An 83-year-old man presented to the clinic with the primary concern of hoarseness for the past 4 months that began after an episode of pneumonia.
The patient described increased vocal strain, vocal fatigue, and difficulty projecting his voice. Additionally, he complained of dysphagia with thin liquids for the past 4 months. He denied abdominal pain, nausea, vomiting, postnasal drainage, or change in his bowels. He had a history of acid reflux, but he reported good control on daily ranitidine.
His past medical history was significant for hyperlipidemia, hypertension, left C6 radiculopathy, and remote L2-L4 laminectomy. He had no history of tobacco use or exposure. He takes simvastatin, hydrochlorothiazide, losartan, and ranitidine.
The patient's BP was 125/63 mm Hg; pulse, 77; and weight, 79.8 kg (175.9 lb, for a BMI of 28.4). His ear, nose, and throat (ENT) examinations were normal. He had no polyps, septal deviation, or mucopurulence, no lymphadenopathy, and his abdomen was soft and nontender. His voice was soft and sounded strained when he was trying to project.
Because of the severity and longevity of the hoarseness, he was referred to ENT and underwent a flexible laryngoscopy. His hoarseness was thought to be due to chronic postnasal drainage and tension of the muscles around the larynx, a condition called muscle tension dysphonia. The recommended treatment was increased hydration, fluticasone nasal spray, and voice therapy.
Given the patient's recent pneumonia and reported liquid dysphagia, his primary clinicians were concerned about possible aspiration. A swallow study and esophagogastroduodenoscopy (EGD) were completed; both examinations were normal. Despite following voice therapy, the patient returned to primary care after several months because he did not have improvement. In fact, he felt that his voice continued to worsen, and his swallowing was not better. In addition to the previous symptoms, he had recently experienced more problems with gait. He described a feeling of leg weakness. He said he needed a great amount of effort to lift his legs, especially his left leg.
On physical examination, cranial nerves (CN) 2 through 12 were intact. He had 5/5 strength bilaterally with arm abduction, hip flexion, leg extension at the knee, and ankle plantarflexion. He had 4/5 strength on the left with flexion at the elbow, extension at the elbow, and ankle dorsiflexion compared with 5/5 strength of the same areas on the right. Biceps, triceps, brachioradialis, knee, and ankle deep tendon reflexes were 1+ and equal bilaterally. He had no rigidity. His alternate movement rate finger tapping did not suggest significant bradykinesia. He had no tremor. His gait examination showed forward flexion at the waist, decreased arm swing on the left, and a left hip drop reminiscent of an uncompensated Trendelenburg pattern. ENT, lung, and cardiovascular examinations were normal.
The weakness with normal deep tendon reflexes on examination prompted a brain MRI to look for any signs of stroke or brain compression; this study was normal. A complete metabolic panel was ordered to look for hypercalcemia, hypocalcemia, hypophosphatemia, and hepatic myelopathy. A thyroid function cascade was completed looking for thyroid myopathy, hyperthyroidism, or hypothyroidism. Creatine kinase was ordered to look for myopathies. Inflammatory markers including a C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and antinuclear antibodies (ANA) were ordered to screen for inflammation and autoimmune disease. Vitamin B12 was ordered because a deficiency can cause degeneration of the nervous system. Serum protein electrophoresis with immunofixation was ordered to rule out motor neuropathy with monoclonal gammopathy. All laboratory tests came back normal. He was referred to neurology and the orthopedic spine clinic for further evaluation.
Neurology evaluated further with an MRI of the cervical and thoracic spine, which was normal. An electromyogram (EMG) and nerve conduction studies were ordered to further exclude myopathy or neuropathy. These studies revealed chronic active left L5 radiculopathy and a chronic active left C6 radiculopathy. The testing showed no electrodiagnostic evidence of a myopathy.
Because the MRI did not show any active compression on the spinal cord, orthopedic spine did not have any interventions to offer. The chronic active left L5 radiculopathy was thought to explain the left hip weakness. The chronic active left C6 radiculopathy could account for the left arm weakness on initial examination. Because no surgical intervention was indicated, the patient was referred to physical therapy to help strengthen his gait.
A few months later, the patient presented to the clinic again accompanied by his children. They were concerned about their father and his rapid decline in function. They noted unintentional weight loss of 10 lb (4.5 kg) and loss of muscle mass. He was starting to have problems maintaining his posture and was leaning forward more with walking. Over the past year, he had transitioned from a cane to a walker and was in a wheelchair at this appointment. He continued to have difficulty with swallowing and now coughed with eating and drinking. His voice had become soft and continued to sound strained.
Physical examination revealed severe dysarthria with a strained vocal quality and slow speech. CN 2 through 12 were intact. Fasciculations were observed along the thoracic paraspinal muscles and triceps bilaterally. He had 4/5 strength bilaterally with arm abduction, hip flexion, leg extension at the knee, and ankle plantarflexion. He had 3/5 strength on the left with flexion at the elbow, extension at the elbow, and ankle dorsiflexion compared with 4/5 strength of the same areas on the right. Left biceps, triceps, and brachioradialis reflexes were 2+; the same reflexes on the right were 1+. His knee and ankle deep tendon reflexes were 1+ and equal bilaterally. He was able to stand with effort, pushing off from the chair. Once he stood, he had a flexed spinal posture that he could intentionally overcome until he seemed to fatigue. His gait was narrow-based, somewhat shuffling, with left Trendelenburg. He took three to four steps to turn. He seemed to have difficulty relaxing, so it was difficult to determine if he had spasticity or hypertonia or both. He had no ankle clonus and a negative Babinski reflex.
A repeat EMG and nerve conduction studies continued to show electrodiagnostic evidence of both active and chronic motor degeneration with progression since the previous study. Sensory nerve conduction results were normal. Spontaneous motor function including muscle fasciculations were noted in both the upper and lower extremities. The physical examination findings and EMG results led to development of the following differential diagnosis to explain his condition.
- amyotrophic lateral sclerosis (ALS)
- progressive muscular atrophy
- primary lateral sclerosis
- flail leg syndrome
The patient was diagnosed with ALS, a rapidly progressive and fatal neurodegenerative disorder of the motor neurons. The diagnosis was based on evidence of both upper and lower motor neuron dysfunction in one of four body segments (bulbar, cervical, thoracic, or lumbosacral) followed by the spread to other segments.1 Upper motor neurons (UMNs) are in the brain and lower motor neurons (LMNs) are in the brainstem and spinal cord. UMN symptoms include spasticity, hyperreflexia, and pathologic reflexes. LMN symptoms include weakness, fasciculations, and muscle atrophy.2,3
Physical examination, EMG and nerve function studies, and laboratory studies often are performed to support the diagnosis of ALS and to rule out other diseases that can have similar presentation. UMN symptoms can only be found on physical examination; LMN disease can be diagnosed on physical examination and EMG. LMN symptoms present on EMG as normal sensory response but decreased motor amplitude and chronic motor axon loss pattern. At rest, muscles also show abnormal spontaneous activity including fibrillation potentials and fasciculation potentials.2,3
The EMG findings were suggestive of motor neuron disease because they revealed progressive decreased motor amplitude with normal sensory response and captured spontaneous motor function including muscle fasciculations. Laboratory testing including a complete metabolic panel, thyroid function studies, serum electrophoresis with immunofixation, creatinine kinase, inflammatory/autoimmune markers (ESR, CRP, ANA), and B12 were normal, ruling out other causes of symptoms. MRI of the brain, cervical, and thoracic spine done earlier also were normal, ruling out stroke, myelopathy, and significant cord compression. The tests completed in this case are commonly ordered in evaluation of motor neuron disorders apart from thyroid studies, ESR, CRP, and ANA.2 Although neuroimaging studies often are ordered at some point in the evaluation of patients with ALS and other motor neuron disorders, neuroimaging is not necessary for the diagnosis of motor neuron disorders. As in this case, neuroimaging and laboratory evaluation often is ordered early in the disease course when the typical pattern and evolution of ALS are not present or if a patient has atypical signs and symptoms.2
ALS, progressive muscular atrophy, primary lateral sclerosis, and flail leg syndrome are all motor neuron diseases. Progressive muscular atrophy is a progressive LMN disorder. Some experts believe that it may be a form of ALS because UMN symptoms can develop in some patients late in the disease.4 Primary lateral sclerosis is a progressive isolated UMN neurodegenerative disorder.2 Flail leg syndrome is characterized by progressive LMN weakness and wasting with onset in the distal leg.2 Because he had both UMN and LMN symptoms and imaging and laboratory evaluation ruled out other causes or his symptoms, ALS was the correct diagnosis.
The estimated prevalence of ALS in the United States is 5.2 per 100,000 persons with 6,000 new patients diagnosed with ALS each year.5 Male sex has been a longstanding risk factor for ALS; recent studies report a male-to-female ratio of 1.6:1.5 The mean age of ALS symptom onset is 51 to 66 years and the mean age of diagnosis is 54 to 69 years.6 The gap between the age of symptom onset and the age of diagnosis is thought to be because the initial symptoms of ALS are often nonspecific and reliable diagnostic biomarkers are lacking in this disease. In addition, the diagnosis of ALS must be made based on evidence of a progressive spread of symptoms, which takes time to demonstrate. Along with older age and male sex, the other leading risk factor is family history. An increasing number of susceptibility genes have been reported.6 Testing for these genetic mutations is possible but does not affect clinical care because the treatment for ALS is the same whether it is genetic or sporadic.
ALS onset most often presents as weakness in the limbs (spinal onset) or difficulty speaking or swallowing (bulbar onset). Between 58% and 82% of ALS patients have spinal onset.6 The mean survival time from symptoms to death or invasive respiratory support is 24 to 50 months.6 ALS has no cure and treatment is mostly aimed at managing symptoms. For example, muscle cramps can be managed with physical and massage therapy, exercise and stretching, or drugs (levetiracetam, phenytoin, carbamazepine, baclofen, tizanidine, and mexiletine).7 Two disease-modifying treatments, riluzole and edaravone, are approved in the United States and have been found beneficial.7
Because ALS has a heterogenous clinical phenotype, it can be misdiagnosed or the diagnosis delayed, especially in early disease.1 By the time patients experience ALS signs and symptoms, 50% to 70% of the motor neurons are nonfunctional.3 Given the lack of reliable diagnostic biomarkers, the diagnosis of ALS must be made clinically and involves the need to prove progressive spread of both UMN and LMN symptoms, which takes time.6 The delay in diagnosis means that often, patients do not get early disease treatment. Although ALS has no cure, disease-modifying medications and symptomatic treatment options can improve patient quality of life.
1. van den Bos MAJ, Geevasinga N, Higashihara M, et al. Pathophysiology and diagnosis of ALS: insights from advances in neurophysiological techniques. Int J Mol Sci
2. Goutman SA. Diagnosis and clinical management of amyotrophic lateral sclerosis and other motor neuron disorders. Peripheral Nerve Motor Neuron Disord
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4. Kim W-K, Liu X, Sandner J, et al. Study of 962 patients indicates progressive muscular atrophy is a form of ALS. Neurology
5. Mehta P, Kaye W, Raymond J, et al. Prevalence of amyotrophic lateral sclerosis—United States, 2015. MMWR Morb Mortal Wkly Rep
6. Longinetti E, Fang F. Epidemiology of amyotrophic lateral sclerosis: an update of recent literature. Curr Opin Neurol
7. Schultz J. Disease-modifying treatment of amyotrophic lateral sclerosis. Am J Manag Care
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