Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 24-27: Degenerative Motor Neuron Diseases + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Weakness and wasting of muscles No sensory loss or sphincter disturbance Progressive course No identifiable underlying cause other than genetic basis in familial cases Cigarette smoking may be a risk factor +++ General Considerations ++ There is degeneration of the Anterior horn cells in the spinal cord Motor nuclei of the lower cranial nerves Corticospinal and corticobulbar pathways Five varieties have been characterized on clinical grounds +++ PROGRESSIVE BULBAR PALSY ++ Bulbar involvement predominates Disease processes affect primarily the motor nuclei of the cranial nerves +++ PSEUDOBULBAR PALSY ++ Bulbar involvement predominates Due to bilateral corticobulbar disease and thus reflects upper motor neuron dysfunction +++ PROGRESSIVE SPINAL MUSCULAR ATROPHY ++ A lower motor neuron deficit in the limbs Due to degeneration of the anterior horn cells in the spinal cord +++ PRIMARY LATERAL SCLEROSIS ++ There is a purely upper motor neuron deficit in the limbs +++ AMYOTROPHIC LATERAL SCLEROSIS ++ A mixed upper and lower motor neuron deficit is found in the limbs Approximately 10% of cases of amyotrophic lateral sclerosis are familial This disorder is sometimes associated with cognitive decline (in a pattern consistent with frontotemporal dementia), a pseudobulbar affect, or parkinsonism +++ Demographics ++ Symptoms generally begin between 30 and 60 years of age The disease is usually sporadic, but familial cases may occur + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Difficulty in swallowing, chewing, coughing, breathing, and talking (dysarthria) occur with bulbar involvement In progressive bulbar palsy, there is Drooping of the palate A depressed gag reflex Pooling of saliva in the pharynx A weak cough A wasted, fasciculating tongue In pseudobulbar palsy, the tongue is contracted and spastic and cannot be moved rapidly from side to side Limb involvement is characterized by motor disturbances (weakness, stiffness, wasting, fasciculations) reflecting lower or upper motor neuron dysfunction There are no objective changes on sensory examination, though there may be vague sensory complaints The sphincters are generally spared +++ Differential Diagnosis +++ UPPER MOTOR NEURON DISEASE ++ Stroke Space-occupying lesion Compressive spinal cord lesion Multiple sclerosis +++ LOWER MOTOR NEURON DISEASE ++ Infections of anterior horn cells (eg, poliovirus or West Nile virus) Radiculopathy, plexopathy, peripheral neuropathy, and myopathy are distinguished by clinical examination Pure motor syndromes resembling motor neuron disease may occur in association with Monoclonal gammopathy Multifocal motor neuropathies with conduction block, which can be distinguished by electrodiagnostic studies A motor neuronopathy may develop in Hodgkin disease and has a relatively benign prognosis + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ The serum creatine kinase may be slightly elevated but never reaches the extremely high values seen in some of the muscular dystrophies Hexosaminidase A and leukocytes are reduced in serum in patients with juvenile spinal muscular atrophy due to hexosaminidase deficiency The cerebrospinal fluid is normal Rectal biopsy shows abnormal findings +++ Diagnostic Procedures ++ Electromyography may show signs of acute and chronic partial denervation with reinnervation In patients with suspected amyotrophic lateral sclerosis, the diagnosis should not be made with confidence unless such changes are found in three spinal regions (cervical, thoracic, lumbosacral) or two spinal regions and the bulbar muscles Motor conduction velocity is usually normal but may be slightly reduced Sensory conduction studies are also normal Biopsy of a wasted muscle shows the histologic changes of denervation, but is not necessary for diagnosis To diagnose spinal muscular atrophy (SMA), molecular genetic testing for pathogenic variants of SMN1 is available + Treatment Download Section PDF Listen +++ +++ Medications ++ Riluzole, 50 mg twice daily orally Reduces the presynaptic release of glutamate May slow progression of amyotrophic lateral sclerosis Otherwise, no specific treatment is available except in patients with gammopathy, in whom plasmapheresis and immunosuppression may lead to improvement Drooling may be treated with Over-the-counter decongestants Anticholinergic medications (such as trihexyphenidyl, amitriptyline, or atropine) Botulinum toxin injections into the salivary glands Use of a portable suction machine Combination dextromethorphan/quinidine (20 mg/10 mg, one tablet orally once or twice daily) may relieve symptoms of pseudobulbar affect Nusinersen Treatment of SMA An antisense oligonucleotide that modulates pre-messenger RNA splicing of the SMN2 gene and results in increased production of the full-length protein Approved for use in all ages Dosage: 12 mg intrathecally every 14 days for three doses, then once after a 30-day interval, then once every 4 months Gene therapy with intravenous delivery of an intact SMN1 gene using a viral vector (onasemnogene abeparvovec) Improves ventilator-free survival compared to historical controls Approved by the FDA for use in children under 2 years of age with bi-allelic mutations in SMN1 +++ Surgery ++ Tracheostomy may be necessary if respiratory muscles are severely affected However, in the terminal stages of these disorders, the aim of treatment should be to keep patients as comfortable as possible +++ Therapeutic Procedures ++ Physical and occupational therapy and helpful throughout the disease course A semiliquid diet or liquid artificial nutrition via a gastrostomy may be needed if dysphagia is severe; it is advisable to perform the gastrostomy procedure before the forced vital capacity falls below 50% of predicted to minimize the risk of surgical complications Noninvasive ventilation at least 4 hours per day in patients with a maximal inspiratory pressure < 60 cm H2O may prolong survival + Outcome Download Section PDF Listen +++ +++ Prognosis ++ The disorder is progressive Amyotrophic lateral sclerosis is usually fatal within 3–5 years Death usually results from pulmonary infections Patients with bulbar involvement generally have the poorest prognosis, while patients with primary lateral sclerosis often have a longer survival despite profound quadriparesis and spasticity +++ When to Refer ++ All patients should be referred to a physician with expertise in the diagnosis and treatment of these disorders +++ When to Admit ++ For creation of a gastrostomy to enable liquid artificial nutrition For initiation or titration of noninvasive ventilation For periods of increased requirement of noninvasive ventilatory support during pulmonary infections + References Download Section PDF Listen +++ + +Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled trial. Lancet Neurol. 2017 Jul;16(7):505–12. [PubMed: 28522181] + +Mendell JR et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017 Nov 2;377(18):1713–22. [PubMed: 29091557] + +Mercuri E et al; CHERISH Study Group. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018 Feb 15;378(7):625–35. [PubMed: 29443664]