesions cervical spondylosis

parasaggital/foramen magnum tumor

spinal cord AV malformation

Neuropathies CIDP

Myopathies PM, inclusion body myositis

NM Junction Myasthenia gravis

Neurodegenerative Diseases Parkinson’s, Progressive Supranuclear

Palsy, Multiple sclerosis.

Malignancy Primary/metastasis to CNS

Motor neuron syndromes with MM, Lymphoma, lung, breast.

Toxic Exposure alcohol, heavy metals.

Endocrine hyperthyroidism

hyperparathyroidism.

Infectious HIV, CMV

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PHARMACOLOGIC TREATMENT

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Riluzole — Three separate mechanisms of riluzole are thought to reduce glutamate-induced excitotoxicity:

• inhibition of glutamic acid release

• noncompetitive block of NMDA receptor mediated responses

• direct action on the voltage-dependent sodium channel

Dose and side effects — The recommended dose of Riluzole is 100 mg per day.

Riluzole

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The American Academy of Neurology has issued a practice advisory on the treatment of ALS with Riluzole.

Patients most likely to benefit from treatment include those who have:

• Definite or probable ALS by El-Escorial criteria , in whom other causes of progressive muscle atrophy have been ruled out

• Symptoms present for less than five years

• Vital capacity (VC) greater than 60 percent of predicted

• No tracheostomy

Recommendations 

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SIDE EFFECTSVery Common Asthenia.Nausea.

Common

Alterations in liver function tests.Headache.Abdominal pain.Pain.Vomiting.Dizziness.Tachycardia.Somnolence.Oral Paraesthesia.

Uncommon

Anaemia.Anaphylactoid reaction.Neutropenia.Angioedema.Pancreatitis

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CONTRAINDICATIONS•Hepatic disease or baseline transaminases greater than 3 times the upper limit of normal or raised bilirubin.

•Pregnancy and breastfeeding

MONITORING•Regular hepatic function blood tests (baseline then every month for 3 months, then every 3 months for a further 9 months and annually thereafter) are recommended to monitor tolerability.

• ALT levels should be measured more frequently in patients who develop elevated ALT levels >2x upper limit of normal.

• If patient presents with febrile illness then monitoring white blood cell count for neutropenia is strongly recommended.

STOP TREATMENT IF• Liver function tests – ALT greater than 5 times the upper limit of normal .

• Blood disorders - absolute neutrophil count less than 500/mm3 .

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•A cephalosporin antibiotic.

•It increases expression of EAAT2/GLT1 and prolongs survival in MND patients.

•Has good brain penetration and has a good short-term safety record.

•However, intravenous administration is required.

13-ROTHSTEIN JD, PATEL S, REGAN MR et al. : β-lactam antibiotics offer neuroprotection

by increasing glutamate transporter expression. Nature ( 2005 ) 433: 73 - 77 .

Ceftriaxone

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•IV ceftriaxone, 4 gm/day, four sequential days weekly in early 2004.

•Patient improvement was rapidly evident.

•Objective muscle strength was significantly improved and muscle atrophy was visibly diminishing.

•After 12 weeks of assistance was no longer required for mobility, and squats became possible for the first time since presentation.

•Ceftriaxone cessation after 12 weeks resulted in partial return of signs and symptoms typical of als but with improvement on re-infusion.

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Has multiple ALS-relevant mechanisms of action, including• free radical scavenging.

• blocking the mitochondrial transition pore and upregulating bcl-2 expression.

• there was a suggestion of slowed disease progression as measured by the ALS Functional Rating Scale .[14]

14-YOSHINO H , KIMURA A :Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. ( 2006 ) 7 :241 - 245

Edavarone

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• 20 subjects with ALS received either 30 mg (5 ) or 60 mg (15) of edaravone via intravenous drip once per day.

•Two weeks of administration was followed by a two-week observation period. This four-week cycle was repeated six times.

•There was the change in the revised ALS functional rating scale (ALSFRS-R) score.[14]

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• Used to treat breast cancer.

• Acts as an anti-inflammatory through inhibition of PKC. In a Phase II study of patients with ALS, it was safe and well tolerated; furthermore, there was a suggestion of efficacy with increased survival at certain dosages [18] .

•Tamoxifen has been extensively used in humans and has a good safety profile.

Tamoxifen

18-TRAYNOR BJ , BRUIJN L , CONWIT F et al. : Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology ( 2006 ) 67 :20 - 27 .

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•Two-year study of 60 people with (ALS)who took varying dosages of tamoxifen.

•Participants who took more than 20 milligrams a day had a better survival rate than those who took fewer than 10 milligrams a day.

•After two years, 27 out of 37 (73 percent) of the participants in the high-dose tamoxifen group had survived, while only 11 of 23 (48 percent) of those in the low-dose groups were still living.

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•Heat shock proteins are involved in protein repair, and thus are cytoprotective.

•Motor neurons appear to have a high threshold for activation of the heat shock protein pathway, and mutant SOD1 may contribute to reduced anti-apoptotic capability.

•Treatment with Arimoclomol, a co-inducer of heat shock proteins, delayed disease progression and improved survival.[19]

19. CUDKOWICZ M , SHEFNER M , SIMPSON E et al. : A multicenter, dose ranking safety and pharmacokinetic study of arimoclomol in ALS. Amyotrophic Lateral Sclerosis ( 2006 ) 7 ( S1 ) : 113

Arimoclomol 

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•An antiapoptotic agent that promotes autophagy , and may therefore have neuroprotective effects.

• An open-label ALS clinical trial compared 16 patients treated with Riluzole plus Lithium to 28 patients treated with Riluzole alone [20] .

• At the end of the 15 month follow-up period, all patients in the Lithium group were alive, while mortality in the Riluzole monotherapy group was 29 percent.

• In addition, disease progression, as measured by Functional Rating Scales and pulmonary function was slower in patients, treated with lithium.

Lithium

20-Lithium induces autophagy by inhibiting inositol monophosphatase. AU - Sarkar S; Floto RA; Berger Z; Imarisio S; Cordenier A; Pasco M; Cook LJ; Rubinsztein DCSO - J Cell Biol. 2005 Sep 26;170(7):1101-11

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Stem cellsThere are a number of ways in which stem cells could bebeneficial in ALS. These include•Replacement of dying motor neurons.

•Replacement of defective glial cells.

•Sources of growth factor production.

•‘sinks’ for excitotoxins such as glutamate.Even more recently, eight patients with ALS were given intrathecal injections of autologous mesenchymal stem cells, along with intravenous erythropoietin. Transient benefits on strength, and a trend toward a reducedslope of decline in ALS Functional Rating Scale was reported.15. BRUIJN L , CUDKOWICZ M :Therapeutic targets for amyotrophic lateral sclerosis: current treatments and prospects for more effective therapies expert rev.neorotherapeutics(2006) 6(3): 417-428.17. KIM S , KIM H , KOH S et al. :Effectiveness of recombinant human erythropoietin therapy in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. ( 2006 ) 7 ( S1 ) : 9.

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ANTISENSE OLIGONUCLEOTIDE •Another approach to gene therapy employs antisense

oligonucleotides

•To downregulate or silence mutant genes.

•The antisense strategy targets specific RNA sequences by constructing complementary oligonucleotides that bind to the native mRNA sequences and reduce their translation and subsequent protein expression.

•In a preliminary study, continuous intraventricular infusion of antisense oligonucleotides to SOD1 reduced both SOD1 protein and mRNA levels.

•This treatment significantly slowed disease progression when initiated near disease onset.12. SMITH RA , MILLER TM ,YAMANAKA K et al. : Antisense oligonucleotide therapy for neurodegenerative disease. J. Clin.Invest. ( 2006 ) 116 ( 8 ) : 290 - 2297 .

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COMPOUNDS ALS Research Stage

MECHANISM

Co-enzyme q10 Phase II Antioxidant.Facilitates mitochondrial respiration.

Creatinine. Phase II Antioxidant.Facilitates mitochondrial respiration.

Glatirmer acetate.

Phase II Evokesneuroprotective T.cell response.

Minocycline. Phase III Prevents microglial activation.Prevents caspase activation.

Dex-pramipexole Phase II Antioxidant.

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SUPPORTIVE TREATMENT

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MUSCLE SPASM & WEAKNESS Spasticity

Baclofen 5 to 10 mg twice daily to three times daily.

Tizanidine 2 to 4 mg by mouth twice daily up to a total dose of 24 mg daily.

Memantine starting at 5 mg daily, increasing by 5 mg a week to a maximum of 20 mg twice a day.

Tetrazepam 50 mg at bedtime, increasing by 25 mg a day to a maximum dose of 150 mg taken two to three times a day.

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SECRETION MANAGEMENTAAN PRACTICE PARAMETERS

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SECRETION MANAGEMENT Non-pharmacologic management

Suction machine (not usually helpful for thick mucus, but helpful with sialorrhea)

Mechanical insufflation-exsufflation (In-Exsufflator cough machine)

Manually assisted coughing techniques

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DYSPHAGIA AND NUTRITION AAN

PRACTICE PARAMETERS

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RESPIRATORY CARE AAN

PRACTICE PARAMETER

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PSEUDOBULBAR AFFECT Also known as: pseudobulbar palsy,

emotional incontinence, pathologic crying/laughing

The emotional lability is NOT a mood disorder, but is an uncontrolled outburst and is a very troubling symptom for patients.

It is an abnormal affective display that can be seen in about 50% of ALS patients.

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PSEUDOBULBAR AFFECT Amitriptyline 100-150mg QHS Fluvoxamine 100-200mg QD Alternatively may try Lithium or L-Dopa

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DYSARTHRIA Speech therapy often helpful early Computer technology offer many

options to assist with patient communication

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OTHER SYMPTOMS

Urinary frequency/urgency In the absence of UTI, often due to spasticity

that responds well to Oxybutinin Peripheral edema

Often dependent: elevation, massage, compression hose (r/o DVOT)

LaryngospasmSudden reflex closure of vocal cords due to

variety of stimuli, usually resolves spontaneously

H1 and H2 blocking agents may be helpful

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FAMOUS PEOPLE WITH ALS

Steven Hawking Proved Einstein's

Theory of Relativity He currently uses an

electric wheelchair to get around

A computerized voice synthesizer operated by facial muscles in order to speak

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1. ROWLAND LP , SCHNEIDER N : Amyotrophic lateral sclerosis . New. Engl J. Med. ( 2002) 344 ( 22 ) :

1691 – 1700

2. Worms, pm .the epidemiology of motor neuron disorder;a review of recent studies.j neuro sci 2001;191.

3. Cronin s, hardiman o,traynor BJ ethnic variation in the incidence of als ; a systemic review.neurology 2007;68;1002.

6-ANDERSEN PM : Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene. Curr. Neurol. Neurosci. Rep. ( 2006 ) 6 ( 1 ) : 37 - 46 .

7-WANG J , XU G , SLUNT HH : Coincident thresholds of mutant protein for paralytic disease and protein aggregation caused by restrictively expressed superoxide dismutase cDNA. Neurobiol. Dis. ( 2005 ) 20 :943 - 952

8-MOISSE K , STRONG M : Innate immunity in amyotrophic lateral sclerosis. Biochimica et Biophysica Acta ( 2006 ) 1762: 1083 - 1093

9-VAN DEN BOSCH L , VAN DAMME P , BOGAERT E , ROBBERECHT W : The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. biochimica et Biophysica Acta ( 2006 ) 1762: 1068 - 1082

10-BOILLEE S , VANDE VELDE C , CLEVELAND D : ALS: a disease of motor neurons and their nonneuronal neighbors . Neuron ( 2006 ) 52 :39 - 59 .

11-MANFREDI G , BEAL M : Mitochondrial dysfunction and energy metabolism in amyotrophic lateral sclerosis.In: Amyotrophic Lateral Sclerosis.Brown RH, Swash M, Pasinelli P (Eds) ,Informa Healthcare, London, UK( 2006 ); 323-331

5-Kurland, LT, Mulder, DW. Epidemiologic investigations of amyotrophic lateral sclerosis. I. Preliminary report on geographic distribution, with special reference to the Mariana Islands, including clinical and pathologic observations. Neurology 1954; 4:355

4- Physical activity and the association with sporadic ALS. AU - Veldink JH; Kalmijn S; Groeneveld GJ; Titulaer MJ; Wokke JH; van den Berg LH SO - Neurology 2005 Jan 25;64(2):241-5.

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12. SMITH RA , MILLER TM ,YAMANAKA K et al. : Antisense oligonucleotide therapy for neurodegenerative disease. J. Clin.Invest. ( 2006 ) 116 ( 8 ) : 290 - 2297 .

13-ROTHSTEIN JD, PATEL S, REGAN MR et al. : β-lactam antibiotics offer neuroprotection

by increasing glutamate transporter expression. Nature ( 2005 ) 433: 73 - 77 .

14-YOSHINO H , KIMURA A :Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. ( 2006 ) 7 :241 - 24515. BRUIJN L , CUDKOWICZ M :Therapeutic targets for amyotrophic lateral sclerosis: current treatments and prospects for more effective therapies expert rev.neorotherapeutics(2006) 6(3): 417-428.16-LI M , ONA VO , GUEGAN C et al. : Functional role of caspase 1 and 3 in ALS. Science ( 2000 ) 288 :335 - 33917. KIM S , KIM H , KOH S et al. :Effectiveness of recombinant human erythropoietin therapy in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. ( 2006 ) 7 ( S1 ) : 9.

18-TRAYNOR BJ , BRUIJN L , CONWIT F et al. : Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology ( 2006 ) 67 :20 - 27 .

19. CUDKOWICZ M , SHEFNER M , SIMPSON E et al. : A multicenter, dose ranking safety and pharmacokinetic study of arimoclomol in ALS. Amyotrophic Lateral Sclerosis ( 2006 ) 7 ( S1 ) : 11320-Lithium induces autophagy by inhibiting inositol monophosphatase. AU - Sarkar S; Floto RA; Berger Z; Imarisio S; Cordenier A; Pasco M; Cook LJ; Rubinsztein DCSO - J Cell Biol. 2005 Sep 26;170(7):1101-11