para>Infantile and juvenile spinal muscular atrophies are conditions distinct from ALS, both clinically and pathologically.
Symptoms of ALS may inappropriately be attributed to age.
Pregnancy Considerations
Uncommon among affected individuals
If pregnancy did occur, the only foreseeable difficulties would be related to weakness.
EPIDEMIOLOGY
Incidence
- In United States, 5,600 newly diagnosed per year
- Rate = 2/100,000 per year
Prevalence
- Estimated 3,000 Americans may have the disease at any given time without socioeconomic boundaries
- ALS is more common among white males, non-Hispanics, and persons aged 60 to 69 years (1).
- Predominant age: uncommon before age 40 years
- Predominant sex: male > female in sporadic ALS:
- After 70 years: male = female
ETIOLOGY AND PATHOPHYSIOLOGY
- Sporadic ALS: Unknown cause, but elevated levels of glutamate have been found in serum and CSF.
- Familial ALS: Neurodegenerative disease passed on directly or indirectly by skipping generation (2).
- Guam ALS and Parkinson-dementia complex: possible relationship to ingestion of the cycad nut or to some other environmental toxin
- Degeneration of the upper motor neuron (UMN) and lower motor neuron (LMN) with gliosis replacing lost neurons; leads to spinal cord atrophy, thin ventral roots, and loss of large myelinated fibers in motor nerves
- Progressive weakness of both skeletal and smooth muscles that leads to progressive loss of function related to movement, speech, swallowing, and breathing
Genetics
- Currently 18 types of genetic mutations
- Familial ALS, most common (5% of cases); can be autosomal dominant or autosomal recessive; X-linked cases have been reported.
- Gene locus has been localized to the long arm of chromosome 21 and encodes the superoxide dismutase (SOD1) enzyme in 20% of familial ALS cases.
- Mutation in the gene encoding fused in sarcoma (FUS) was identified in familial ALS type 6.
- Mutations in the angiogenin gene (ANG) have been recently discovered to be associated with sporadic ALS.
- Mutations in transcription of RNA activating protein (TARDP) region encoding TAR DNA-binding protein TDP-43 have also been identified in familial and sporadic ALS.
- FIG4 gene accounts for 3% of familial ALS.
- C9ORF72 repeat expansions found in 2011 is a major cause of ALS.
RISK FACTORS
- Family history
- Age >40 years and <60 years
- Smoking
GENERAL PREVENTION
Genetic counseling is advised if there is a family history of ALS; however, sporadic ALS is not associated with genetic transmission.
DIAGNOSIS
- Diagnosis can be established according to Revised El Escorial World Federation of Neurology criteria.
- The presence of:
- Evidence of LMN degeneration by clinical, electrophysiologic, or neuropathologic examination
- Evidence of UMN degeneration by clinical examination
- Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination
- The absence of
- Electrophysiologic and pathologic evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration
- Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiologic sign
- The newer Awaji criteria may offer higher sensitivity and earlier diagnosis of ALS (3)[C].
HISTORY
ALS is suggested when symptoms are consistent with UMN and LMN dysfunction that worsens over time. Symptoms include the following:
- Loss of muscle strength and coordination
- Difficulty opening and closing the jaw, drooling
- Voice change, hoarseness
- Muscle cramps and stiffness, difficulty breathing, difficulty swallowing, paralysis (3)[C]
PHYSICAL EXAM
Variable combinations of
- Unexplained weight loss
- Limb weakness with variable symmetry and distribution
- Gait disorder (steppage-waddling)
- Slurring of speech
- Inability to control affect (inappropriate laughing, crying, yawning)
- Focal atrophy of muscle groups (initially in a myotomal distribution)
- Fasciculations (other than calves)
- Hyperreflexia (including jaw jerk-Hoffmann sign)
- Babinski sign, present in 50% of patients
- Spasticity
- Sialorrhea
- Spares cognitive, oculomotor, sensory, and autonomic functions
DIFFERENTIAL DIAGNOSIS
- Multifocal motor neuropathy
- Cervical radiculomyelopathy
- Cervical spondylosis
- Lead intoxication
- Spinal muscular atrophy (adult form)
- Primary lateral sclerosis
- Familial spastic paraparesis
- Benign fasciculations
- Lyme disease
- Spinal multiple sclerosis
- Tropical spastic paraparesis
- Myasthenia gravis
- Hyperthyroidism
- Paraneoplastic syndromes
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- No simple reliable laboratory test or imaging test is available that confirms the diagnosis. Creatinine kinase levels may be elevated.
- Rule out other conditions (i.e., check serum protein electrophoresis [SPEP]/urine protein electrophoresis [UPEP], TSH, PTH, B12, 24-hour urine for heavy metals, HIV, human T-lymphotropic virus [HTLV], Lyme, syphilis, tick-borne encephalitis):
- Elevated levels of glutamate in CSF and serum
- Anti-monosialoganglioside autoantibodies in low titer commonly found (of unclear significance)
- Possibly reduced levels of nerve growth factor
- MRI is used to exclude other possible diagnoses:
- MRI is usually normal in ALS, although increased signal in the corticospinal tracts on T2-weighted and FLAIR images, and hypointensity of the motor cortex on T2-weighted images have been reported.
- Should be performed in all areas rostral to clinical findings
- Experimental MR spectroscopy testing is underway (3)[C].
Diagnostic Procedures/Other
- Electromyography (EMG): EMG findings include evidence of ongoing denervation, fibrillation or positive sharp waves, and chronic partial reinnervation implying frequently unstable, increased duration motor unit action potentials with a reduced interference pattern.
- Nerve conduction studies: usually elicit normal values in recordings from relatively unaffected muscles. However, during disease progression, compound motor action potential (CMAP) amplitude elicited by distal stimulation may induce greater physiologic phase cancellation, such as a pathologic conduction block.
- Motor unit number estimation: attractive end point measure in clinical drug trials in ALS because it directly assesses loss of LMNs and is sensitive to disease progression
- Muscle biopsy: not a routine part of the diagnostic evaluation of ALS but may be performed if myopathy is suspected on clinical, electrodiagnostic, or serologic grounds (3)[C]
- Muscle biopsy will show groups of shrunken angulated muscle fibers (grouped atrophy) that are darkly staining amid other groups of fibers with a uniform fiber type (fiber type grouping); however, these are nonspecific findings of chronic denervation with reinnervation.
Test Interpretation
- Loss of Betz cells in the motor cortex
- Atrophic or absent anterior horn cells of spinal cord
- Atrophic or absent neurons within the motor nuclei of the medulla and pons
- Degeneration of the lateral columns of the spinal cord
- Atrophy of the ventral roots
- Grouped atrophy of muscle (motor units)
TREATMENT
GENERAL MEASURES
- Multidisciplinary care should be available as this may extend survival, decrease medical complications, and improve quality of life (4)[C].
- Outpatient may need nursing home placement or hospice (4)[C].
- Supportive care is necessary for complicating emergencies (aspiration, respiratory failure). Use of a respirator is a major ethical dilemma (4)[C]. Consideration should be given to those with selective respiratory dysfunction.
- Discussion of advance directives, focusing on patient's specific values about which interventions are to be used, is critical to meeting the patient's needs (4)[C].
- Prosthetic devices
MEDICATION
Riluzole: 50 mg PO BID; the only FDA-approved drug for ALS. It produces a slight prolongation in life expectancy by decreasing the release of glutamate, and it slows the disease progression (5)[A].
ALERT
Riluzole withhold should be considered for patients developing fatigue. Monitor LFTs for hepatic dysfunction and CBC for neutropenia (5)[A].
ISSUES FOR REFERRAL
- Early exam by a neurologist can confirm diagnosis of ALS.
- Tracheostomy or gastrostomy tube placement may be performed by surgeon or GI doctor (4)[C].
- Pulmonologist and respiratory therapist for ventilator assistance and management of concurrent infections and tracheostomy
- Referral to ongoing clinical trials may be beneficial (https://clinicaltrials.gov/)
- Palliative care management is beneficial to both patient and patient's family at end stage (4)[C].
ADDITIONAL THERAPIES
- These drugs may be used to relieve severe spasticity:
- Baclofen: 5 mg PO TID initially, followed by gradual increase of 5 mg/day every 4 to 7 days; not to exceed 80 mg/day divided QID (4)[C]
- Tizanidine: 4 to 8 mg PO q8h PRN; not to exceed 36 mg/day (4)[C]
- Treatment for refractory sialorrhea:
- Botulinum toxin B (4)[B]
- Low-dose radiation therapy to the salivary glands (4)[C]
SURGERY/OTHER PROCEDURES
- Percutaneous endoscopic gastrostomy (PEG) tube should be considered with early signs of malnutrition to stabilize weight and prolong survival (4,6)[C].
- Noninvasive ventilation (NIV) can lengthen survival and improve quality of life (6)[C].
- Elective tracheostomy should be considered in patients with early signs of respiratory difficulty (6)[C].
COMPLEMENTARY & ALTERNATIVE MEDICINE
- Currently, insufficient evidence to recommend disease-modifying treatment other than Riluzole
- Research offering therapy with stem cells is evolving, providing a new approach in cellular replacement and support for patients (7)[C].
- Several therapy options are under current investigation, including ceftriaxone, dexpramipexole, memantine, tamoxifen, and insulin-like growth factor.
- Therapeutic trials of the efficacy of antioxidants (vitamin E and vitamin C and β-carotene), nerve growth factor, gabapentin, myotrophin, thyrotropin-releasing hormone, and creatine have been undertaken. Reports are not encouraging.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patients should be involved in regular exercise and a physical therapy program (8)[C].
Patient Monitoring
- Initially every 3 months; frequency to be increased as needed for symptomatic therapy
- Patients with a presumed diagnosis of ALS should have neuroimaging and electrodiagnostic studies (8)[C].
- Screening for cognitive/behavioral impairment (4)[B]
DIET
- Evaluate swallowing to quantify any dysphagia.
- Modify the patient's diet to prevent aspiration.
- Consider a gastrostomy tube when patient cannot swallow fluids or soft foods (8)[C].
PATIENT EDUCATION
Printed material for patients (and reference lists for physicians) available from:
- The Muscular Dystrophy Association: (520) 529-2000; (800) 572-1717; http://www.mdausa.org/
- The ALS Association: (800) 782-4747; http://www.alsa.org/
- Families of SMA: http://www.fsma.org.hk/
PROGNOSIS
- Median survival of patients with ALS is 3 to 5 years from diagnosis.
- Patients who predominantly manifest progressive muscular atrophy have a better prognosis.
- There have been reports of spontaneous arrest of the disease.
COMPLICATIONS
- Aspiration pneumonia
- Pulmonary embolism
- Nutritional deficiency
- Complications from wheelchair-bound or bedridden states, including decubitus ulcers and skin infections
REFERENCES
11 Mehta P, Antao V, Kaye W, et al. Prevalence of amyotrophic lateral sclerosis-United States, 2010-2011. MMWR Surveill Summ. 2014;63 (Suppl 7):1-14.22 Andersen PM, Borasio GD, Dengler R, et al. Good practice in the management of amyotrophic lateral sclerosis: clinical guidelines. An evidence-based review with good practice points. EALSC Working Group. Amyotroph Lateral Scler. 2007;8(4):195-213.33 Andersen PM, Abrahams S, Borasio GD, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)-revised report of an EFNS task force. Eur J Neurol. 2012;19(3):360-375.44 Miller RG, Brooks BR, Swain-Eng RJ, et al. Quality improvement in neurology: amyotrophic lateral sclerosis quality measures. Report of the Quality Measurement and Reporting Subcommittee of the American Academy of Neurology. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15(3-4):165-168.55 Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994;330(9):585-591.66 Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73(15):1218-1226.77 Kim SU, de Vellis J. Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res. 2009;87(10):2183-2200.88 Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73(15):1227-1233.
ADDITIONAL READING
Morren JA, Galvez-Jimenez N. Current and prospective disease-modifying therapies for amyotrophic lateral sclerosis. Expert Opin Investig Drugs. 2012;21(3):297-320.
CODES
ICD10
- G12.21 Amyotrophic lateral sclerosis
- G12.22 Progressive bulbar palsy
- G12.29 Other motor neuron disease
ICD9
- 335.20 Amyotrophic lateral sclerosis
- 335.22 Progressive bulbar palsy
- 335.23 Pseudobulbar palsy
- 335.21 Progressive muscular atrophy
- 335.24 Primary lateral sclerosis
SNOMED
- Amyotrophic lateral sclerosis (disorder)
- Progressive bulbar palsy (disorder)
- Amyotrophic lateral sclerosis with dementia
- Progressive muscular atrophy (disorder)
CLINICAL PEARLS
- ALS is a progressive upper and lower motor neuron degenerative disease.
- Diagnosis is made by history, physical exam, EMG, and NCS.
- Riluzole is the only available treatment that might increase survival.