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Motor Neuron Disease

JALS

Several conditions constitute the group of motor neuron diseases, including amyotrophic lateral sclerosis, and cause progressive degeneration of upper and lower motor neurons, depending on the subtype. Their cause remains unknown and they are slightly more frequently encountered in males. Clinical presentation involves muscle weakness and atrophy in all forms. To make the diagnosis, numerous diseases have to be excluded, while treatment mainly rests on supportive measures.


Presentation

The clinical presentation somewhat varies on the subtype of MND, but progressive muscle weakness, muscle atrophy and a variety of bulbar and pseudobulbar symptoms are present [1] [2]:

  • In ALS, initial weakness in distal extremities progresses to involve all limbs, together with features of both UMN and LMN injury. Fasciculations, hyperreflexia, fatigue, stiff movement and weight loss are common manifestations. As the disease goes on, chewing, swallowing and speech issues appear, together with increased salivation and involuntary emotional outbursts. It is important to note that the senses, voluntary functions of the oculomotor nerve and both urinary and anal sphincters are almost never involved.
  • Progressive muscular atrophy has a somewhat milder course and primarily involves LMN injury, with fasciculations, muscle wasting and eventual generalized weakness are main clinical features.
  • Progressive bulbar palsy is characterized by involvement of UMNs, mainly the corticospinal and corticobulbar tracts. Impaired gag reflex, movement of the tongue and palate, together with severe dysphagia are most commonly observed in patients.
  • Primary lateral sclerosis has a somewhat similar clinical presentation to progressive muscular atrophy, but it is often accompanied with pseudobulbar symptoms. Progressive pseudobulbar palsy has an almost identical presentation to primary lateral sclerosis.

In final stages of MNDs, respiratory failure eventually occurs and is the main cause of death across all subtypes.

Amyloidosis
  • Medicines can relieve symptoms and, sometimes, prolong survival An autosomal dominant inherited form of amyloidosis Diseases characterized by a selective degeneration of the motor neurons of the spinal cord, brainstem, or motor cortex.[icd9data.com]
Short Stature
  • NTE-MND resembles Troyer syndrome, except that short stature, cognitive impairment, and dysmorphic features, which often accompany Troyer syndrome, are not features of NTE-MND.[ncbi.nlm.nih.gov]
Fasciculation of the Tongue
  • Neither atrophy nor fasciculation of the tongue was observed. Both cases showed rapid progression to mutism within a few years. Neuropathologically, frontal lobe degeneration including the precentral gyrus was observed.[ncbi.nlm.nih.gov]
  • Fasciculations of the tongue, which are a prominent feature of SMA, are helpful in making this distinction.[neuropathology-web.org]
  • Wasting and fasciculation of the tongue. Dysphagia (usually a late feature with significant speech difficulties). Accompanying emotional lability (inappropriate laughing or crying) - as with pseudobulbar palsies.[patient.info]
Abnormal Eye Movement
  • The patient had noted clumsiness and weakness in all extremities 5 years before presentation of abnormal eye movements. The results of electromyography and muscle biopsy were compatible with ALS.[ncbi.nlm.nih.gov]
Muscular Atrophy
  • Patients with spinal muscular atrophy may appear to be stable for long periods, but improvement should not be expected. Some MNDs, such as ALS and some forms of spinal muscular atrophy, are fatal.[ninds.nih.gov]
  • atrophies (NMAs) and compared these patterns to mouse models of neurogenic muscular atrophy.[ncbi.nlm.nih.gov]
  • In progressive muscular atrophy and related syndromes (see muscular atrophy, spinal) the motor neurons in the spinal cord are primarily affected.[icd9data.com]
  • Primary lateral sclerosis has a somewhat similar clinical presentation to progressive muscular atrophy, but it is often accompanied with pseudobulbar symptoms.[symptoma.com]
  • The Repository also banks subjects with MNDs that have known genetic causes, including Spinal Bulbar Muscular Atrophy (Kennedy’s Disease) and Spinal Muscular Atrophy.[coriell.org]
Muscle Weakness
  • RESULTS: All patients had slowly progressive muscle weakness and wasting in combination with downbeat nystagmus, which was clinically most obvious in downward and lateral gaze.[ncbi.nlm.nih.gov]
  • Because of progressive muscle weakness and atrophy, he became bed-ridden at age 65. At age of 68, he died.[ncbi.nlm.nih.gov]
  • The muscle weakness, typically with signs of upper and lower motor neuron dysfunction, is uniquely relentless.[ncbi.nlm.nih.gov]
  • Author information 1 Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected] Abstract A 12 year-old female presented with a seven-year history of progressive muscle weakness, atrophy, tremor and fasciculations[ncbi.nlm.nih.gov]
  • Unlike previous reports of trapped fourth ventricle, his presentation was motor neuron disease-like syndrome, including hand muscle weakness and atrophy, generalized brisk deep tendon reflexes, and absence of sensory deficits.[ncbi.nlm.nih.gov]
Muscle Twitch
  • RESULTS: A 69-year-old man with long-standing depression and failing memory presented with muscle twitches of 8 months' duration. He was found to have choreoathetoid movements and distal weakness on neurological examination.[ncbi.nlm.nih.gov]
  • Usually, the first things people notice are: weakness in the hands and grip slurred speech weakness in the legs, and a tendency to trip weakness of the shoulder, making lifting difficult cramps and muscles twitching Later on, people with MND: have little[healthdirect.gov.au]
  • We describe a patient who presented reporting of muscle twitches in whom fasciculations and choreoathetoid movements were apparent in all extremities on the initial examination.[jamanetwork.com]
  • Symptoms vary from person to person, but can include: Wasting and weakness of muscles Twitching of muscles (called fasciculations) Stiffness of muscles Problems with articulation (production of speech) such that the speech may sound slurred Problems with[ftdtalk.org]
Limb Weakness
  • Selective distal upper limb muscle weakness and atrophy with non-significant lower limb weakness during follow-up was the most frequent motor pattern, present in 18 patients - in 15 of them associated with severe dysphagia.[ncbi.nlm.nih.gov]
  • Multifocal motor neuropathy with conduction block: Often presents in young or middle-aged men as unilateral distal upper limb weakness with little evidence of wasting initially.[patient.info]
  • Symptoms Initial stage: Clumsiness Tiredness Muscular pain Cramps A weakening of grip, so that picking up or holding objects may become hard Twitching Slurred or difficult to understand speech Limb weakness Advanced stage: Weakness in the muscles, in[newhealthadvisor.com]
  • However, continued progression of limb weakness following surgical correction argues against its contribution to the patient's symptoms. Therefore, we suggest that motor neuron disease could be one of the presenting features of HD.[jamanetwork.com]
  • Limb weakness with both lower and upper motor neuron signs is almost always evident but less prominent.[web.archive.org]
Guillain-Barré Syndrome
  • Myasthenia gravis presenting like guillain-barré syndrome. Case Rep Neurol. 2012 Sep;4(3):137-43. doi: 10.1159/000342448. Epub 2012 Sep 12. PubMed PMID: 23271998; PubMed Central PMCID: PMC3529579.[lifeinthefastlane.com]
  • Guillain-Barré syndrome . Post-polio syndrome . Myasthenia gravis or Lambert-Eaton myasthenic syndrome . Peripheral nerve lesions, particularly due to diabetic neuropathy . Thyrotoxicosis with associated myopathy . Spinal cord tumours .[patient.info]
Cerebellar Sign
  • MMND variant has the additional features of optic atrophy and cerebellar signs.[ncbi.nlm.nih.gov]

Workup

To make the diagnosis of a MND, the following diagnostic criteria should be fulfilled [3]:

  • Evidence of LMN injury on electromyography (EMG studies)
  • Evidence of UMN injury on electromyography
  • Marked progression of symptoms within a specific region
  • Absence of EMG findings and brain MRI that suggest other causes of symptoms.

Prior exclusion of various more common and possibly treatable conditions should be made. Infectious diseases, such as Lyme disease, hepatitis C and neurosyphilis should be excluded by appropriate serological testing, while myasthenia gravis, dermatomyositis, lead poisoning, multiple sclerosis, disorders of the thyroid and adrenal gland and spinal muscular atrophy are some of the conditions that may present with similar symptoms [1] [3]. To exclude these conditions, a complete blood count, serum and urine protein immunofixation, levels of electrolytes and creatine kinase, while a lumbar puncture may be useful as well, especially if the presence of leukocytes is established. The cornerstone, however, is EMG studies together with MRI, which may reveal the presence of typical changes in nerve conduction and potential presence of tumors or other structures that may be responsible for the development of symptoms, respectively.

Treatment

There is no cure for MNDs and the focus of treatment currently remains on supportive measures. A multidisciplinary approach is necessary to manage neurological, respiratory and psychiatric symptoms [2]. Baclofen may be effectively used for management of spasticity, while anticholinergic drugs may be given to reduce excessive salivation. Antidepressants such as amitriptyline and other serotonin-selective reuptake inhibitors [2]. Since the majority of patients die of respiratory failure, ensuring adequate ventilation is key in prolonging the patient's life for at least some time. Riluzole is a drug that has shown to prolong survival rate in patients with ALS due to its antagonistic effects to glutamate, but only for a few months.

Prognosis

The prognosis for virtually all forms of MNDs are very poor, as these conditions are universally fatal. In the case of ALS, 5-year survival rates are 20% and 10-year survival rates are 10% [11], while studies show a median survival rate of approximately 4 years [12]. Progressive bulbar palsy is fatal within 1-3 years in the vast majority of patients, as dysphagia becomes intolerable and various respiratory complications occur, but progressive muscular atrophy has a somewhat better prognosis, since patients can reach up to 25 years [1]. Primary lateral sclerosis results in total disability within several years, indicating that these conditions present as a significant burden to patients and their families.

Etiology

It is hypothesized that a combination of genetic and environmental factors contribute to development of MNDs [2]. The majority of cases are sporadic, meaning that mutations develop de novo, but approximately 10% of cases are familial. Familial MND is considered to be transmitted by autosomal dominant pattern of inheritance and in approximately 20% of patients, SOD mutations have been observed [3]. Additionally, mutations of various genes and compounds, including TDP43, FUS, angiogenin, dynactin, vesicle-associated membrane-protein and several other have been documented [2]. On the other hand, sporadic forms have shown a strong association with alterations in vascular endothelial growth factor and apolipoprotein A4 [6]. The exact events that lead to progressive neuronal death, however, require further studies.

Epidemiology

Incidence and prevalence rates currently rely on isolated studies that reflect the overall burden of the disease. In the United Kingdom, studies have established that prevalence rates of ALS, progressive muscular atrophy and primary lateral sclerosis combined are approximately 6 per 100,000 individuals, with an incidence rate of 1-2 per 100,000 [3]. Similar reports are seen in Italy and Canada, where a crude incidence rate of 2.5 per 100 000 has been established [7] [8]. When looking at ALS alone, studies report an annual incidence rate of 1.5-2.5 per 100,000 [9]. MNDs are slightly more frequent among males and the onset is usually after 50 years [1]. Risk factors are currently unknown, but smoking has shown to be one of the most prominent candidates for sporadic ALS [10].

Sex distribution
Age distribution

Pathophysiology

Changes observed in MNDs invariably include pathological events in both UMNs and LMNs. Lower motor neurons include the cells in the anterior horn of the spinal cord and motor nuclei of certain cranial nerves, while upper motor neurons constitute the motor cortex and the corticospinal and corticobulbar tract. Although the exact pathophysiological mechanisms of disease are not understood, damage of nervous tissue occurs via several mechanisms. Oxidative stress, as a result of SOD mutations, excessive stimulation of NMDA receptors by glutamate in the CNS, mitochondrial injury, as well as intracellular protein and filament aggregation have all been observed in both human and animal models [2]. The end-result is apoptosis and progressive, irreversible death of neuronal cells which significantly impairs normal signal conduction throughout the body. In the setting of LMN damage, hyporeflexia, atrophy, decreased muscle tone and fasciculations develop, while diseases that affect UMNs cause spasticity, increased muscle tone, hyperreflexia and atrophy in later stages of disease, but fasciculations are absent [1].

Prevention

Current prevention strategies do no exist, as the exact pathophysiologic basis of these disease remain unknown. Having in the fact that these conditions are managed by supportive measures only, little can be done regarding prevention and treatment.

Summary

Motor neuron disease (MND) is a term that comprises several neurodegenerative disorders - amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PCS), progressive bulbar palsy, progressive pseudobulbar palsy and progressive muscular atrophy, although ALS is most extensively studied [1]. ALS (also known as Lou Gehrig's disease) is the most common MND, with an approximate incidence of 1.5 per 100 000 individuals. The sixth and seventh decade of life is the period of most frequent onset [2]. The hallmark of all MNDs is progressive degeneration of upper and lower motor neurons (UMN and LMN, respectively), depending on the subtype. The cause remains unknown. The majority of MNDs develop sporadically, but up to 10% of cases are classified into familial forms and their clinical presentation is identical [3]. Several mutations have been described, such as genes encoding superoxide dismutase (SOD), one of the main enzymes involved in suppressing free-radical injury, certain RNA-binding proteins such as FUS/TLS and TDP43, whereas alterations in promoter genes, angiogenin, apolipoprotein E4 and several other have been established as well [4] [5]. Although the etiology of MNDs are not known, nerve damage is thought to be a result of several pathophysiological changes. In addition to oxidative stress, excessive glutamate stimulation that leads to neuronal death and aggregation of proteins and neurofilaments that are supposedly toxic to cells leads to apoptosis and cell death [2]. As a result of these changes, progressive degeneration of neuronal tissue is observed in patients suffering from MNDs and gives rise to the appearance of symptoms that may involve both lower and upper motor neurons. The clinical presentation somewhat varies depending on the subtype of MND, but weakness and muscle atrophy are usually seen in all disorders. A progressive deterioration of nervous system occurs, as weakness and atrophy eventually affect all limbs, together with the onset of fasciculations, dysphagia, dysarthria, hoarseness and excessive salivation [1]. Pseudobulbar affects are commonly observed and are characterized by excessive laughter, yawning and crying [2]. In the setting of ALS, a distinguishing feature from other disorders is the fact that the senses, urinary sphincters, oculomotor nerve functions and cognition are almost always spared, for unknown reasons. Making the diagnosis of MND is difficult, as there are no specific diagnostic tests, but also because numerous conditions may present with similar symptoms. Myasthenia gravis, polymyositis, Lyme disease and many other have to be excluded in the workup [1]. Electromyography, magnetic resonance imaging, serum and urine protein electrophoresis and genetic testing, as well as numerous other tests to exclude other conditions, should be included in the diagnostic protocol. Treatment rests on supportive measures, as there is no cure for neither of MNDs and is primarily aimed at ensuring adequate respiratory function and acceptable everyday life. The overall prognosis of patients with MND is quite poor, as these disorders are universally fatal. 3-year survival rate for ALS is 50% after onset, progressive bulbar palsy is universally fatal within 1-3 years, while patients suffering from progressive muscular atrophy may live up to 25 years [1].

Patient Information

Motor neuron disease (MND) is a term that encompasses several neurodegenerative disorders that affect the nerves that are responsible for innervation of muscles and various other structures in the central nervous system. Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) is the most common MND, occurring in approximately 2 per 100,000 individuals, while progressive bulbar palsy, progressive pseudobulbar palsy, primary lateral sclerosis and progressive muscular atrophy are other subtypes. Their cause remains unknown, but it is hypothesized that a combination of various genetic factors is responsible for the development of these diseases. Namely, mutations in enzymes that are responsible for fighting free radicals, superoxide dismutase (SOD), have been identified in a significant number of patients, while alterations in several other genes have been documented. Moreover, approximately 10% of all MNDs are familial, meaning that some inherited factors may also play a role. Risk factors are currently not established, but some studies have associated smoking and MNDs. These disease are slightly more commonly encountered in males and their onset is usually between 50-70 years. Patients may present with diverse symptoms, the most prominent being muscle weakness and atrophy. Because these diseases are progressive in nature, gradual worsening of symptoms and appearance of various other complaints is the usual clinical course. Main neurological symptoms include either diminished or increased reflexes and abnormal muscle tone, while difficulties chewing, eating, talking, as well as voice changes and clumsiness are all frequently observed in patients. In some MNDs, such as progressive bulbar palsy, significant emotional reactions may be observed, such as intense involuntary crying or laughing. To make the diagnosis, it is necessary to perform electromyography, a procedure that evaluates nerve conduction signaling, but various other conditions that may present with similar symptoms have to be excluded. Myasthenia gravis, syphilis, hepatitis C, Lyme disease, lead poisoning, diseases of the thyroid gland and many other may mimic MNDs, which is why a thorough diagnostic workup is necessary, often including various laboratory studies and magnetic resonance imaging (MRI) of the head. Treatment, unfortunately, is focused on supportive measures, as there is no cure for these universally fatal diseases. The prognosis of MNDs are very poor and all subtypes eventually lead to fatal outcomes. Approximately 50% of patients suffering from ALS die within 3 years, whereas the majority of patients with progressive bulbar palsy die within 1-3 years after the onset of symptoms. A somewhat better prognosis is seen in progressive muscular atrophy, where patients live up to 25 years. Overall, MNDs cause a rapidly progressive deterioration of the nervous system that always leads to fatal outcomes.

References

Article

  1. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.
  2. Williams UE, Philip-Ephraim EE, Oparah SK. Multidisciplinary Interventions in Motor Neuron Disease. J Neurodegener Dis. 2014;435164.
  3. Wood-Allum C, Shaw PJ. Motor neurone disease: a practical update on diagnosis and management. Clin Med (Lond). 2010;10(3):252-258.
  4. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
  5. Millecamps S, Boillée S, Le Ber I, Seilhean D, Teyssou E, Giraudeau M. Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes. J Med Genet. 2012;49(4):258-263.
  6. Lambrechts D., Storkebaum E., Morimoto M., et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genetics. 2003;34(4):383–394.
  7. Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis (PARALS). Incidence of ALS in Italy: evidence for a uniform frequency in Western countries. Neurology. 2001;56(2):239-244.
  8. Wolfson C, Kilborn S, Oskoui M, Genge A. Incidence and prevalence of amyotrophic lateral sclerosis in Canada: a systematic review of the literature. Neuroepidemiology. 2009;33(2):79-88.
  9. Logroscino G., Traynor B. J., Hardiman O., et al. Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. Journal of Neurology, Neurosurgery and Psychiatry. 2008;79(1):6–11.
  10. Armon C. Smoking may be considered an established risk factor for sporadic ALS. Neurology. 2009;73(20):1693-1698.
  11. Bäumer D1, Talbot K, Turner MR. Advances in motor neurone disease. J R Soc Med. 2014;107(1):14-21.
  12. Ringel SP, Murphy JR, Alderson MK, et al. The natural history of amyotrophic lateral sclerosis. Neurology. 1993;43:1316–1322.

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Last updated: 2018-06-22 03:29