A 30-year-old man complains of bilateral leg weakness and clumsiness of fine movements of the right hand. Five years previously he had an episode of transient visual loss. On physical examination, there is hyperreflexia with Babinski sign and cerebellar dysmetria with poor finger-to-nose movement. When the patient is asked to look to the right, the left eye does not move normally past the midline. Nystagmus is noted in the abducting eye. A more detailed history suggests the patient has had several episodes of gait difficulty that have resolved spontaneously. He appears to be stable between these episodes. He has no systemic symptoms of fever or weight loss.
Which of the following is the most appropriate next test to order?
This patient’s episode of transient blindness was likely a result of optic neuritis. This transient loss of vision in one eye occurs in 25% to 40% of multiple sclerosis patients (a similar presentation can occur in SLE, sarcoidosis, or syphilis). In addition, the patient gives a history of a relapsing-remitting process. There are abnormal signs of cerebellar and upper motor neuron disease. Signs and symptoms therefore suggest multiple lesions in space and time, making multiple sclerosis the most likely diagnosis. All patients with suspected multiple sclerosis should have MRI scanning of the brain. MRI is sensitive in defining demyelinating lesions in the brain and spinal cord. Disease-related changes are found in more than 95% of patients who have definite evidence for MS. Most patients do not need lumbar puncture or spinal fluid analysis for diagnosis, although 70% have elevated IgG levels, and myelin basic protein does appear in the CSF during exacerbations. When the diagnosis is in doubt, lumbar puncture is indicated. Pleocytosis of greater than 75 cells per microliter or finding polymorphonuclear leukocytes in the CSF makes the diagnosis of MS unlikely. In some cases, chronic infection such as with syphilis or HIV may be in the differential of MS. Quantitative IgG levels would not be specific enough for diagnosis. Oligoclonal banding of CSF IgG is determined by agarose gel electrophoresis, but this is not the first test chosen. Two or more bands are found in 70% to 90% of patients with MS. CT scans are much less sensitive than MRIs in detecting demyelinating lesions, especially in the posterior fossa and cervical cord.
A 76-year-old woman consults you because of leg discomfort. Her legs are comfortable during the day, but in the evening she develops an uncomfortable creepy-crawly sensation that keeps her awake for hours. The feeling is temporarily relieved by movement; she will awaken, pace around, and sometimes run water on her legs to achieve relief.
Which of the following is the best initial treatment for her condition?
This woman has restless leg syndrome, a common sensory complaint in the elderly. It is characterized by ill-defined leg discomfort that occurs in the evening when the patient is reclining or at night when the patient is trying to sleep. The uncomfortable sensation is relieved by movement. Examination is normal or shows at most mild distal sensory loss. There are no motor or reflex changes. Although most often idiopathic, RLS can be associated with iron-deficiency or renal insufficiency. Although several agents (benzodiazepines, opioids) can provide symptomatic relief, dopamine-enhancing drugs are most effective. Levodopa-carbidopa is effective but may lead to rebound effects, so direct dopamine agonists (pramipexole, ropinirole) are now preferred. Soporifics such as zolpidem or trazodone are usually ineffective. RLS is a sensory, not a motor, syndrome, so muscle stretching exercises or muscle relaxants rarely provide symptom relief.
A 50-year-old man complains of slowly progressive weakness over several months. Walking has become more difficult, as has using his hands. There are no sensory, bowel, or bladder complaints; he denies problems with thinking, speech, or vision. Examination shows distal muscle weakness with muscle wasting and fasciculations. There are also upper motor neuron signs, including extensor plantar reflexes and hyperreflexia in wasted muscle groups.
Which of the following tests is most likely to be abnormal in this patient?
The disease described involves motor neurons exclusively. Amyotrophic lateral sclerosis affects both upper and lower motor neurons. In this patient, there is upper and lower motor neuron involvement without sensory deficit. Lower motor neuron signs include focal weakness, focal wasting, and fasciculations. Upper motor neuron signs include an extensor plantar response and an increased tendon reflex in a weakened muscle. Peripheral neuropathy and dementia do not occur in ALS. Muscular dystrophy, polymyositis, and the neuromuscular junction disorder myasthenia gravis cause (usually proximal) muscle weakness but not the atrophy and upper motor neuron signs seen in this patient. EMG in the patient with ALS shows widespread denervation and fibrillation potentials with preserved nerve conduction velocities. Sensory testing is normal. There is no inflammatory reaction in the CSF. CT or MRI of the brain may be necessary to rule out a mass in the region of the foramen magnum. In most patients, a CT of the cervical spine is necessary to rule out a structural lesion of the spine, which could mimic ALS. Thyroid studies and vitamin B12 levels may be useful in peripheral neuropathy but not in motor neuron disease.
A 22-year-old woman seeks advice for the treatment of headaches. The first of these headaches began at age 16, but their frequency has increased to 2 to 3 per month over the past year. The headaches are not preceded by an aura. The headaches are usually bilateral, are throbbing, and are so intense that she has to go home from work. Loud noise and physical activity make the pain more severe. Each headache lasts until the evening; she will awaken the next morning without pain or nausea, and will be able to return to work. She takes acetaminophen at the onset of the headache but without benefit. She is on no other medications including oral contraceptives. Neurological examination is benign.
What is the best step in the management of these headaches?
Although the classic migraine is unilateral and is preceded by an aura, many patients experience migraines without aura (formerly termed “common” migraines). This patient’s female gender, the onset of the headaches in adolescence, the severity of the pain, and the worsening with light, noise, or activity are all suggestive of migraine. Muscle contraction headaches are often bilateral but occur more frequently (often every afternoon), are less intense (rarely debilitating), and are usually relieved by simple analgesics. Medication overuse headaches are often bilateral but occur more frequently (usually daily); this patient’s occasional use of acetaminophen is insufficient to cause medication overuse headache. Space-occupying lesions can cause bilateral headaches, but the headaches occur more frequently, at increasing severity (as the lesion expands), often worsen at night or with Valsalva maneuver, and are usually associated with (sometimes subtle) focal abnormalities on neurological examination.
Triptans are very effective medications to abort migraines and are usually the first agents tried in patients either with or without aura. Parenteral or nasal triptans are favored if the patient needs rapid relief or if vomiting precludes the use of oral medications. It is often necessary to try two of three different agents to find which one works best for the individual patient. If the headaches occur frequently or are debilitating despite triptan treatment, prophylactic medications are called for. These medications are administered daily in order to prevent the migraines from occurring; they are ineffective if used at the onset of the headache. Beta-blockers, tricyclic antidepressants, and certain anticonvulsants (topiramate, valproate) are the usual prophylactic agents that are tried. Gabapentin is less effective. Narcotics such as hydrocodone are often less effective than triptans and carry the risk of habituation if used frequently.
A 20-year-old woman complains of weakness that is worse in the afternoon, worse during prolonged activity, and improved by rest. When fatigued, the patient is unable to hold her head up or chew her food. On physical examination, she has no loss of reflexes, sensation, or coordination.
Which of the following is the likely pathogenesis of this disease?
The disease process described is myasthenia gravis, a neuromuscular disease marked by muscle weakness and fatigability. Myasthenia gravis results from a reduction in the number of junctional acetylcholine receptors as a result of autoantibodies. Antibodies cross-link these receptors, causing increased endocytosis and degradation in lysosomes. A decreased number of available acetylcholine receptors results in decreased efficiency of neuromuscular transmission. Successive nerve impulses result in the activation of fewer muscle fibers and produce fatigue. Myasthenia presents with weakness and fatigability, particularly of cranial muscles, causing diplopia, ptosis, nasal speech, and dysarthria. Asymmetric limb weakness also occurs. Diseases of the central nervous system (poliomyelitis, Friedreich ataxia, or multiple sclerosis, as in choices b, c, and d) cause changes in reflexes, sensation, or coordination. ALS, a pure motor disorder, causes fasciculations and muscle atrophy as a result of lower motor neuron involvement. McArdle disease, a glycogen storage disease, causes muscle cramping and occasionally rhabdomyolysis with heavy exertion but only very rarely with usual daily activities. Ten percent of myasthenia patients have thymic tumors. Surgical removal of a thymoma is necessary because of local tumor spread. Even in the absence of tumor, 85% of patients clinically improve after thymectomy. It is now consensus that thymectomy be performed in all patients with generalized MG who are between puberty and age 55.
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