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Objective: To determine how clinical features at the first evaluation and in follow-up can be used to suggest a diagnostic outcome for patients with only upper motor neuron (UMN) signs at disease onset. Methods: We reviewed the records of 34 patients (9 primary lateral sclerosis [PLS], 15 UMN-dominant amyotrophic lateral sclerosis [ALS], and 10 randomly selected control patients with ALS) seen in 1984–2007. Analysis of variance F tests for continuous variables and χ 2 tests for categorical variables analyzed differences in baseline data among the diagnostic categories. Linear and generalized mixed effects models assessed the relation between examination data and diagnostic group over time. Results: At first examination, the lowest score of the weakest muscle ( p p = 0.041), and time to evaluation ( p = 0.05) discriminated between eventual diagnostic group; patients with PLS were stronger, slower in progressing, and more likely to have limb onset than the other groups. Strength ≤4 on any muscle was associated with the diagnosis of ALS ( p = 0.0001), but not PLS. Across all visits, muscle strength ( p = 0.003), ALS Functional Rating Scale score ( p = 0.009), and vital capacity ( p = 0.026) predicted group assignment. UMN-dominant and ALS groups had more weight loss ( p = 0.004), even when controlled for dysphagia ( p = 0.021) and muscle atrophy ( p = 0.009), and patients with ALS were more likely to have hyporeflexia ( p = 0.001). Conclusions: Features at baseline most suggestive of eventual lower motor neuron signs were focal muscle weakness or bulbar onset. Later, weight loss, reduced forced vital capacity, and limb weakness predicted lower motor neuron dysfunction. We suggest that patients with only upper motor neuron signs have periodic evaluations of strength, weight, forced vital capacity, Amyotrophic Lateral Sclerosis Functional Rating Scale score, and EMG, because a change in any can signal the imminent development of lower motor neuron signs. ALS = amyotrophic lateral sclerosis; ALSFRS-R = ALS Functional Rating Scale; FVC = forced vital capacity; LMN = lower motor neuron; MMT = manual muscle testing; MRC = Medical Research Council; MRS = magnetic resonance spectroscopy; PLS = primary lateral sclerosis; UMN = upper motor neuron; UMN-D = upper motor neuron dominant.

ALS is diagnosed by finding clinical upper motor neuron (UMN) and lower motor neuron (LMN) signs. LMN dysfunction can be confirmed objectively through electromyography, whereas UMN dysfunction lacks a comparable established marker. Detection of subclinical UMN dysfunction would be helpful for diagnostic purposes, and objective markers of UMN dysfunction may also help clarify the relationship between ALS and its variants, including progressive muscular atrophy (PMA). PMA has been diagnosed by the absence of clinical UMN signs in the presence of LMN findings for several years. However, autopsies on patients with clinically diagnosed PMA show corticospinal tract degeneration in half of the patients. Therefore, clinical examination alone does not disclose all relevant UMN pathology.1–3 Transcranial magnetic stimulation (TMS) is a neurophysiologic technique used to assess the function of central motor pathways. Standard TMS measures include motor threshold, central motor conduction time (CMCT), and motor evoked potential (MEP) amplitudes. There have been numerous studies of TMS in ALS for over 20 years, investigating a multitude of issues on UMN physiology, cortical excitability and inhibition, the utility of the silent period and other responses to detect early changes in ALS, and the relationship between the UMN and LMN, many of which have been contradictory.4–11 Threshold, CMCT, and MEP are three useful measures of single pulse TMS; however, the diagnostic success of these nonspecific UMN measures varies widely from 16% to 100%.5,9,12–17 Reasons include different muscle recording sites, different methods of calculating CMCT,4,18 and different thresholds for defining diagnostic success (i.e., 1/4 sites prolonged vs 4/4). The TMS MEP is activated through both UMN and LMN pathways after magnetic stimulation of the cortex. In ALS, TMS amplitudes are often attenuated or absent19–21; even patients with pseudobulbar features are prone to have small, desynchronized MEPs.12 Reduced TMS MEP/M-wave amplitude ratio may be more closely correlated with pyramidal tract involvement than prolonged CMCT.21 There are fewer investigations of TMS amplitude compared to CMCT. One study found TMS amplitude abnormalities in only 16 of 54 patients with ALS (30%),5 whereas another found a significant difference between patients and controls at three recording sites, with amplitude reductions in almost all patients.19 The sensitivity of baseline TMS measures in ALS has been studied extensively, with mixed results, but there have been few longitudinal studies of TMS changes in ALS. Most reports showed no change in TMS threshold with time6,22,23 but one noted significant increase.17 CMCT has generally been reported to not increase with time.6,22,24 In a small series, TMS MEP amplitude and MEP/peripheral compound motor action potential (CMAP) ratio did not change with disease progression.22 In this study, we report on TMS threshold, CMCT, and amplitude data that were not included in an overarching report on neurophysiologic, brain imaging, and clinical methods to quantify and track progression in patients with ALS.25

Objective: To define the syndrome of primary lateral sclerosis (PLS) and disorders that contain features of both ALS and PLS, to determine the time beyond which PLS is less likely to become ALS clinically, and to determine the outcome of people with PLS and those who develop lower motor neuron (LMN) signs. Methods: The authors reviewed the records of all 39 patients initially diagnosed with PLS in 1984 to 2004. Diagnostic subgroups were defined based on clinical features. The authors used Kaplan-Meier methods to estimate the time to diagnosis, linear regression analyses to assess function, and a Cox proportional hazard model to assess survival in subgroups. Results: Of the 39 patients, 29 had only upper motor neuron (UMN) signs on initial evaluation. Thirteen of the 29 were later classified as having UMN-dominant ALS (UMN-D) because they acquired evidence of denervation by EMG (3.17 years) or examination (3.67 years). Sixteen of the 29 patients, classified as clinically pure PLS, retained only UMN signs and a normal EMG (mean follow-up 8.7 years). Ten patients who met criteria for ALS at the initial visit were used as controls. The UMN-dominant ALS group had lower functional scores ( p = 0.033) than the PLS group, and similar scores to those with ALS. Survival was longer in both the PLS group ( p = 0.027) and the UMN-D group ( p = 0.067) than the ALS group. Conclusions: Clinically pure PLS can be defined by isolated UMN signs 4 years after symptom onset, and is a syndrome of slow progression with high levels of function. Prior to the fourth year, the diagnosis of PLS cannot be made with certainty because many patients develop LMN signs. UMN-dominant ALS, defined by predominantly UMN disease with minor LMN signs, has disability similar to ALS, but slower progression.

Objective: To determine the prevalence of depressive disorders and symptoms in patients with late-stage ALS, to identify possible risk and protective factors associated with depression, and to determine whether depression increases as death approaches. Methods: Semistructured interviews were conducted monthly with hospice-eligible patients with ALS and caregivers until the study endpoints of death or tracheostomy. Standardized measures were administered to assess depressive disorders and symptoms, hopelessness, spiritual beliefs, attitudes toward hastened death, quality of life, and related constructs. Results: Sixty-three percent of eligible patients were enrolled. Of the 80 participants, 17 were seen only once; the number of monthly assessments for the others ranged from 2 to 18. For the 53 patients who died, median interval between last assessment and death was 30 days. At study baseline, 81% had no depressive disorder, 10% had minor depression, and 9% had symptoms consistent with major depression. Diagnoses of depression were made on 16% of 369 monthly assessments. Fifty-seven percent of patients never had a depression diagnosis at any visit, and 8% were depressed at all visits. There was no trend toward increasing depression as death approached. Presumed protective factors including spiritual beliefs, spouse as care partner, financial situation, depression in caregiver, and hospice participation did not distinguish between those who were depressed and those who were not. Conclusions: Results of multiple measures of depression and distress converged to indicate that major depression in people with late-stage ALS is rare, although transient depressive symptoms may occur, and depression does not generally increase as death approaches.

Dr. Theodore Leon Munsat (Ted) died on Friday, November 22, at home in Waltham, Massachusetts, from complications of vasculitis, surrounded by his loving family.

Robert A. Fishman, MD, former President of the American Neurological Association (1983–1984) and Editor-in-Chief of Annals of Neurology (1993–1997), died on December 4, 2012, from complications of Alzheimer disease. He was 88 years old. In many respects, his personal story parallels the evolution of the field of neurology, a specialty that was emerging throughout his long and highly productive career.

Dewey K. Ziegler led the Section of Neurology at the University of Kansas from 1966 until it became the Department of Neurology in 1974, when he became the founding Chairman, serving until 1985. He became Professor Emeritus in 1990. He was among the neurologists who established the field as an independent field, rather than a subsidiary of either internal medicine or psychiatry. Indeed, he and his generation of neurologists who trained in New York and Boston then spanned across the nation to create departments of neurology from coast to coast. He was one of the first specialists in headache neurology and was an inspirational leader as physician, neurologist, and world citizen.

Amyotrophic lateral sclerosis (ALS) is a familial disease in 10% of cases and is sporadic in 90%; investigations prior to the early 1990s focused on the more prevalent sporadic disease. A paradigm shift in approaches to disease pathogenesis began almost 2 decades ago, with the publication of 2 articles1,2 that documented the presence of mutations in Cu/Zn superoxide dismutase–1 in 20% of familial cases. These seminal studies refocused investigative efforts to patients with familial ALS, unleashing the power of genetics to illuminate the many different ways neurons succumb to the degenerative process. Discoveries …

Lewis P. Rowland, MD Russell N. DeJong was the first Editor-in-Chief of the Green Journal. He served for 26 years. When Dr. DeJong retired in 1976, Robert A. Fishman was President of the American Academy of Neurology (AAN), and he set a limit of 10 years for the next editor, a limit that is still in place. To select the second editor, Dr. Fishman appointed a search committee, headed by Melvin Greer, and I became editor in 1976. When I completed my term in 1986, I wrote about the changes in the journal and in our profession.1 Perhaps the most notable factoid was the number of papers submitted to Neurology ®, which rose from 460 in 1977 to over …

In this issue of Neurology ®, Wills et al.1 report that they found no association between paraoxonase genes and amyotrophic lateral sclerosis (ALS). Remarkably, 19 of the 23 authors of that article had previously published evidence that paraoxonase gene ( PON1 ) single nucleotide polymorphisms (SNPs) are associated with an increased risk of ALS. The story started in the 1991 Gulf War, when reports of a possible excess of ALS cases among deployed troops generated controversy.2–3 Although electrophysiologic studies found no increase of ALS or any neuromuscular disease in the Gulf War or other modern wars,4 the controversy persists.5–6 The paraoxonases are encoded by a three-gene cluster on chromosome 7 ( PON1 , PON2 , and PON3 ). These enzymes are involved in detoxifying products of oxidative stress, which is presumed to be important in the pathogenesis of ALS. Because they protect against the oxidation of neuronal membrane lipids, defects in these genes could be a mechanism by which genetic susceptibility to toxic environmental factors come about. Also, one ALS risk factor is exposure to organophosphate insecticides, chemicals that are metabolized by an oxidative process. In 2006,7 association studies suggested that PON genes are involved in ALS susceptibility but the same genes are also activated in stroke, Alzheimer disease, Parkinson disease, and other conditions. Wills et al. used data from six candidate gene studies; …

Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase, a key enzyme in the de novo (but not the salvage) pathway of purine synthesis. Since lymphocytes exclusively use the de novo pathway (whereas other cells use both pathways), the drug selectively inhibits proliferation of T and B lymphocytes and has been used safely and effectively in managing patients with renal transplants. The first case report suggesting efficacy of mycophenolate as an immunosuppressive agent in myasthenia gravis appeared in 1998.1 This was followed by uncontrolled case series,2–4 one small double-blind controlled trial,5 and a Cochrane review.6 These studies and conversations among neurologists treating myasthenia popularized use of the drug. Until now, however, there have not been any adequately powered controlled trials.7,8 In the Muscle Study Group (MSG) trial8 reported in this issue, patients with myasthenia who were taking no other immunosuppressive therapy were randomized to receive either mycophenolate plus prednisone 20 mg/day or placebo plus prednisone 20 mg/day, with the dose of prednisone remaining constant throughout the study. The goal was to examine the short-term (12 week) efficacy of mycophenolate plus prednisone (compared to prednisone alone) in patients receiving no other immunosuppressive therapy. A second article in this week’s issue of Neurology ®describes an international …

The revered Anita E. Harding died in 1995 at age 43. Among her numerous pioneering achievements in neurogenetics,1 she was the one who classified hereditary spastic paraplegia (HSP) as “pure” or “complicated” forms.2 In the uncomplicated HSPs, the clinical manifestations are dominated by upper motor neuron signs in the legs, allowing pes cavus and some loss of vibration sense as well. In complicated HSP, on the other hand, the more serious neurologic manifestations include ataxia, deafness, cataracts, epilepsy, dementia, or other signs.3 Genetic heterogeneity is prominent in the HSPs; inheritance may be autosomal dominant, autosomal recessive, or X-linked. Among the autosomal dominant forms, 40% are attributed to mutations in the gene for spastin ( SPG4 ) and 10% for atlastin ( SPG3 ). In contrast, some mutations are so rare they account for less than 1% each. With the two families reported in this issue of Neurology ® by Orlacchio et al.,4 the number of …

[][1] Figure. Sidney Carter, MD Dr. Sidney Carter, one of the most eminent and beloved of neurologists and a founder of child neurology, died on Sunday, January 16th, on Cape Cod. He was 92 years old. Dr. Carter was born in Boston and attended Dartmouth College. He received his medical degree from Boston University in 1938. He interned at St. Mary’s Hospital in Waterbury, CT and then trained in psychiatry in 1939 to 1940 at the Westboro State Hospital in Westboro, MA. In 1941, he started his residency in neurology on the Harvard Unit at Boston City Hospital, where Houston Merritt had recently been appointed Acting Director, following the departure of Tracy Putnam to the Neurologic Institute of New York. In addition to Merritt, Carter worked closely with Raymond Adams, then also at the Boston City Hospital. In 1943, Derek Denny-Brown was named Director of the Neurology Service and, 2 years later, Merritt left to direct Columbia’s neurology program at Montefiore Hospital in the Bronx. Carter had the distinction of being Merritt’s last chief resident at Boston City, and Denny-Brown’s first. During World War II, Carter joined other physicians from the Boston City Hospital at the Seventh General Army Hospital in England, where he was assistant chief of the neuropsychiatric section and the principal neurologic consultant for army casualties. His military career had … [1]: /embed/graphic-1.gif

Dr. Richard Lambert Masland, a former chairman of neurology at Columbia University who led a landmark study of the causes of birth defects that became a template for US-funded biomedical research, died December 19, 2003 of pneumonia at his home in Englewood, New Jersey. He was 93. ⇓ Richard Lambert Masland Inspired as a boy to become a physician by the accounts of medical missionaries, Masland gravitated to brain science. He was especially interested in finding the causes of mental retardation, hoping to find measures that could lower the number of affected persons. He also promoted efforts to find effective therapies for epilepsy and dyslexia. From 1959 to 1968, Dr. Masland served as the director of the National Institute of Neurologic Diseases and Blindness of the NIH. In that position, he was part of a team that crafted the merit-based peer-review system that has been the foundation of medical research in the United States. He was unusually willing to join forces with laymen to sponsor research, campaign for laws to protect the rights of the handicapped, and to develop policies that might prevent brain injury. Masland developed a program of “paired research grants” to neuroscientists in Poland and Yugoslavia. Each investigator from those countries was matched with a scientist in the United States who would visit the European center at least once a year. Originally, these impoverished countries could not pay for food they imported from the United States during and after World War II. Masland credited US Congress Representative John Fogarty (from Rhode Island) with the idea of using credits from those debts to support medical research. Masland was …

Proposed treatments for ALS have almost all proved ineffective in controlled clinical trials (Rowland LP, Shneider N, unpublished observation, 2001).1 Riluzole is the only Food and Drug Administration–approved agent. Although it has no visible benefits, treatment prolongs life by 3 to 6 months. Riluzole is thought to decrease glutamate excitotoxicity, a player in the pathogenesis of ALS.1 In this issue of Neurology , Miller et al.3 describe a phase III trial of another glutamate antagonist, gabapentin, in 204 patients with ALS. This trial did not confirm a trend toward slowing the decline in arm strength, which was noted in an earlier study.4 The authors conclude that gabapentin therapy is not beneficial for ALS. To their credit, they refrain from putting a positive spin on the results or suggesting that design limitations masked a possibly beneficial effect. This study demonstrates the importance of confirmatory randomized trials. It also disproves the notion that patients will not participate in a …

To determine whether ALS patients' preferences for ameliorative or life-extending technologies elicited early in the disease were related to later treatment choices.In this prospective cohort study, 121 patients were seen at a tertiary ALS care center and followed for a median of 12 months. At baseline, patient preferences for use of tracheostomy and percutaneous endoscopic gastrostomy (PEG) placement were elicited. All patients received the same educational information before being interviewed about treatment preferences. Patients were then followed to determine if patients who viewed the interventions favorably at baseline were significantly more likely to use the interventions over follow-up.Six to twelve percent of patients were certain they wanted tracheostomy and 28.2% wanted PEG. Preferences were related to later treatment choices: 20% of patients who found tracheostomy acceptable had one in the follow-up period, compared with 3.4% of those not in favor (p0.001). For PEG, similar findings were obtained: 48.5% who initially found it acceptable had PEG, versus 8.1% of those not in favor of this treatment (p0.001). Patients who found the interventions acceptable were more likely to be recently diagnosed, expressed greater attachment to life, and showed greater declines in pulmonary function over follow-up.Patients with ALS were able to express their preferences for life-extending or ameliorative technologies and made choices consistent with these preferences. However, patient preferences may change over time, and clinical education efforts are required throughout the course of disease.

Ade T. Milhorat was born in 1899 and died on June 26, 1997, at age 98. Most of the early obituaries focused on his role as the key founder of the Muscular Dystrophy Association (MDA), the organization that has played the major private role for research for neuromuscular diseases for almost 50 years, and that set the pace for research programs of voluntary health agencies. This was surely an important contribution by Dr. Milhorat. But another aspect of his life warrants historical documentation. He was not a neurologist, but he set an example that had a profound effect on research for neuromuscular diseases. The formalities include an undergraduate degree from Columbia University(where he studied with Thomas H. Morgan, the 1933 Nobelist in genetics) and a medical degree from Cornell in 1928, followed by an internship at Presbyterian Hospital in New York. From 1930 to 1932 he was a Fellow at the Institute of Physiological Chemistry in Leipzig, Germany. He returned as a …

Intravenous immune globulin (IVIg) is advocated as a safe treatment for immune-mediated neurologic disease. We reviewed the medical records of 88 patients who were given IVIg for a neurologic illness. Major complications in four patients (4.5%) included congestive heart failure in a patient with polymyositis, hypotension after a recent myocardial infarction, deep venous thrombosis in a bed-bound patient, and acute renal failure with diabetic nephropathy. Other adverse effects included vasomotor symptoms 26, headache 23, rash 5, leukopenia 4, fever 3, neutropenia 1, proteinuria (1.9 g/day) 1, viral syndrome 1, dyspnea 1, and pruritis 1. Fifty-two patients (59%) had some adverse effect of IVIg infusion, most commonly vasomotor symptoms, headaches, fever, or shortness of breath in 40 (45%), which improved with reduced infusion rate or symptomatic medications. Five (6%) had asymptomatic laboratory abnormalities and seven (8%) had other minor adverse effects. Adverse effects led to discontinuation of therapy in 16% and permanent termination of therapy in 10% of patients. There was no mortality or long-term morbidity. Although adverse effects were frequent, serious complications were rare except in patients with heart disease, renal insufficiency, and bed-bound state.NEUROLOGY 1996;47: 674-677

Reply from the Authors: We thank Dr. Steck et al. for discussing our paper. [1] We agree with them in two essentials: (1) Almost all patients with high titers of antibodies to SGPG also have antibodies to MAG; (2) Almost all patients with high titers of anti-MAG and anti-SGPG have a sensorimotor peripheral neuropathy. [2] They cite as a patient who had a ``motor neuropathy'' (not motor neuron disease) who had two siblings with full-blown ALS. Was that merely a coincidence? Were there really two entirely different and unrelated diseases of the lower motor neuron in the same sibship? Or is that family another reminder that peripheral nerves may be affected in some patients with motor neuron …

Competition for the limited space in Neurology is intense, and well-written papers have the best chance of being accepted. Be certain your words express your ideas and message. Write simply and concisely, adhering to Billings' rules [1]: "(1) Have something to say; (2) Say it; (3) Stop as soon as you have said it." Otherwise, the scientific value of your manuscript may be obscured. The editor's office and publisher will not rewrite poorly written manuscripts. Those not fluent in English should seek help from a colleague or a professional author's editor who does this for a fee. 1. Adhere strictly to the format of Neurology as described in the Information for Authors of a current issue. Incorrect style irritates reviewers and editors, and the wrong reference style suggests that another journal previously rejected the manuscript. 2. Edit your paper carefully and eliminate errors in spelling, punctuation, and grammar. Good writing requires rewriting. 3. After you type the final draft (especially if someone else types it for you), read it once more before you submit it. Check the accuracy of your references with the original, not secondary, sources. Incorrect citations inconvenience the publisher and are a disservice to the reader. 4. Double-check numerical data. Numbers in the abstract, text, tables, and legends should be consistent. 5. The Abstract should be substantive and brief. Do not tease; avoid sentences such as, "The implications are summarized." Instead, summarize the implications. 6. …

In a prospective study of patients with different forms of motor neuron disease, we performed bone marrow biopsy to evaluate the possibility that the patient might have an otherwise asymptomatic lymphoma. By the time 37 patients had been studied, two patients had been found to have lymphoma, one with and one without paraproteinemia.

Surgical procedures on the cervical spine are accepted therapies for the myelopathy of cervical spondylosis. However, reported improvement rates vary widely, and many reports indicate improvement in about onehalf of the cases. It has not been proven that outcome after surgery is better than the natural history or conservative therapy. Radiographic or imaging evidence of cord impingement or compression may be seen in asymptomatic people. There are no clear guides to the selection of patients who may benefit from the operation and there has been no standardization of preoperative evaluation, trials of conservative therapy, ascertainment of progressive disability, or assessment of outcome. A multicenter controlled trial might answer these questions.

From 1984 to 1988, 11 of 120 patients (9%) with motor neuron disease (MND) had paraproteins detected by serum immunofixation electrophoresis (IFE), compared with 4 (3%) by cellulose acetate gels: 1 patient had progressive spinal muscular atrophy, 5 patients had amyotrophic lateral sclerosis (ALS), and 5 patients had ALS with probable upper motor neuron signs. Four of 5 patients (80%) with cerebrospinal fluid (CSF) protein content above 75 mg/dl had paraproteins, as did 6 of 30 with values above 50 mg/dl. Four of 14 patients with cerebrospinal oligoclonal bands (OCB) also had paraproteins. Two patients with ALS, CSF protein content above 75 mg/dl, and paraproteinemia had lymphoma. We conclude the following about patients with MND: high CSF protein content (especially above 75 mg/dl) or CSF OCB makes paraproteinemia more likely; some of these patients may have lymphoma; there is an inordinately high occurrence of paraproteinemia in MND; and IFE on agarose is more sensitive than electrophoresis on cellulose acetate in detecting paraproteins. Syndromes of paraproteinemia and high CSF protein are not restricted to the lower motor neuron but qualify as “ALS” with coexisting upper motor neuron signs.