A SELF-TEST IM BOARD REVIEW JAMES K. STOLLER, MD, EDITOR ON A ANDREY S. STOJIC, MD, PhD TAREK MEKHAIL, MD BRYAN E. TSAO, MD CLINICAL Department of Neurology, Cleveland Clinic Department of Hematology and Department of Neurology, Oncology, Cleveland Clinic Cleveland Clinic CASE Leg weakness in a 66-year-old woman: A common presentation of an uncommon disease 66-YEAR-OLD WOMAN presents with pro- Blood pressure while sitting is 153/81 mm A gressive, painless weakness of the proxi- Hg, heart rate 75; blood pressure while stand- mal legs, which began 2 years ago. The onset ing is 106/71 mm Hg, heart rate 87. She is alert was gradual: at first she had difficulty standing and appropriate, and her cognition is intact. from a sitting position, such as when rising Cranial nerves II to XII are normal except for a from a chair, but over a 1-year period the weak- soft voice. She can swallow water normally. ness progressed to the point where she could no She has no ptosis. longer stand or walk without assistance. Arm Motor examination shows normal tone strength is not impaired. Six months before her and muscle bulk throughout. There is no visit she developed numbness and tingling in pain to palpation over the spine. Strength in the legs to the mid-calf level. her neck flexors and extensors is graded 4 on Review of systems reveals she has unin- the 5-point Medical Research Council scale. She has: tentionally lost 50 pounds over the past 2 She has normal strength in her arms; both •Leg years. She reports that her mouth is dry, and her legs are weak, graded 2/5 proximally and she feels light-headed when rising from a sit- 3/5 distally. weakness ting or lying position. She denies any oculo- Deep tendon reflexes are absent in all •Weight loss bulbar symptoms, incontinence, back pain, four extremities; sustained muscle contrac- myalgias, or arthralgias. tion of the quadriceps muscles resulted in • Dry mouth Previous evaluations included an electro- trace patellar reflexes. Vibratory and propri- • Orthostasis diagnostic examination 1 year earlier that sug- oceptive sensation are diminished in the dis- gested a mild motor radiculopathy involving tal lower extremities, with normal tempera- • Diminished the left L4–S1 roots and segments. At that ture and pin testing. Finger-to-nose testing sensation time, magnetic resonance imaging (MRI) of and evaluation of rapid alternating move- the lumbar spine showed moderate spondylo- ments reveal no evidence of cerebellar dys- in arms and sis with foraminal narrowing at the L4–S1 lev- function. legs els. A multilevel hemilaminectomy (L4–L5) was performed, but it produced little improve- ■ DIFFERENTIAL DIAGNOSIS ment in her weakness. She has 80 pack-years of tobacco use. She Which is the most likely cause of this has no personal or family history of neurolog- 1 patient’s lower-extremity weakness? ic disorders. ❑ Infiltrative (metastatic) disease of the lumbar spinal cord Physical examination ❑ Amyotrophic lateral sclerosis On physical examination, the patient is ❑ Sensorimotor peripheral neuropathy cachectic and in a wheelchair. She can stand ❑ Neuromuscular junction disease with assistance but cannot walk. ❑ Inflammatory myopathy CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 74 • NUMBER 1 JANUARY 2007 23 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. LOWER-EXTREMITY WEAKNESS STOJIC AND COLLEAGUES This patient presented with slowly progressive ical for amyotrophic lateral sclerosis. leg weakness (proximal greater than distal) Moreover, our patient’s distal large-fiber sen- and distal paresthesias. Several red flags were sory loss (including loss of vibration and pro- noted on the review of systems, namely signif- prioceptive sensation) and symptoms of auto- icant weight loss, dry mouth, and orthostatic nomic failure are not consistent with motor intolerance. The distribution of her weakness neuron disease. points to the lower motor neurons, which extend (proximal to distal) from the spinal Sensorimotor peripheral neuropathy cord, anterior horn cells, peripheral nerves, The most common form of sensorimotor and neuromuscular junction to the muscle. peripheral neuropathy involves loss of longer Her associated autonomic symptoms suggest a axons, manifesting as distal sensory loss, weak- more systemic disorder. ness, and loss of reflexes starting distally and Let’s look at the diagnostic possibilities. progressing proximally. However, a few notable peripheral neuropathies present with Infiltrative (metastatic) disease proximal weakness. of the lumbar spinal cord Diabetic amyotrophy is a self-limited Primary spinal cord tumors in this age group form of lumbosacral plexopathy that presents include astrocytoma and ependymoma, while with weight loss, severe thigh pain, and neu- secondary spread occurs in a number of can- rogenic weakness of the anterior thigh mus- cers, eg, cancers of the lung and breast and cles. In most cases, pain and weakness lymphomas. Patients with malignant inva- become maximal within a few months. The sion of the lumbosacral spine can present absence of pain and the duration of symp- with cauda equina syndrome, characterized toms in our patient essentially exclude this by subacute flaccid leg weakness, inconti- diagnosis. nence, and pain. In some cases, there is anes- Chronic inflammatory demyelinating thesia in the groin and perineum, with a sad- polyradiculoneuropathy, a form of acquired dle pattern of sensory loss.1 neuropathy due to demyelination (as opposed Cancer in the Our patient’s course of weakness was more to axon loss), can present with weakness lumbosacral indolent than would be expected from direct (proximal greater than distal), areflexia, and cancer spread. In addition, she had more wide- mild autonomic failure.3 spine can spread symptoms (sensory disturbance in the Thus, her differential diagnosis should cause cauda arms, dry mouth, and lightheadedness) than include this disorder, although a few notable could be accounted for by lumbosacral cord features of her case argue against it. First, her equina disease alone. prior electrodiagnostic evaluation did not syndrome show features of an acquired demyelinating Amyotrophic lateral sclerosis polyneuropathy. Second, significant weight Amyotrophic lateral sclerosis or progressive loss is atypical in this disorder and raises the motor neuron disease is a relentless neurode- concern for systemic disease. Third, the incre- generative disorder. By definition, it affects mental response of deep tendon reflexes fol- both the upper and lower motor neurons. lowing sustained muscle contraction is not Early in its course there may be a predomi- seen with this disorder. nance of either upper motor neuron signs Nutritional neuropathies (eg, vitamin (spastic weakness, hyperreflexia) or lower B12 deficiency) should be considered in any motor neuron signs (flaccid weakness, muscle patient with significant weight loss, but the atrophy, fasciculations). rapid progression over 2 years and lack of sig- However, even though amyotrophic lat- nificant involvement in her arms relative to eral sclerosis may initially present with symp- the advanced state of disease in her legs make toms and signs primarily affecting the bulbar, this unlikely. cervical, or lumbosacral segments, in the end, all are invariably affected.2 Lumbosacral Neuromuscular junction disease weakness lasting at least 2 years without any Diseases of the neuromuscular junction (the other segmental involvement would be atyp- most likely cause of this patient’s symptoms) 24 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 74 • NUMBER 1 JANUARY 2007 Downloaded from www.ccjm.org on September 29, 2021. 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TABLE 1 Lambert-Eaton myasthenic syndrome and myasthenia gravis LAMBERT-EATON MYASTHENIA GRAVIS MYASTHENIC SYNDROME Weakness Yes, nonfluctuating Yes, often fluctuating Diplopia, dysphagia Rare Common Tendon reflexes Absent or reduced Normal (even in severe cases) Autonomic failure Yes No (dry mouth, orthostasis, constipation, sluggish papillary reflexes) Repetitive nerve stimulation Slow Decrement Decrement Fast Increment No change Commonly associated malignancy Small-cell lung cancer Thymoma Associated antibodies Voltage-gated calcium Acetylcholine receptor channel are divided into presynaptic and postsynaptic drome, myasthenia gravis has a predilection disorders. for the extraocular and pharyngeal muscles; Lambert-Eaton myasthenic syndrome, diplopia, ptosis, and dysarthria are common the most common presynaptic disorder, is an in myasthenia gravis and rare in Lambert- autoimmune disease that presents with slowly Eaton myasthenic syndrome.5 Respiratory progressive proximal weakness and loss of ten- failure is another feature seen in myasthenia Lambert- don reflexes. The finding of weakness of the gravis (TABLE 1). Eaton neck flexors and extensors is sensitive but not specific for either neuromuscular junction dis- Inflammatory myopathy syndrome orders or myopathic disorders. However, ten- Inflammatory myopathy or myositis includes affects the don reflexes tend to be preserved until the end the categories of dermatomyositis, polymyosi- stages of myopathies and preserved in even tis, and inclusion-body myositis. presynaptic severe myasthenia gravis (see below), while Myositis and the collagen vascular dis- neuromuscular early areflexia is a pathognomonic feature of eases can overlap; dermatomyositis is associat- Lambert-Eaton myasthenic syndrome. An ed with a higher rate of malignancy,