A 55-year-old male patient was evaluated for foot drop (bilateral), which had begun subtly 4 months earlier with the onset of muscle cramping in the right calf as a result of volitional movement (known as volitional cramping) and had progressed to severe weakness of ankle dorsiflexion and knee extension more so on the right side. In addition to these features, the physical examination revealed atrophy of the right calf and hyperreflexia of the right biceps and of deep tendon reflexes at both knees and both ankles. The patient had fasciculations in the right calf. We appear to be dealing with upper motor neuron lesion in the right arm and both legs. This lesion does not appear to have a definite level. The neurologic examination was otherwise normal. Electromyography showed evidence of acute muscle denervation (fibrillations) in all four limbs and muscle reinnervation in the right calf (high-amplitude compound muscle action potentials).
Why is further imaging required?
In amyotrophic lateral sclerosis the imaging is done to exclude other diseases which might be part of a differential diagnosis. There is no one test or imaging technique which gives a definite diagnosis. Imaging of the head and neck revealed no structural lesions impinging on motor tracts, and the results of laboratory studies were normal.
What did these laboratory tests rule out?
They ruled out several disorders in the differential diagnosis, such as peripheral neuropathy, Lyme disease, vitamin B12 deficiency, thyroid disease, and metal toxicity. What metals are likely to be involved? A high level of lead in the blood is a possibility and high CSF manganese level are associated with ALS.
A full evaluation disclosed no evidence of a reversible motor neuron disorder, such as multifocal motor neuropathy with conduction block, which is typically associated with autoantibodies (e.g., anti-GM1 ganglioside antibodies) and can be effectively treated with intravenous immune globulin.
You can see from this chart and pictures (taken from July 13, 2017
N Engl J Med 2017; 377:162-172 DOI: 10.1056/NEJMra1603471) That the survival in general is dismal being worst for bulbar onset disease and then spinal onset disease. The tongue shows lateral furrowing and atrophy; and the picture of the trunk shows generalised atrophy of the muscles.
Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder characterized by degeneration of motor neurons in the brain and spinal cord. It begins insidiously with focal weakness but spreads relentlessly to involve most muscles, including the diaphragm. Typically, death due to respiratory paralysis occurs in 3 to 5 years. When corticospinal (upper) motor neurons fail, muscle stiffness and spasticity result. When lower motor neurons become affected, they initially show excessive electrical irritability, leading to spontaneous muscle twitching (fasciculations); as they degenerate, they lose synaptic connectivity with their target muscles, which then atrophy. In a patient you can see both upper and lower motor neurons being affected simultaneously. Hence exaggerated reflexes in atrophic muscles.
ALS typically begins in the limbs, but about one third of cases are bulbar, heralded by difficulty chewing, speaking, or swallowing. Why is the patient unlikely to complain of diplopia or urinary incontinence? Until late in the disease, ALS spares neurons that innervate the eye and sphincter muscles. The diagnosis is based primarily on:
- clinical examination
- in conjunction with electromyography, to confirm the extent of denervation
- laboratory testing, to rule out reversible disorders that may resemble ALS such as as peripheral neuropathy, Lyme disease, vitamin B12 deficiency, thyroid disease, and metal toxicity as given above.
What is pseudobulbar palsy?
When there is prominent involvement of frontopontine motor neurons that serve bulbar functions, a striking finding is emotional lability, indicating pseudobulbar palsy, which is characterized by facial spasticity and a tendency to laugh or cry excessively in response to minor emotional stimuli.
Progressive bulbar palsy — Progressive bulbar palsy is a progressive upper and lower motor neuron disorder of cranial muscles. This condition may occasionally stay isolated to the bulbar segment, but more commonly, upper and lower motor neuron signs and symptoms spread to involve other segments. This is then referred to as bulbar-onset ALS. There have been no reports of specific pathology in progressive bulbar palsy.
Flail arm syndrome
The flail arm syndrome (also called brachial amyotrophic diplegia) is characterized by progressive lower motor neuron weakness and wasting that predominantly affects the proximal arm. It usually begins proximally and spreads distally to the point where arm and hand function is severely impaired. It is often asymmetric. Patients presenting with the flail arm variant of ALS have a slower rate of progression both to the spread of signs and symptoms in other body segments and to development of respiratory muscle weakness.
Flail leg syndrome
The flail leg syndrome (also called the pseudopolyneuritic variant of ALS/motor neuron disease) is characterized by progressive lower motor neuron weakness and wasting with onset in the distal leg. Patients presenting with the flail leg syndrome have a slower rate of progression to involvement of other body segments and of the development of respiratory muscle weakness.
Autonomic symptoms may occur in ALS as the disease progresses, although this is not an initial manifestation of the disease. Constipation occurs frequently and is likely multifactorial. Delayed colonic motility has been demonstrated. Dysphagia for thin liquids related to pharyngeal muscle weakness may lead to dehydration that can exacerbate constipation. Symptoms of early satiety and bloating consistent with delayed gastric emptying also occur as the disease progresses. Urinary urgency without incontinence is common, while incontinence is uncommon.
Parkinsonism and supranuclear gaze palsy
Extrapyramidal symptoms and signs of parkinsonism may precede or follow the upper and lower motor neuron symptoms. These extrapyramidal features may include facial masking, tremor, bradykinesia, and postural instability.
At times, a supranuclear gaze abnormality occurs that is similar to that seen in progressive supranuclear palsy.
The progressive course of ALS eventually produces one or both of the life-threatening aspects of the disease, neuromuscular respiratory failure and dysphagia. Respiratory muscle weakness may be the first manifestation of the disease but more commonly develops after months or years of progressive limb and/or bulbar muscle weakness.
What is primary lateral sclerosis?
In primary lateral sclerosis, there is selective involvement of corticospinal and corticopontine motor neurons, with few findings of lower motor neuron dysfunction. Primary lateral sclerosis is ruled out in the representative case described above because of the atrophy and electromyographic findings, which are indicative of lower motor neuron disease. Primary lateral sclerosis progresses slowly, with severe spastic muscle stiffness and little muscle atrophy. This disorder overlaps clinically with a broad category of corticospinal disorders designated as hereditary spastic paraplegias, which are typically symmetrical in onset, slowly progressive, and sometimes associated with sensory loss and other multisystem findings. In primary lateral sclerosis but not hereditary spastic paraplegias, bulbar involvement may be prominent.
In progressive muscular atrophy, lower motor neuron involvement is predominant, with little spasticity.
During the past two decades, it has been recognized that 15 to 20% of persons with ALS have progressive cognitive abnormalities marked by behavioral changes, leading ultimately to dementia. Since these behavioral alterations correlate with autopsy evidence of degeneration of the frontal and temporal lobes, the condition is designated frontotemporal dementia. It was formerly called Pick’s disease.
You can expect to approximately 3 to 5 cases per 100,000 population. Most cases are sporadic and 10% are familial with a dominant autosomal inheritance. In cases of sporadic ALS, the ratio of affected males to affected females may approach 2:1; in familial ALS, the ratio is closer to 1:1. ALS is the most frequent neurodegenerative disorder of midlife, with an onset in the middle-to-late 50s. An onset in the late teenage or early adult years is usually indicative of familial ALS.
What is the pathology behind ALS?
The core pathological finding in ALS is motor neuron death in the motor cortex and spinal cord; in ALS with frontotemporal dementia, neuronal degeneration is more widespread, occurring throughout the frontal and temporal lobes. Degeneration of the corticospinal axons causes thinning and scarring (sclerosis) of the lateral aspects of the spinal cord. In addition, as the brainstem and spinal motor neurons die, there is thinning of the ventral roots and denervational atrophy (amyotrophy) of the muscles of the tongue, oropharynx, and limbs. Until late in the disease, ALS does not affect neurons that innervate eye muscles or the bladder. Degeneration of motor neurons is accompanied by neuroinflammatory processes, with proliferation of astroglia, microglia, and oligodendroglial cells.
A common feature in cases of both familial and sporadic ALS is aggregation of cytoplasmic proteins, prominently but not exclusively in motor neurons. Some of these proteins are common in most types of ALS. This is exemplified by the nuclear TAR DNA-binding protein 43 (TDP-43), which in many cases of ALS is cleaved, hyperphosphorylated, and mislocalized to the cytoplasm. Aggregates of ubiquilin 2 are also common, as are intracytoplasmic deposits of wild-type superoxide dismutase 1 (SOD1) in sporadic ALS.
Do genes matter?
More than 120 genetic variants have been associated with a risk of ALS. It has proved almost impossible to predict a variant’s relevance to ALS from the biologic features of the gene itself. At least 25 genes have now been reproducibly implicated in familial ALS, sporadic ALS, or both.
Gene discovery since 1990.
Concepts in pathology.
A comprehensive explanation for ALS must include both its familial and sporadic forms, as well as categories of phenotypic divergence that arise even with the same proximal trigger, such as a gene mutation. A general presumption has been that the disease reflects an adverse interplay between genetic and environmental factors. An alternative view postulates that all cases of ALS are a consequence primarily of complex genetic factors. Several perspectives suggest that the pathogenesis of ALS entails a multi-step process.
There is striking heterogeneity in the genetic causes of familial ALS, but familial ALS and sporadic ALS have similarities in their pathological features, as well as in their clinical features, suggesting a convergence of the cellular and molecular events that lead to motor neuron degeneration. These points of convergence define targets for therapy. A working view of the present panel of ALS genes is that they cluster in three categories, involving protein homeostasis, RNA homeostasis and trafficking, and cytoskeletal dynamics. Downstream of each category are diverse forms of cellular abnormalities, including the deposition of intranuclear and cytosolic protein and RNA aggregates, disturbances of protein degradative mechanisms, mitochondrial dysfunction, endoplasmic reticulum stress, defective nucleocytoplasmic trafficking, altered neuronal excitability, and altered axonal transport. This means that therapy will need to address multiple sites.
Despite the absence of a family history in sporadic ALS, studies involving twins show that the heritability is about 60%. Furthermore, mutations usually found in familial ALS can be found in sporadic ALS. This can be partly explained by the difficulty in ascertaining whether patients with late-onset disease have a family history of ALS. The situation is confounded by the observation that some familial ALS gene variants increase the risk of phenotypes other than ALS, such as frontotemporal dementia.
Therapeutics and Beyond
No therapy offers a substantial clinical benefit for patients with ALS. The drugs riluzole and edaravone, which have been approved by the Food and Drug Administration for the treatment of ALS, provide a limited improvement in survival. Riluzole acts by suppressing excessive motor neuron firing, and edaravone by suppressing oxidative stress. Numerous other compounds that have been investigated have not been shown to be effective. Currently, the mainstay of care for patients with ALS is timely intervention to manage symptoms, including use of nasogastric feeding, prevention of aspiration (control of salivary secretions and use of cough-assist devices), and provision of ventilatory support (usually with bilevel positive airway pressure). Some interventions raise serious ethical issues, such as whether to perform tracheostomy for full ventilation and, if so, when and how to withdraw respiratory support once it has been instituted.