Case 22-2006 — A 77-Year-Old Man with a Rapidly Progressive Gait Disorder
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《新英格兰医药杂志》
Presentation of Case
Dr. Robert H. Ackerman: A 77-year-old man was admitted to this hospital because of recent episodes of falling. He had been well until 18 months earlier, when an abscess of the right foot caused by Staphylococcus aureus developed. This was treated with surgical débridement, ciprofloxacin, and rest. Six weeks later, a right popliteal deep venous thrombosis developed that responded to warfarin. After these illnesses he felt chronically fatigued and reduced his physical activity, but returned to work. Eight months before admission he resumed working out at a gym and playing tennis, but his pace had slowed; he tired easily, which he attributed to being deconditioned because of prolonged inactivity.
Six months before admission, pain developed in the right shoulder, and two months later it developed in the left shoulder. A diagnosis of bilateral shoulder impingement syndrome was made, and both shoulders were injected with bupivacaine and methylprednisolone acetate. Four months before admission he slipped and fell, tearing the right hamstring muscle. During this time, he occasionally described his legs as feeling like jelly. Physical therapy was initiated, and during the next three months the shoulder pain diminished and strength improved; he commented to the therapist on one occasion that his legs felt like "spaghetti," as if they might "give out."
Two months before admission he required assistance rising from a sitting position on one occasion. At approximately that time imipramine was started for urinary stress incontinence, which had developed after a radical prostatectomy for prostate cancer eight years earlier. During the following month a shuffling gait, slurred speech, and increased fatigue developed; these symptoms improved after the imipramine was stopped, but they did not entirely disappear. A persistent, dry cough developed.
Three weeks before admission he began to stumble while walking, and he once fell on his face. Five days before admission, at his annual visit with his primary care physician, he walked into the office using a cane. His vital signs and mental status were normal. His physician noted an ataxic gait. Strength in all extremities appeared normal. A chest radiograph was normal.
Two days before admission the patient collapsed to his knees at work and was unable to rise. He went to the emergency department of his local hospital. He reported that his gait had become increasingly unsteady during the preceding three weeks and that he had become increasingly forgetful, with intermittently slurred speech. On examination, he was oriented, but recalled only one of three objects at three minutes, and he seemed confused by instructions. The blood pressure was 153/86 mm Hg, the pulse was 107, the respirations were 28, and the oxygen saturation was 96 percent while the patient was breathing room air. He had mild dysarthria. His gait was minimally ataxic, with the right leg swinging out slightly as he walked. Sensation and motor strength were intact. Romberg's sign was absent. An electrocardiogram showed no cardiac ischemic changes. Computed tomographic (CT) scanning of the brain without the administration of contrast material showed mild, diffuse, nonspecific white-matter changes and a small lacune in the right caudate. CT scanning of the abdomen after the administration of intravenous contrast material showed an abdominal aortic aneurysm, 4.7 by 4.6 cm, without evidence of bleeding.
Two days later the patient was admitted to the medical service of this hospital. At that time, he stated that he had not had cognitive changes, headache, light-headedness, or focal or lateralizing sensorimotor symptoms other than the problems with his shoulder and right hamstring. He had difficulty climbing stairs and rising from a chair. He described soreness in his anterior thighs on prolonged walking. He attributed his falls to weakness in his legs, stating that when he lifted them he was not sure where they would land.
He had a history of hyperlipidemia. He had smoked heavily until 25 years earlier and had consumed alcohol until 14 years earlier. There was no family history of neurologic disease. He lived with his family in a suburb and worked full time as an executive. Before the onset of these problems he had been physically active, commuting to work daily by train and walking from the station, working out at a gym three to four days per week, playing tennis, and racing his sailboat. His medications were warfarin and valdecoxib.
The vital signs were normal. The patient was alert and oriented. He was stooped, but he did not appear ill. The general physical examination showed diminished right dorsalis pedis and posterior tibial pulses. Mental-status testing was normal. Cranial-nerve examination was normal, except that his speech occasionally seemed slightly slurred. Motor examination showed generally slowed movements. Assessment of strength at the shoulders was restricted by pain and stiffness. Motor strength in the finger extensors was 4+/5 bilaterally, 4/5 at both hip flexors, and 5/5 in other muscle groups in the arms and legs. Tests for dysmetria and dexterity in the upper extremities were performed slowly but accurately. He had difficulty raising his legs for heel-to-shin testing. He walked on a narrow base slowly and unsteadily, took small steps, and bent over, looking at his feet. On tandem walking he fell to either side. Sensory examination was normal except for diminished vibratory sensation in both lower legs and feet. Joint-position sense was intact in the arms and legs. Deep-tendon reflexes were normal, and Babinski signs were absent. Parkinsonian facies, increased motor tone, and fasciculations were not noted.
A complete blood count was normal. The prothrombin time (expressed as the international normalized ratio) was 1.8. Levels of serum electrolytes, calcium, phosphorus, magnesium, creatine kinase, vitamin B12, folate, glycated hemoglobin, thyroid-stimulating hormone, and serum immunoglobulin were normal, as were the results of liver-function tests and serum electrophoresis. A rapid plasma reagin card test on the serum was negative. No Bence Jones protein was detected.
On the second hospital day a consultant in neurology noted brisk reflexes and bilateral Babinski signs. Magnetic resonance imaging (MRI) of the brain showed an old lacunar infarct in the right caudate head and a possible old infarct in the right cerebellum. Intensive physical and occupational therapy were begun. On the third day the patient's articulation had improved, although the rate of speech was still slow, and a consultant in speech and language pathology found decreased speed and articulation of speech and a suggestion of left-sided weakness of the tongue.
A CT angiogram of the abdomen and pelvis on the same day showed an aneurysm of the infrarenal aorta, extending into the right common iliac artery. MRI of the spine on the fourth day showed multilevel degenerative disease of the cervical spine, worst at the C4–C5 level, where there was mild canal stenosis, with severe narrowing of the right neural foramen and moderate narrowing of the left. There was no evidence of marked central-canal stenosis or an abnormal cord signal in the thoracic spine. In the lumbar spine there was multilevel degenerative disk disease and osteoarthritis, resulting in mild impingement of the right L3, L4, and L5 nerve roots. Peripheral vascular ultrasound studies of the lower extremities showed normal arterial hemodynamics bilaterally.
With intensive physical and occupational therapy, the patient and his family noted improvement in both his speech and walking. The patient thought his legs felt stronger; he had less fatigue and soreness in his legs, and his balance seemed improved. He required assistance to get out of bed and transfer to a walker, but he could also walk with a cane.
A lumbar puncture showed anti-AB42 peptide antibodies (513 pg per milliliter) and anti-Tau protein antibodies (905 pg per milliliter). Cerebrospinal fluid (CSF) pressures, cell counts, protein and glucose determinations, cytologic studies, and anti-MATA, antineuronal nuclear, and anti-Purkinje cell antibody studies were normal. The patient was discharged on the eighth day, to follow-up with his physician and continue physical therapy.
He returned home and continued intensive physical therapy; however, he became progressively weaker and occasionally fell. Six weeks after discharge he was unable to walk without assistance and was admitted to a local hospital for neurologic evaluation after mild numbness developed bilaterally in the tips of fingers in the median-nerve distributions. He had no problem with mentation or swallowing. The mental-status examination was normal. Cranial-nerve functions were normal. No fasciculations of the tongue or neck muscles were seen. Head rotation and neck extension were strong, but there appeared to be some weakness of neck flexion. Widespread fasciculations were present in the arms and legs and were most obvious in the intrinsic muscles of the hand, but they were also apparent in the muscles of the forearms and the legs. There was mild atrophy of the intrinsic muscles of both hands. Motor testing showed strength of 4/5 to 4+/5 in all groups of the arms and legs and 3+/5 in the wrist extensors and intrinsic muscles of the hands. Deep-tendon reflexes, except the ankle jerks, were hyperactive. A Babinksi sign was present on the right and probably on the left. Coordination and findings on sensory examination were unchanged.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Gilmore N. O'Neill: This 77-year-old man had an 18-month history of progressive debilitation that began in the legs and later involved the arms; bulbar dysfunction developed, manifesting initially as dysarthria without dysphagia. These changes occurred without deterioration of a preexisting dysfunction of the urinary sphincter and with minor abnormalities of vibration sensation that were appropriate for his age.1,2 The patient's report of sensory symptoms in his hands is not supported by abnormal results on a sensory examination; in my experience, patients with mildly abnormal dexterity may describe "numbness" of the fingers, which more detailed questioning clarifies as clumsiness. Examination revealed that other sensory modalities were normal. He did not have muscle cramping. Very late in his course, atrophy of the intrinsic hand muscles and diffuse fasciculations became apparent.
Pure Motor Syndromes
After eliminating further consideration of the sensory features in this case, we are left with the diagnosis of a pure motor syndrome. Pure motor weakness can be anatomically restricted to muscle, the neuromuscular junction, the motor nerve, and the central nervous system, or a combination thereof. This patient's syndrome evolved with a combination of muscle atrophy and fasciculation suggesting lower motor neuron disease; spasticity is suggested by the observed circumducting gait and slowed dexterity; and hyperreflexia and pathologic reflexes suggest an upper motor neuron lesion. The pattern of weakness was variable, but the combination of disproportionate wrist extensor and hip flexor weakness would be compatible with an upper motor neuron lesion.
At the patient's initial presentation, easily reversible causes of a myeloradiculopathy, a process involving the cord tracts and nerve roots, needed to be considered. The normal level of vitamin B12, the absence of abnormal vibration and joint-position sense, and the preservation of reflexes ruled out cyanocobalamin (vitamin B12) deficiency. The negative rapid plasma reagin test, absence of CSF pleocytosis, and failure to find associated sensory ataxia eliminates luetic meningomyelitis from the differential diagnosis. Intoxication with heavy metals, particularly lead, can manifest with a pure lower motor neuropathy that is absent in this case.3 A combined upper and lower motor neuron disease is associated with chronic chickpea ingestion and beta-N-oxalylaminoalanine intoxication, but includes marked sensory and autonomic dysfunction, which did not occur in this case.4
This patient lacked any pathological sensory findings, history of neck pain, and bladder dysfunction, largely ruling out most structural and infectious causes of myeloradiculopathies, including cervical spondylosis, human immunodeficiency virus, human T-cell lymphotropic virus type 1, and foramen magnum tumors. Lyme radiculopathy can manifest as a pure motor syndrome, but upper motor neuron dysfunction, as seen in this patient, has not been described.5,6 MRI of the vertebral column demonstrated bilateral cervical foraminal narrowing and impingement of the lumbar disk root; however, there was no marked spinal canal narrowing or abnormal cord signal, and he did not have symptoms of spinal claudication.
May we see the radiologic studies?
Dr. R. Gilberto Gonzalez: MRI shows mild chronic changes in the brain, minor abnormalities due to degenerative disk disease in the spine, and degenerative changes in the intervertebral disks of the cervical spine that result in mild narrowing of the spinal canal. The cord appears entirely normal. Narrowing of the neural foramina is appreciated at C4–C5, where there is moderate narrowing. MRI of the lumbar spine also demonstrates the presence of mild degenerative disk disease.
Dr. O'Neill: Various forms of myositis can present as pure motor disorders, but evidence of an upper motor neuron lesion would rule these out.7,8 Polymyositis can present as a pure bulbar syndrome; a normal creatine kinase level does not eliminate this diagnosis. Inclusion-body myositis may mimic motor neuron disease on electrophysiological studies, because polyspike activity produced by hyperirritable muscle membranes may be mislabeled as fibrillation potentials; in addition, up to 30 percent of patients have electrophysiological evidence of a neuropathy.9 Inclusion-body myositis is characterized by very slow progression and the presence of characteristic deep finger flexor weakness, not seen in this man.
Fasciculations developed six weeks after discharge. Fasciculations are visible muscle twitches resulting from the contraction of one or several motor units; they reflect the generation of ectopic impulses by degenerating lower motor neurons (Video Clip 1, available with the full text of this article at www.nejm.org). This twitching should be distinguished from the simultaneous spontaneous contraction of multiple motor units known as myokymia, which may be a manifestation of hyponatremia associated with hypothyroidism. This patient's level of thyrotropin was normal. Primary disorders of the parathyroid can be associated with motor neuron disease, but they have not been proved to cause the disease; in this patient, levels of serum calcium, phosphate, and magnesium were normal.10
The presence of both fasciculations and a Babinski sign indicates that this is a combined upper and lower motor neuron syndrome.
Combined Upper and Lower Motor Neuron Disease
Hereditary syndromes can manifest as combined upper and lower motor neuron disease, but they are unlikely in this patient, who had the onset of disease late in life. Familial amyotrophic lateral sclerosis (ALS), which accounts for 8 to 10 percent of the cases, usually manifests earlier. X-linked spinal-bulbar muscular atrophy (Kennedy's disease) is characterized by a slowly progressive lower motor neuron disease of the proximal limbs, usually affecting the upper extremities and bulbar muscles. Late-onset Tay–Sachs disease can present with upper and lower motor neuron disease, but it is associated with cerebellar dysfunction, mild peripheral sensory neuropathy, and dementia or psychosis.11 Polyglucosan body disease, a recessive disorder characterized by hypofunction of glycogen branching enzyme activity, is unlikely because of the absence of sensory dysfunction and dementia and the relative preservation of bladder function.12
An association of motor neuron disease with solid cancers has been described,13 but a firm causal relationship has yet to be determined. In most described cases the syndrome was either a rapidly developing pure lower motor neuropathy associated with anti-Hu antibodies or a slowly progressive pure upper motor neuropathy resembling primary lateral sclerosis without antibodies. Motor neuron disease has been reported in association with monoclonal gammopathy.14 Reversal of a motor neuropathy after successful treatment of an underlying cancer is exceptional. A search for an underlying malignant tumor or monoclonal gammopathy in this case was unrevealing.
An elevated CSF level of tau protein (a phosphorylated microtubule-associated protein that can be released when neuronal damage has occurred) was reported in this patient. Elevations of tau protein levels in the CSF have been described in patients with stroke (embolic and hemorrhagic), meningoencephalitis, active multiple sclerosis, and ALS, but not in patients with spinal stenosis or neuroborreliosis.15,16
Amyotrophic Lateral Sclerosis
This patient's syndrome of progressing upper and lower motor neuron dysfunction in multiple anatomical regions supports a diagnosis of ALS of the sporadic variety. Although ALS is commonly regarded as a disease of younger people, the median age of onset is actually around 65 years, and in some cohorts the incidence of this rare disorder (2 per 100,000 per year) continues to increase with age.17 Thus, the patient's age does not argue against the diagnosis. The most common abnormalities at the time of presentation of ALS are weakness (in approximately 60 percent of cases), bulbar dysfunction (in approximately 20 percent) and muscle atrophy (in 10 percent). This patient presented with weakness, and at the time of his first hospitalization he had signs of bulbar dysfunction. Fasciculations, although considered the hallmark of the disease, are exceptional at first presentation, occurring in only 3 percent of cases. Thus, although the absence of fasciculation early in the course of this patient's illness made establishing the diagnosis of ALS difficult, that diagnosis needs to be considered.18
The El Escorial criteria for diagnosing ALS were developed to aid clinical trials and are not meant to be rigidly adhered to in clinical practice, but they do enhance the specificity of the diagnosis and can predict syndromes that mimic ALS.8,19 The criteria were updated in 1998 (www.wfnals.org/guidelines/1998elescorial/elescorial1998.htm). At the time of this patient's first admission, he had upper- and lower-limb weakness with evidence of upper motor neuron disease (Babinski sign) and possibly early bulbar signs (the intermittent suggestion of dysarthria); thus, ALS could be in the differential diagnosis, but only a diagnosis of clinically possible ALS could be supported. Six weeks later, when fasciculations and atrophy of the muscles of the upper and lower extremities developed, the El Escorial criteria for a diagnosis of clinically probable ALS were met.
Although patients with ALS usually survive from three to five years after diagnosis, up to 20 percent of patients die or require mechanical ventilation in the first year. Although the prediction of the prognosis is difficult, patients, such as this one, who have signs of bulbar disease at initial presentation may have a shorter length of survival.20 On a few occasions this patient was described as confused. Frontotemporal dementia has been described rarely in association with ALS; however, Lomen-Hoerth et al.21 have demonstrated that up to a third of patients with the diagnosis of ALS have frontotemporal dysfunction, even after respiratory insufficiency as a cause of confusion is ruled out. Since this man was working as an executive until just before his admission to the hospital and his apparent confusion was intermittent, it is tempting to speculate that it was a manifestation of hypercapnic respiratory failure. Although he had normal oxygen saturation on admission, this finding does not rule out the possibility of hypercapnia.
My final diagnosis is ALS with possible respiratory failure. I believe the diagnostic procedure was electromyography with nerve-conduction studies, which would have shown normal or low compound motor action potentials, normal sensory-nerve action potentials, and evidence of both active (fibrillation potentials, positive sharp waves, and fasciculation potentials) and chronic (large-amplitude, large-duration motor-unit action potentials) denervation in multiple sites without conduction block. Although central motor conduction studies might have been abnormal, the results would not have added clinically useful information.
Dr. Nancy Lee Harris (Pathology): Dr. Venna, will you comment on your clinical impression at the time of the patient's initial hospitalization?
Dr. Nagagopal Venna (Neurology): The most disconcerting aspect of this patient's presentation was the disparity between the severe functional impairment that he described and the paucity of the physical findings. The only concrete finding was the presence of upper motor neuron signs in the form of reflex changes. We took a pragmatic approach and looked for potentially reversible causes of this subacute deterioration of gait; MRI was performed to search for abnormalities such as subdural hematomas, normal pressure hydrocephalus, and ischemic leukoencephalopathy, and we made sure that there was no compressive myelopathy. We also considered Parkinson's disease and vitamin B12 deficiency. At the time of his discharge, we had ruled out the important reversible causes, but we did not understand the pathogenesis of his disability. He was scheduled for follow-up examinations and electrophysiological testing, but his rapid deterioration led to his admission to another hospital.
Clinical Diagnosis
Amyotrophic lateral sclerosis.
Dr. Gilmore N. O'Neill's Diagnosis
Amyotrophic lateral sclerosis with possible respiratory failure.
Pathological Discussion
Dr. Harris: Dr. Cros, will you discuss the diagnostic testing?
Dr. Didier P. Cros: The diagnostic procedure was an electromyographic examination including nerve-conduction studies and needle electromyography. Motor and sensory nerve-conduction studies were performed in three limbs. Motor-nerve conduction studies yielded normal conduction velocities and distal motor latencies, with low amplitude of the compound motor action potentials. The results of sensory-nerve conduction studies were normal. Needle electromyographic study showed florid spontaneous activity (fibrillations and positive sharp waves), abundant fasciculations (Figure 1 and Video Clip 2), and changes in the configuration of motor unit potentials that were of normal amplitude and increased duration and were markedly polyphasic. These changes indicate disconnection of the muscle fibers from their motor axon and remodeling of the motor units following denervation. Maximum contraction yielded a decreased interference pattern indicative of a net motor unit loss, also documented by the low amplitude of compound motor action potentials. These findings are consistent with a generalized disorder of the lower motor neurons, their axons, or both, as seen in ALS, progressive muscular atrophy, or pure motor axonal neuropathies. They meet the El Escorial criteria (1994) for the neurophysiologic diagnosis of ALS. No evidence for primary demyelination was noted in the nerve-conduction studies.19
Figure 1. Electromyographic Tracing from Another Patient Showing Fasciculations.
Image courtesy of Dr. Peter Siao, Neurology, Massachusetts General Hospital.
Neurophysiological testing using transcranial magnetic stimulation can also help in the recognition of upper motor neuron disorders when corresponding clinical evidence is equivocal or absent.22,23,24,25,26 The sensitivity of this test for the diagnosis of ALS among lower motor neuron syndromes was 85.7 percent, with a specificity of 93.9 percent.26
Dr. Harris: Dr. Ackerman, will you tell us about the remainder of this patient's course?
Dr. Ackerman: The striking features of this case were the initial difficulty in recognizing that the patient had a primary neurologic disease and the rapid course of his subsequent decline. His course was characterized by medical and orthopedic problems that required immobilization, to which his evolving motor debilitation was understandably ascribed, given the paucity of neurologic signs and the transient improvements in motor function in response to physical therapy.
After an electromyographic examination confirmed the diagnosis of ALS, the patient went to a rehabilitation hospital, where the goals of his physical therapy were changed to teach him to conserve energy, rather than to strengthen his muscles. Swallowing studies showed some impairment of deglutition; his diet was altered, and he was taught how to handle secretions and nutritional intake. He went home in an electric wheelchair. His cough progressed, and aspiration pneumonia developed. He was admitted to a local hospital, where a gastrostomy tube was placed. He had progressive respiratory deterioration and died 8 days later, 15 weeks after the fall that led to his first hospitalization.
Dr. Harris: Although there was no autopsy in this case, I have asked Dr. Stemmer-Rachamimov to show us the pathology of ALS.
Dr. Anat Stemmer-Rachamimov: The classic pathological finding in sporadic ALS is the presence of degenerative changes that are relatively confined to the motor system. There is loss of motor neurons throughout the neuraxis: in the motor cortex, cranial-nerve nuclei (in particular the 12th), and ventral horns of the spinal cord. Microscopical findings include loss of motor neurons, central chromatolysis, and gliosis. A variety of neuronal inclusions have been described in ALS, but only Bunina bodies are considered specific for ALS (Figure 2A).27 Superoxide dismutase 1 (SOD1) immunopositive inclusions are specific for SOD1 gene mutant familial cases.28
Figure 2. Pathological Features of ALS from Other Cases (Luxol Fast Blue–Hematoxylin and Eosin).
A Bunina body is present in an anterior horn motor neuron; these small, bright red cytoplasmic inclusions (Panel A, arrow) are considered specific for ALS (photomicrograph courtesy of Dr. David Louis). A transverse section of a spinal cord (Panel B), oriented so that the posterior aspect is at the top of the picture, shows selective degeneration of the corticospinal tracts, seen as areas lacking the normal blue staining of myelin (arrows). In contrast, the posterior tracts are normally myelinated (arrowheads). There is severe loss of myelinated fibers and gliosis of the anterior nerve root (Panel C, right) with sparing of the posterior nerve root (Panel C, left).
Degeneration of the corticospinal tracts, with loss of myelinated fibers and gliosis, is so characteristic in cases of ALS that the disease was named for this feature (Figure 2B). Tract degeneration is most marked in the spinal cord, particularly the lower segments, but it can be traced in the brain stem and as far as the internal capsule. The anterior spinal nerve roots appear withered, in contrast to the normal appearance of the posterior roots (Figure 2C).
Involvement of nonmotor systems may be seen in cases of long duration or in some forms of familial ALS. Small ubiquitin-positive, cytoplasmic inclusions may be found in frontotemporal cortical neurons and in dentate granule cells of the hippocampus in patients who have ALS with or without cognitive abnormalities.
Dr. Harris: Blood was drawn two days before the patient's death and sent for genetic testing.
Dr. Robert H. Brown, Jr.: The screening for mutations in the SOD1 gene was negative. ALS caused by mutations in this gene is a highly penetrant disorder, so that there is almost always a positive family history. However, several cases of an I113T mutation in which the disorder appeared as a sporadic mutation in the absence of a family history have been reported.
Dr. Harris: The patient's family is here, and his wife would like to comment.
The Patient's Wife: Going through this illness was terrifying for my husband and those who loved him, because its progress was both mystifying and relentless. We saw a vital, active man rendered helpless seemingly overnight. This discussion emphasizes the often difficult and lengthy process of making the diagnosis of ALS. Equally, it underscores how rapid the course can be. When a diagnosis was finally made, my husband was eager to see a specialist in ALS, but he was given an appointment for almost two months later. When I requested an earlier appointment, I was assured that that would be unnecessary, because ALS is a chronic illness. Ultimately, three weeks after the diagnosis was made, we saw a specialist. Two weeks later, my husband was dead. Although that visit did not extend his life, it was a comfort to him. We had an expert to guide us, answer questions, provide adaptive devices, and help us set goals and make reasonable decisions, thereby lightening our burden of anxiety, uncertainty, and frustration.
Final Diagnosis
Amyotrophic lateral sclerosis.
Dr. O'Neill is a Director of Medical Research at Biogen-Idec. Dr. Cros reports having received consulting fees from Biogen-Idec. Dr. Brown reports having received consulting fees from Cytrx, Biogen-Idec, and Acceleron and research funding from Cytrx. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Departments of Neurology (G.N.O., D.P.C., R.H.A., R.H.B.), Radiology (R.G.G., R.H.A.), and Pathology (A.S.-R.), Massachusetts General Hospital; and the Departments of Neurology (G.N.O., D.P.C., R.H.B.), Radiology (R.G.G., R.H.A.), and Pathology (A.S.-R.), Harvard Medical School.
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Dr. Robert H. Ackerman: A 77-year-old man was admitted to this hospital because of recent episodes of falling. He had been well until 18 months earlier, when an abscess of the right foot caused by Staphylococcus aureus developed. This was treated with surgical débridement, ciprofloxacin, and rest. Six weeks later, a right popliteal deep venous thrombosis developed that responded to warfarin. After these illnesses he felt chronically fatigued and reduced his physical activity, but returned to work. Eight months before admission he resumed working out at a gym and playing tennis, but his pace had slowed; he tired easily, which he attributed to being deconditioned because of prolonged inactivity.
Six months before admission, pain developed in the right shoulder, and two months later it developed in the left shoulder. A diagnosis of bilateral shoulder impingement syndrome was made, and both shoulders were injected with bupivacaine and methylprednisolone acetate. Four months before admission he slipped and fell, tearing the right hamstring muscle. During this time, he occasionally described his legs as feeling like jelly. Physical therapy was initiated, and during the next three months the shoulder pain diminished and strength improved; he commented to the therapist on one occasion that his legs felt like "spaghetti," as if they might "give out."
Two months before admission he required assistance rising from a sitting position on one occasion. At approximately that time imipramine was started for urinary stress incontinence, which had developed after a radical prostatectomy for prostate cancer eight years earlier. During the following month a shuffling gait, slurred speech, and increased fatigue developed; these symptoms improved after the imipramine was stopped, but they did not entirely disappear. A persistent, dry cough developed.
Three weeks before admission he began to stumble while walking, and he once fell on his face. Five days before admission, at his annual visit with his primary care physician, he walked into the office using a cane. His vital signs and mental status were normal. His physician noted an ataxic gait. Strength in all extremities appeared normal. A chest radiograph was normal.
Two days before admission the patient collapsed to his knees at work and was unable to rise. He went to the emergency department of his local hospital. He reported that his gait had become increasingly unsteady during the preceding three weeks and that he had become increasingly forgetful, with intermittently slurred speech. On examination, he was oriented, but recalled only one of three objects at three minutes, and he seemed confused by instructions. The blood pressure was 153/86 mm Hg, the pulse was 107, the respirations were 28, and the oxygen saturation was 96 percent while the patient was breathing room air. He had mild dysarthria. His gait was minimally ataxic, with the right leg swinging out slightly as he walked. Sensation and motor strength were intact. Romberg's sign was absent. An electrocardiogram showed no cardiac ischemic changes. Computed tomographic (CT) scanning of the brain without the administration of contrast material showed mild, diffuse, nonspecific white-matter changes and a small lacune in the right caudate. CT scanning of the abdomen after the administration of intravenous contrast material showed an abdominal aortic aneurysm, 4.7 by 4.6 cm, without evidence of bleeding.
Two days later the patient was admitted to the medical service of this hospital. At that time, he stated that he had not had cognitive changes, headache, light-headedness, or focal or lateralizing sensorimotor symptoms other than the problems with his shoulder and right hamstring. He had difficulty climbing stairs and rising from a chair. He described soreness in his anterior thighs on prolonged walking. He attributed his falls to weakness in his legs, stating that when he lifted them he was not sure where they would land.
He had a history of hyperlipidemia. He had smoked heavily until 25 years earlier and had consumed alcohol until 14 years earlier. There was no family history of neurologic disease. He lived with his family in a suburb and worked full time as an executive. Before the onset of these problems he had been physically active, commuting to work daily by train and walking from the station, working out at a gym three to four days per week, playing tennis, and racing his sailboat. His medications were warfarin and valdecoxib.
The vital signs were normal. The patient was alert and oriented. He was stooped, but he did not appear ill. The general physical examination showed diminished right dorsalis pedis and posterior tibial pulses. Mental-status testing was normal. Cranial-nerve examination was normal, except that his speech occasionally seemed slightly slurred. Motor examination showed generally slowed movements. Assessment of strength at the shoulders was restricted by pain and stiffness. Motor strength in the finger extensors was 4+/5 bilaterally, 4/5 at both hip flexors, and 5/5 in other muscle groups in the arms and legs. Tests for dysmetria and dexterity in the upper extremities were performed slowly but accurately. He had difficulty raising his legs for heel-to-shin testing. He walked on a narrow base slowly and unsteadily, took small steps, and bent over, looking at his feet. On tandem walking he fell to either side. Sensory examination was normal except for diminished vibratory sensation in both lower legs and feet. Joint-position sense was intact in the arms and legs. Deep-tendon reflexes were normal, and Babinski signs were absent. Parkinsonian facies, increased motor tone, and fasciculations were not noted.
A complete blood count was normal. The prothrombin time (expressed as the international normalized ratio) was 1.8. Levels of serum electrolytes, calcium, phosphorus, magnesium, creatine kinase, vitamin B12, folate, glycated hemoglobin, thyroid-stimulating hormone, and serum immunoglobulin were normal, as were the results of liver-function tests and serum electrophoresis. A rapid plasma reagin card test on the serum was negative. No Bence Jones protein was detected.
On the second hospital day a consultant in neurology noted brisk reflexes and bilateral Babinski signs. Magnetic resonance imaging (MRI) of the brain showed an old lacunar infarct in the right caudate head and a possible old infarct in the right cerebellum. Intensive physical and occupational therapy were begun. On the third day the patient's articulation had improved, although the rate of speech was still slow, and a consultant in speech and language pathology found decreased speed and articulation of speech and a suggestion of left-sided weakness of the tongue.
A CT angiogram of the abdomen and pelvis on the same day showed an aneurysm of the infrarenal aorta, extending into the right common iliac artery. MRI of the spine on the fourth day showed multilevel degenerative disease of the cervical spine, worst at the C4–C5 level, where there was mild canal stenosis, with severe narrowing of the right neural foramen and moderate narrowing of the left. There was no evidence of marked central-canal stenosis or an abnormal cord signal in the thoracic spine. In the lumbar spine there was multilevel degenerative disk disease and osteoarthritis, resulting in mild impingement of the right L3, L4, and L5 nerve roots. Peripheral vascular ultrasound studies of the lower extremities showed normal arterial hemodynamics bilaterally.
With intensive physical and occupational therapy, the patient and his family noted improvement in both his speech and walking. The patient thought his legs felt stronger; he had less fatigue and soreness in his legs, and his balance seemed improved. He required assistance to get out of bed and transfer to a walker, but he could also walk with a cane.
A lumbar puncture showed anti-AB42 peptide antibodies (513 pg per milliliter) and anti-Tau protein antibodies (905 pg per milliliter). Cerebrospinal fluid (CSF) pressures, cell counts, protein and glucose determinations, cytologic studies, and anti-MATA, antineuronal nuclear, and anti-Purkinje cell antibody studies were normal. The patient was discharged on the eighth day, to follow-up with his physician and continue physical therapy.
He returned home and continued intensive physical therapy; however, he became progressively weaker and occasionally fell. Six weeks after discharge he was unable to walk without assistance and was admitted to a local hospital for neurologic evaluation after mild numbness developed bilaterally in the tips of fingers in the median-nerve distributions. He had no problem with mentation or swallowing. The mental-status examination was normal. Cranial-nerve functions were normal. No fasciculations of the tongue or neck muscles were seen. Head rotation and neck extension were strong, but there appeared to be some weakness of neck flexion. Widespread fasciculations were present in the arms and legs and were most obvious in the intrinsic muscles of the hand, but they were also apparent in the muscles of the forearms and the legs. There was mild atrophy of the intrinsic muscles of both hands. Motor testing showed strength of 4/5 to 4+/5 in all groups of the arms and legs and 3+/5 in the wrist extensors and intrinsic muscles of the hands. Deep-tendon reflexes, except the ankle jerks, were hyperactive. A Babinksi sign was present on the right and probably on the left. Coordination and findings on sensory examination were unchanged.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Gilmore N. O'Neill: This 77-year-old man had an 18-month history of progressive debilitation that began in the legs and later involved the arms; bulbar dysfunction developed, manifesting initially as dysarthria without dysphagia. These changes occurred without deterioration of a preexisting dysfunction of the urinary sphincter and with minor abnormalities of vibration sensation that were appropriate for his age.1,2 The patient's report of sensory symptoms in his hands is not supported by abnormal results on a sensory examination; in my experience, patients with mildly abnormal dexterity may describe "numbness" of the fingers, which more detailed questioning clarifies as clumsiness. Examination revealed that other sensory modalities were normal. He did not have muscle cramping. Very late in his course, atrophy of the intrinsic hand muscles and diffuse fasciculations became apparent.
Pure Motor Syndromes
After eliminating further consideration of the sensory features in this case, we are left with the diagnosis of a pure motor syndrome. Pure motor weakness can be anatomically restricted to muscle, the neuromuscular junction, the motor nerve, and the central nervous system, or a combination thereof. This patient's syndrome evolved with a combination of muscle atrophy and fasciculation suggesting lower motor neuron disease; spasticity is suggested by the observed circumducting gait and slowed dexterity; and hyperreflexia and pathologic reflexes suggest an upper motor neuron lesion. The pattern of weakness was variable, but the combination of disproportionate wrist extensor and hip flexor weakness would be compatible with an upper motor neuron lesion.
At the patient's initial presentation, easily reversible causes of a myeloradiculopathy, a process involving the cord tracts and nerve roots, needed to be considered. The normal level of vitamin B12, the absence of abnormal vibration and joint-position sense, and the preservation of reflexes ruled out cyanocobalamin (vitamin B12) deficiency. The negative rapid plasma reagin test, absence of CSF pleocytosis, and failure to find associated sensory ataxia eliminates luetic meningomyelitis from the differential diagnosis. Intoxication with heavy metals, particularly lead, can manifest with a pure lower motor neuropathy that is absent in this case.3 A combined upper and lower motor neuron disease is associated with chronic chickpea ingestion and beta-N-oxalylaminoalanine intoxication, but includes marked sensory and autonomic dysfunction, which did not occur in this case.4
This patient lacked any pathological sensory findings, history of neck pain, and bladder dysfunction, largely ruling out most structural and infectious causes of myeloradiculopathies, including cervical spondylosis, human immunodeficiency virus, human T-cell lymphotropic virus type 1, and foramen magnum tumors. Lyme radiculopathy can manifest as a pure motor syndrome, but upper motor neuron dysfunction, as seen in this patient, has not been described.5,6 MRI of the vertebral column demonstrated bilateral cervical foraminal narrowing and impingement of the lumbar disk root; however, there was no marked spinal canal narrowing or abnormal cord signal, and he did not have symptoms of spinal claudication.
May we see the radiologic studies?
Dr. R. Gilberto Gonzalez: MRI shows mild chronic changes in the brain, minor abnormalities due to degenerative disk disease in the spine, and degenerative changes in the intervertebral disks of the cervical spine that result in mild narrowing of the spinal canal. The cord appears entirely normal. Narrowing of the neural foramina is appreciated at C4–C5, where there is moderate narrowing. MRI of the lumbar spine also demonstrates the presence of mild degenerative disk disease.
Dr. O'Neill: Various forms of myositis can present as pure motor disorders, but evidence of an upper motor neuron lesion would rule these out.7,8 Polymyositis can present as a pure bulbar syndrome; a normal creatine kinase level does not eliminate this diagnosis. Inclusion-body myositis may mimic motor neuron disease on electrophysiological studies, because polyspike activity produced by hyperirritable muscle membranes may be mislabeled as fibrillation potentials; in addition, up to 30 percent of patients have electrophysiological evidence of a neuropathy.9 Inclusion-body myositis is characterized by very slow progression and the presence of characteristic deep finger flexor weakness, not seen in this man.
Fasciculations developed six weeks after discharge. Fasciculations are visible muscle twitches resulting from the contraction of one or several motor units; they reflect the generation of ectopic impulses by degenerating lower motor neurons (Video Clip 1, available with the full text of this article at www.nejm.org). This twitching should be distinguished from the simultaneous spontaneous contraction of multiple motor units known as myokymia, which may be a manifestation of hyponatremia associated with hypothyroidism. This patient's level of thyrotropin was normal. Primary disorders of the parathyroid can be associated with motor neuron disease, but they have not been proved to cause the disease; in this patient, levels of serum calcium, phosphate, and magnesium were normal.10
The presence of both fasciculations and a Babinski sign indicates that this is a combined upper and lower motor neuron syndrome.
Combined Upper and Lower Motor Neuron Disease
Hereditary syndromes can manifest as combined upper and lower motor neuron disease, but they are unlikely in this patient, who had the onset of disease late in life. Familial amyotrophic lateral sclerosis (ALS), which accounts for 8 to 10 percent of the cases, usually manifests earlier. X-linked spinal-bulbar muscular atrophy (Kennedy's disease) is characterized by a slowly progressive lower motor neuron disease of the proximal limbs, usually affecting the upper extremities and bulbar muscles. Late-onset Tay–Sachs disease can present with upper and lower motor neuron disease, but it is associated with cerebellar dysfunction, mild peripheral sensory neuropathy, and dementia or psychosis.11 Polyglucosan body disease, a recessive disorder characterized by hypofunction of glycogen branching enzyme activity, is unlikely because of the absence of sensory dysfunction and dementia and the relative preservation of bladder function.12
An association of motor neuron disease with solid cancers has been described,13 but a firm causal relationship has yet to be determined. In most described cases the syndrome was either a rapidly developing pure lower motor neuropathy associated with anti-Hu antibodies or a slowly progressive pure upper motor neuropathy resembling primary lateral sclerosis without antibodies. Motor neuron disease has been reported in association with monoclonal gammopathy.14 Reversal of a motor neuropathy after successful treatment of an underlying cancer is exceptional. A search for an underlying malignant tumor or monoclonal gammopathy in this case was unrevealing.
An elevated CSF level of tau protein (a phosphorylated microtubule-associated protein that can be released when neuronal damage has occurred) was reported in this patient. Elevations of tau protein levels in the CSF have been described in patients with stroke (embolic and hemorrhagic), meningoencephalitis, active multiple sclerosis, and ALS, but not in patients with spinal stenosis or neuroborreliosis.15,16
Amyotrophic Lateral Sclerosis
This patient's syndrome of progressing upper and lower motor neuron dysfunction in multiple anatomical regions supports a diagnosis of ALS of the sporadic variety. Although ALS is commonly regarded as a disease of younger people, the median age of onset is actually around 65 years, and in some cohorts the incidence of this rare disorder (2 per 100,000 per year) continues to increase with age.17 Thus, the patient's age does not argue against the diagnosis. The most common abnormalities at the time of presentation of ALS are weakness (in approximately 60 percent of cases), bulbar dysfunction (in approximately 20 percent) and muscle atrophy (in 10 percent). This patient presented with weakness, and at the time of his first hospitalization he had signs of bulbar dysfunction. Fasciculations, although considered the hallmark of the disease, are exceptional at first presentation, occurring in only 3 percent of cases. Thus, although the absence of fasciculation early in the course of this patient's illness made establishing the diagnosis of ALS difficult, that diagnosis needs to be considered.18
The El Escorial criteria for diagnosing ALS were developed to aid clinical trials and are not meant to be rigidly adhered to in clinical practice, but they do enhance the specificity of the diagnosis and can predict syndromes that mimic ALS.8,19 The criteria were updated in 1998 (www.wfnals.org/guidelines/1998elescorial/elescorial1998.htm). At the time of this patient's first admission, he had upper- and lower-limb weakness with evidence of upper motor neuron disease (Babinski sign) and possibly early bulbar signs (the intermittent suggestion of dysarthria); thus, ALS could be in the differential diagnosis, but only a diagnosis of clinically possible ALS could be supported. Six weeks later, when fasciculations and atrophy of the muscles of the upper and lower extremities developed, the El Escorial criteria for a diagnosis of clinically probable ALS were met.
Although patients with ALS usually survive from three to five years after diagnosis, up to 20 percent of patients die or require mechanical ventilation in the first year. Although the prediction of the prognosis is difficult, patients, such as this one, who have signs of bulbar disease at initial presentation may have a shorter length of survival.20 On a few occasions this patient was described as confused. Frontotemporal dementia has been described rarely in association with ALS; however, Lomen-Hoerth et al.21 have demonstrated that up to a third of patients with the diagnosis of ALS have frontotemporal dysfunction, even after respiratory insufficiency as a cause of confusion is ruled out. Since this man was working as an executive until just before his admission to the hospital and his apparent confusion was intermittent, it is tempting to speculate that it was a manifestation of hypercapnic respiratory failure. Although he had normal oxygen saturation on admission, this finding does not rule out the possibility of hypercapnia.
My final diagnosis is ALS with possible respiratory failure. I believe the diagnostic procedure was electromyography with nerve-conduction studies, which would have shown normal or low compound motor action potentials, normal sensory-nerve action potentials, and evidence of both active (fibrillation potentials, positive sharp waves, and fasciculation potentials) and chronic (large-amplitude, large-duration motor-unit action potentials) denervation in multiple sites without conduction block. Although central motor conduction studies might have been abnormal, the results would not have added clinically useful information.
Dr. Nancy Lee Harris (Pathology): Dr. Venna, will you comment on your clinical impression at the time of the patient's initial hospitalization?
Dr. Nagagopal Venna (Neurology): The most disconcerting aspect of this patient's presentation was the disparity between the severe functional impairment that he described and the paucity of the physical findings. The only concrete finding was the presence of upper motor neuron signs in the form of reflex changes. We took a pragmatic approach and looked for potentially reversible causes of this subacute deterioration of gait; MRI was performed to search for abnormalities such as subdural hematomas, normal pressure hydrocephalus, and ischemic leukoencephalopathy, and we made sure that there was no compressive myelopathy. We also considered Parkinson's disease and vitamin B12 deficiency. At the time of his discharge, we had ruled out the important reversible causes, but we did not understand the pathogenesis of his disability. He was scheduled for follow-up examinations and electrophysiological testing, but his rapid deterioration led to his admission to another hospital.
Clinical Diagnosis
Amyotrophic lateral sclerosis.
Dr. Gilmore N. O'Neill's Diagnosis
Amyotrophic lateral sclerosis with possible respiratory failure.
Pathological Discussion
Dr. Harris: Dr. Cros, will you discuss the diagnostic testing?
Dr. Didier P. Cros: The diagnostic procedure was an electromyographic examination including nerve-conduction studies and needle electromyography. Motor and sensory nerve-conduction studies were performed in three limbs. Motor-nerve conduction studies yielded normal conduction velocities and distal motor latencies, with low amplitude of the compound motor action potentials. The results of sensory-nerve conduction studies were normal. Needle electromyographic study showed florid spontaneous activity (fibrillations and positive sharp waves), abundant fasciculations (Figure 1 and Video Clip 2), and changes in the configuration of motor unit potentials that were of normal amplitude and increased duration and were markedly polyphasic. These changes indicate disconnection of the muscle fibers from their motor axon and remodeling of the motor units following denervation. Maximum contraction yielded a decreased interference pattern indicative of a net motor unit loss, also documented by the low amplitude of compound motor action potentials. These findings are consistent with a generalized disorder of the lower motor neurons, their axons, or both, as seen in ALS, progressive muscular atrophy, or pure motor axonal neuropathies. They meet the El Escorial criteria (1994) for the neurophysiologic diagnosis of ALS. No evidence for primary demyelination was noted in the nerve-conduction studies.19
Figure 1. Electromyographic Tracing from Another Patient Showing Fasciculations.
Image courtesy of Dr. Peter Siao, Neurology, Massachusetts General Hospital.
Neurophysiological testing using transcranial magnetic stimulation can also help in the recognition of upper motor neuron disorders when corresponding clinical evidence is equivocal or absent.22,23,24,25,26 The sensitivity of this test for the diagnosis of ALS among lower motor neuron syndromes was 85.7 percent, with a specificity of 93.9 percent.26
Dr. Harris: Dr. Ackerman, will you tell us about the remainder of this patient's course?
Dr. Ackerman: The striking features of this case were the initial difficulty in recognizing that the patient had a primary neurologic disease and the rapid course of his subsequent decline. His course was characterized by medical and orthopedic problems that required immobilization, to which his evolving motor debilitation was understandably ascribed, given the paucity of neurologic signs and the transient improvements in motor function in response to physical therapy.
After an electromyographic examination confirmed the diagnosis of ALS, the patient went to a rehabilitation hospital, where the goals of his physical therapy were changed to teach him to conserve energy, rather than to strengthen his muscles. Swallowing studies showed some impairment of deglutition; his diet was altered, and he was taught how to handle secretions and nutritional intake. He went home in an electric wheelchair. His cough progressed, and aspiration pneumonia developed. He was admitted to a local hospital, where a gastrostomy tube was placed. He had progressive respiratory deterioration and died 8 days later, 15 weeks after the fall that led to his first hospitalization.
Dr. Harris: Although there was no autopsy in this case, I have asked Dr. Stemmer-Rachamimov to show us the pathology of ALS.
Dr. Anat Stemmer-Rachamimov: The classic pathological finding in sporadic ALS is the presence of degenerative changes that are relatively confined to the motor system. There is loss of motor neurons throughout the neuraxis: in the motor cortex, cranial-nerve nuclei (in particular the 12th), and ventral horns of the spinal cord. Microscopical findings include loss of motor neurons, central chromatolysis, and gliosis. A variety of neuronal inclusions have been described in ALS, but only Bunina bodies are considered specific for ALS (Figure 2A).27 Superoxide dismutase 1 (SOD1) immunopositive inclusions are specific for SOD1 gene mutant familial cases.28
Figure 2. Pathological Features of ALS from Other Cases (Luxol Fast Blue–Hematoxylin and Eosin).
A Bunina body is present in an anterior horn motor neuron; these small, bright red cytoplasmic inclusions (Panel A, arrow) are considered specific for ALS (photomicrograph courtesy of Dr. David Louis). A transverse section of a spinal cord (Panel B), oriented so that the posterior aspect is at the top of the picture, shows selective degeneration of the corticospinal tracts, seen as areas lacking the normal blue staining of myelin (arrows). In contrast, the posterior tracts are normally myelinated (arrowheads). There is severe loss of myelinated fibers and gliosis of the anterior nerve root (Panel C, right) with sparing of the posterior nerve root (Panel C, left).
Degeneration of the corticospinal tracts, with loss of myelinated fibers and gliosis, is so characteristic in cases of ALS that the disease was named for this feature (Figure 2B). Tract degeneration is most marked in the spinal cord, particularly the lower segments, but it can be traced in the brain stem and as far as the internal capsule. The anterior spinal nerve roots appear withered, in contrast to the normal appearance of the posterior roots (Figure 2C).
Involvement of nonmotor systems may be seen in cases of long duration or in some forms of familial ALS. Small ubiquitin-positive, cytoplasmic inclusions may be found in frontotemporal cortical neurons and in dentate granule cells of the hippocampus in patients who have ALS with or without cognitive abnormalities.
Dr. Harris: Blood was drawn two days before the patient's death and sent for genetic testing.
Dr. Robert H. Brown, Jr.: The screening for mutations in the SOD1 gene was negative. ALS caused by mutations in this gene is a highly penetrant disorder, so that there is almost always a positive family history. However, several cases of an I113T mutation in which the disorder appeared as a sporadic mutation in the absence of a family history have been reported.
Dr. Harris: The patient's family is here, and his wife would like to comment.
The Patient's Wife: Going through this illness was terrifying for my husband and those who loved him, because its progress was both mystifying and relentless. We saw a vital, active man rendered helpless seemingly overnight. This discussion emphasizes the often difficult and lengthy process of making the diagnosis of ALS. Equally, it underscores how rapid the course can be. When a diagnosis was finally made, my husband was eager to see a specialist in ALS, but he was given an appointment for almost two months later. When I requested an earlier appointment, I was assured that that would be unnecessary, because ALS is a chronic illness. Ultimately, three weeks after the diagnosis was made, we saw a specialist. Two weeks later, my husband was dead. Although that visit did not extend his life, it was a comfort to him. We had an expert to guide us, answer questions, provide adaptive devices, and help us set goals and make reasonable decisions, thereby lightening our burden of anxiety, uncertainty, and frustration.
Final Diagnosis
Amyotrophic lateral sclerosis.
Dr. O'Neill is a Director of Medical Research at Biogen-Idec. Dr. Cros reports having received consulting fees from Biogen-Idec. Dr. Brown reports having received consulting fees from Cytrx, Biogen-Idec, and Acceleron and research funding from Cytrx. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Departments of Neurology (G.N.O., D.P.C., R.H.A., R.H.B.), Radiology (R.G.G., R.H.A.), and Pathology (A.S.-R.), Massachusetts General Hospital; and the Departments of Neurology (G.N.O., D.P.C., R.H.B.), Radiology (R.G.G., R.H.A.), and Pathology (A.S.-R.), Harvard Medical School.
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