Search

Background "Ondine's curse" or central hypoventilation, induces an apparently spontaneous failure of automatic respiratory drive, henceforth necessitating a conscious effort to breathe and sleep induced hypoventilation. It is typically seen in congenital central hypoventilation syndrome, but may be acquired. Objectives To highlight Ondine's curse as part of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) secondary to microtubule associated protein tau (MAPT) variants. Methods We describe the clinical and neuropathological findings in two patients with fatal Ondine's curse associated with FTDP-17 and secondary to MAPT variants (FTDP-17t). We discuss neuroanatomical correlates. We review two prior reports of central hypoventilation associated with MAPT variants suggesting that Ondine's curse occurs uncommonly in FTDP-17t. Results Despite variants affecting different regions of MAPT and a degree of heterogeneity in pathological findings, the patients reviewed all experienced central hypoventilation during their disease course. Conclusion Tauopathy should be considered in patients with adult-onset Ondine's curse.

Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5' splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the 'missing' +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the 'stem' when the stem-loop model was first proposed and no mutations have been found within the 'loop' region as expected. Therefore we 'close the tau loop' having 'opened the loop' 21 years ago.

We report a rare case of peripheral T-cell lymphoma arising in a 52-year-old man with biopsy-proven aggressive polymyositis, who had cardiac involvement, progressive bulbar symptoms, and died 11 months post diagnosis due to multiorgan failure. Using a multimodality approach including immunohistochemistry, genome-wide single nucleotide polymorphism (SNP)-array analysis, and high-throughput sequencing of the complementary determining region 3 (CDR3) of T-cell receptor beta (TCRβ) genes, our study demonstrates a molecular link between polymyositis and T-cell lymphoma, and provides evidence of the rapid and possibly late occurrence of genomic instability during neoplastic transformation of an oligoclonal T-cell population. Immunohistochemical analysis revealed loss of CD5, CD7, and CD8 antigen expression in autopsy tissue samples, as well as the occurrence of aberrant CD56 expression, not seen in pre-mortem biopsies, supporting the emergence of a neoplastic T-cell population. Multiplex polymerase chain reaction and next-generation sequencing of the TCRβ CDR3 region displayed two unique T-cell clones in both the diagnostic biopsy confirming polymyositis and the autopsy muscle tissue exhibiting T-cell lymphoma, linking the two pathological processes. SNP-array analysis revealed complex genomic abnormalities at autopsy but not in the pre-mortem muscle biopsies displaying polymyositis, confirming malignant transformation of the oligoclonal T-cell infiltrate. Our findings raise the possibility that clinically aggressive polymyositis might represent a preneoplastic condition in some instances, similar to certain other autoimmune and inflammatory disorders.

Mimic syndromes may differ from a neurodegenerative condition not only in natural history with periods of stability or even spontaneous improvement, but also because the mimic may be treatable. Careful attention to history and clinical examination is required to ensure that important clues to a mimic syndrome are not overlooked. Atypical features, failure to progress, or the development of new or atypical signs should trigger a full re-evaluation and a search for mimic syndrome.

It has long been recognized that signs of motor neuron disease (MND) may accompany clinical evidence of parkinsonism in different neurodegenerative conditions. By using the Columbia University Division of Movement Disorders database, we reviewed data from 5,500 cases of parkinsonism and recorded the presence of upper motor neuron (UMN) dysfunction, lower motor neuron (LMN) dysfunction, or both. Among the 27 patients so identified, we counted those with autonomic dysfunction, cerebellar dysfunction, or dementia. Among the 27 cases, seven had UMN signs and LMN signs as well as parkinsonism and were diagnosed with amyotrophic lateral sclerosis (ALS)-parkinsonism (Brait-Fahn disease). Three of the seven had dementia that was not deemed to be frontotemporal dementia (FTD). Six other patients had no LMN signs but had UMN signs and parkinsonism and were classified as having primary lateral sclerosis (PLS)-parkinsonism. Four patients had both UMN and LMN signs with parkinsonism as well as the characteristic dementia of FTD; they were diagnosed with FTD-parkinsonism-ALS. Seven patients had MND, parkinsonism, and autonomic or cerebellar dysfunction, a combination compatible with multiple system atrophy (MSA). Three patients had syndromes compatible with hereditary spastic paraplegia (HSP). In sum, we found that MND occurs in association with diverse parkinsonian syndromes; some are heritable, others sporadic and causes are uncertain. Having MND may be a risk factor for parkinsonism. A prospective study may elucidate this possibility.

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

Tat'yana Bunina, a Russian neuropathologist, has been immortalized because she discovered a neuronal inclusion and it was named after her. She first recognized these structures in familial ALS and in experiments designed to transmit the disease to primates. Her observations were recorded in a Russian language journal and were brought to the attention of Western neurologists by Professor Asao Hirano of the Albert Einstein College of Medicine and Montefiore Hospital in New York City; he also found the same structures in patients with sporadic, familial, or Guamanian ALS. Subsequently, the inclusion bodies proved to have high sensitivity and specificity for the cellular diagnosis of ALS in post mortem examination; Bunina bodies and ubiquitinated inclusions have almost equal diagnostic value. In later experiments, most attempts to transmit ALS failed, but a few succeeded.

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is the most common mitochondrial disease due to mitochondrial DNA (mtDNA) mutations. At least 15 distinct mtDNA mutations have been associated with MELAS, and about 80% of the cases are caused by the A3243G tRNA(Leu(UUR)) gene mutation. We report here a novel tRNA(Val) mutation in a 37-year-old woman with manifestations of MELAS, and compare her clinicopathological phenotype with other rare cases associated tRNA(Val) mutations.

Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by weakness in the shoulder-girdle and peroneal muscles. In a large Italian-American pedigree with dominant SP myopathy (SPM) previously linked to chromosome 12q, we have mapped the disease to Xq26, and, in all of the affected individuals, we identified a missense change (c.365G--C) in the FHL1 gene encoding four-and-a-half-LIM protein 1 (FHL1). The mutation substitutes a serine for a conserved trypophan at amino acid 122 in the second LIM domain of the protein. Western blot analyses of muscle extracts revealed FHL1 loss that paralleled disease severity. FHL1 and an isoform, FHL1C, are highly expressed in skeletal muscle and may contribute to stability of sarcomeres and sarcolemma, myofibrillary assembly, and transcriptional regulation. This is the first report, to our knowledge, of X-linked dominant SP myopathy and the first human mutation in FHL1.

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.

The EALSC held its second annual Research Workshop in Nice, France on 14–16 May. Following the success of the first workshop, held in Germany in 2003, this second meeting attracted an increased number of investigators. Young investigators were particularly encouraged to attend and present their data in the platform or poster sessions. The workshop was marked by a lively, friendly and informative atmosphere, which encouraged discussion between the participants. Dr. L.P. Rowland (New York) attended as a guest of the consortium, which was organized by Nigel Leigh (London) and Claude Desnuelle (Nice). Professor Desnuelle was also responsible for the excellent local arrangements. The programme comprised 66 papers and posters. Twenty concerned the pathogenesis of human ALS and 16 dealt with the SOD1 transgenic mouse. Twenty papers were clinical and 10 dealt with animal models, cultured cells or slices, or drug discovery. The number of papers and the diversity of subjects gave testimony to the breadth of clinical investigation, in the broadest sense, in Europe. Here, we can summarize only highlights and we apologize to any authors whose work is either not cited at all, or not cited even by implication because we have mentioned only the first author, arbitrarily omitting the term ‘and others’.

The prion protein (PrP) is central to the prion diseases, although a role in other neurodegenerative diseases has been postulated. A common polymorphism (Met or Val) at codon 129 of the PrP gene (PRNP) features prominently in the risk and phenotype, of prion disease, and an abnormality in its distribution frequency may signal a role for PrP in other diseases. We conducted a case-control study to compare the PRNP codon 129 genotype distribution in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and primary progressive aphasia (PPA), including 281 AD, 256 ALS, 39 PPA, and 415 healthy control subjects. Statistical analysis was applied to determine the presence or absence of disease-specific genotype associations. The distribution of codon 129 genotypes was similar among healthy control, AD, and ALS subjects, although the heterozygous state was significantly overrepresented (age-adjusted odds ratio, 8.47) in PPA, a rare condition of unknown cause. Although these findings do not entirely exclude a role for PrP in AD or ALS, they do not support the codon 129 genotype as a risk factor for either disease. However, the strong association between heterozygosity and PPA raises new questions about its cause and the role of PrP in other neurodegenerative diseases.

As we stated in the Preface, a major impetus for organizing the ALS Clinical Trial Meeting held in Tarrytown, New York, was the overall great frustration we have had in treating ALS; that is, since 1996 when riluzole received FDA approval, we have not identified any new medications for ALS. Although we have been prescribing riluzole, its efficacy is modest at best. We desperately need more effective drugs. Although a cure may come only after the cause of ALS is elucidated, we do not have the luxury of waiting when we are confronted by the progressive paralysis of our patients. Vigorous basic research in ALS has offered new hypotheses and opportunities to test novel drugs. In the past two decades, we have had more than 25 randomized clinical trials (RCTs) in ALS (Table 1). Although we surely have made great progress in these trials, the collective experience is still less than that in many other diseases. An important lesson is always to learn from others and from the past. We have therefore decided to provide here not a review but rather an overview of the collective experience in past ALS RCTs, which hopefully will serve as a useful Introduction to this supplement. The issues that we raise are examined in detail by the other contributors to the supplement.

lfred Jaretzki III, Professor Emeritus of ClinicalSurgery at Columbia Presbyterian Medical Centerin New York City, died at age 94 on May 29, 2014.Fred, as he was known to family, friends, and col-leagues, was born in Greenwich, Connecticut. Hehad a distinguished career as a cardiothoracic sur-geon in the Department of Surgery at the Collegeof Physicians and Surgeons of Columbia University,a career that spanned nearly a half century beforehis retirement from the operating room in 1992.Fred remained highly engaged in academic surgeryand medicine after his retirement by continuingclose collaborations with neurologists who sharedhis interest in myasthenia gravis.While at Harvard College, Fred served as cap-tain of the junior varsity football team and treas-urer of the Lampoon troupe. After graduating in1941, he enrolled in Harvard Medical School, latermoving to New York City, where he spent nearlyhis entire academic career. He trained in surgeryat Presbyterian and Lenox Hill Hospitals between1944 and 1955, a period that was interrupted bymilitary service. In 1954, he was hired as aninstructor at the College of Physicians andSurgeons, beginning a 48-year tenure in theiroperating rooms as a member of the surgical fac-ulty. Early in his cardiothoracic surgery career hewas part of the team that developed synthetic vas-cular grafts. In neurology circles, Fred was knownfor the crucial role he played in the definition ofthe anatomy of the thymus and in its complete ornear-complete excision from the anterior mediasti-num as therapy in myasthenia gravis. He pio-neered the maximal thymectomy that includedboth transsternal and transcervical incisions to fullyremove thymic tissue from retrothyroid, cervical,and inferior mediastinal regions. In work per-formed with neurology colleagues from Columbiain the 1990s, he demonstrated that crude remis-sion rates with the maximal thymectomy approachexceeded those from less invasive techniques. Fredhad the reputation of being meticulous in theoperating room, attending personally to everydetail of the surgery. He publically challenged sur-gical colleagues at other institutions to demon-strate that less extensive thymectomy approacheswith less complete thymus removal were equallyeffective in managing myasthenia; in the end, hisviews that a complete resection was needed pre-vailed. Fred also led the charge to standardize clin-ical classifications and outcome assessments inmyasthenia gravis, culminating in the seminal rec-ommendations for clinical research standards pub-lished in 2000.

My assignment was to identify the 6 most important ALS papers published in 1999 but, great to relate, there were too many excellent candidates. Rather than confining the search to individual papers, six major themes seemed appropriate for discussion: 1) The study of transgenic mice that carry a mutated human gene for superoxide dismutase-1 (SOD1) has led to many far-reaching advances in ALS research. The mice are regarded as the best test system to evaluate potential therapies, including creatine. Inconsistencies between efficacy in mice and people are noted, however. 2) Transgenic mice have also been used to evaluate the role of glutamate toxicity in the pathogenesis of ALS, a dominant theory. 3) The role of mitochondria in the pathogenesis of ALS is gathering increasing attention. 4) The role of neurofilaments in the pathogenesis of ALS has provided new twists in mice and people. 5) Motor neuropathy is the most important differential diagnosis of ALS. 6) Gene therapy, as exemplified by the use of stem cells, has been applied successfully to animal models of other inherited diseases of the central nervous system.

Swash, Desai, and Misra [1] use two patients with uncommon, as the authors point out, for such cases to primary lateral sclerosis (PLS) as the foundation for a develop evidence of involvement of other parts of the history-based discussion of that elusive condition. They nervous system and thus place the case in another diagnosconclude that it is a form of motor neuron disease and tic category such as multiple sclerosis, amyotrophic lateral often turns into amyotrophic lateral sclerosis (ALS) before sclerosis, and spinal cord tumor.’’ That skeptical view death. Their inclusionary and exclusionary criteria for the confirms the label given by Swash et al. that this was the clinical diagnosis of PLS are the generally accepted ones. ‘‘era of doubt’’. However, there is no way to prove the diagnosis except by But we now have a paradox. The syndrome is defined autopsy, which has been performed in only 6 cases since and recognized clinically, but it is an unsatisfactory the ‘modern era’ started in 1977 with a report by C. Miller diagnosis-of-exclusion, and can be proven only at autopsy. Fisher [2–4]. It is reasonable to start in 1977 because, at There have been so few autopsy cases that there can be no the time of the earliest reports serological tests for syphilis reliable clinico-pathological correlation; we must rely on and viral infections were not available and B12 deficiency clinical series to define the variations of the syndrome. could not be identified; myelography and electromyogI believe the evidence indicates the following: raphy were not widely available before 1945. CT did not come until 1973 and MRI was even later. The syndrome was named by Erb [5]; in describing 10 1. PLS can be recognized anatomically as a disorder of previously published cases he used the term ‘spastic spinal the corticospinal tracts, implicating the upper motor paralysis’, but, in an aside, he said he had used ‘lateral neuron and sparing the lower motor neurons of sclerosis’ earlier. Four of the 10 cases were familial. Other brainstem and spinal cord; this pattern was seen in all neurology titans described 3 autopsy cases between 1902 6 modern autopsies. Neuronal cellular pathology was and 1910 [6–7]. Even with the limitations of diagnosis in not seen in the motor cortex in 3 of the 6 autopsies, those days there were few postmortem examinations. The but that failure does not exclude the possibility that the literature was then largely silent until the end of World primary disorder affected cortical motor neurons; War II when a new set of well-known neurologists another possibility is that the disease may sometimes reported series of living patients. Some authorities, howarise subcortically, in the corticospinal tracts. Also, the ever, disdained the clinically diagnosed cases. For inlack of visible change in the lower motor neurons of stance, in discussing a 1946 paper by Wechsler and Brody all 6 cases does not exclude the possibility that there [8], Merritt [9] stated: ‘‘The existence of primary lateral would have been symptoms of lower motor neuron sclerosis as a clinical entity has been doubted by most disease had the patients lived longer. modern neurologists. Although cases with symptoms and 2. PLS can be a form of ALS. In the autopsy series of signs limited to those which result from injury to the Brownell et al. [10], 3 patients had only upper motor pyramidal tract are not infrequently encountered, it is not neuron signs in life, but the anterior horn cells were affected at autopsy. Lawyer and Netsky [11] stated they had no such patients. Castaigne et al. [12] *Corresponding author. Tel.: 11-212-305-8551; fax: 11-212-305described two similar cases but the patients actually 6978. E-mail address: 1pr1@columbia.edu (L.P. Rowland) had lower motor neuron signs in life and should have

To evaluate single-voxel proton magnetic resonance (MR) spectroscopy in detection of abnormality of the upper motor neuron in patients with motor neuron diseases.In 43 of 50 patients with motor neuron disease and 14 of 14 control subjects, matching sets of MR spectra were obtained in the left and right motor cortex. The ratio of N-acetylaspartate (NAA) to creatine (Cr) was derived from peak area measurements. Mean ratios were calculated for control subjects and several patient groups, including patients with amyotrophic lateral sclerosis (ALS) or primary lateral sclerosis (PLS). MR images were evaluated for corticospinal tract hyperintensity and central sulcus dilatation.Mean NAA/Cr values were significantly different between control subjects and the ALS or PLS groups (P.05). With an optimal cutoff of 2.5, NAA/Cr values were abnormal in 15 (79%) of 19 patients with ALS, 12 (67%) of 18 patients with PLS, and one (7%) of 14 control subjects. Corticospinal tract hyperintensity, central sulcus enlargement, or both were found in 43% of the ALS group, 24% of the PLS group, and 7% of the control group.NAA/Cr values determined at single-voxel proton MR spectroscopy are more sensitive than are standard findings at MR imaging in the detection of upper motor neuron disease.

This review of the differential diagnosis of amyotrophic lateral sclerosis focuses on two themes. The first is practical, how to establish the diagnosis based primarily on clinical findings buttressed by electrodiagnosis. The main considerations are multifocal motor neuropathy and cervical spondylotic myelopathy. The second theme is the relationship of motor neuron disease to other conditions, including benign fasciculation (Denny-Brown, Foley syndrome), paraneoplastic syndromes, lymphoproliferative disease, radiation damage, monomelic amyotrophy (Hirayama syndrome), as well as an association with parkinsonism, dementia and multisystem disorders of the central nervous system.

We identified large-scale heteroplasmic mitochondrial DNA (mtDNA) rearrangements in a 50-year-old woman with an adult-onset progressive myopathy. The predominant mtDNA abnormality was a 21.2-kb duplicated molecule. In addition, a small population of the corresponding partially deleted 4.6-kb molecule was detected. Skeletal muscle histology revealed fibers that were negative for cytochrome c oxidase (COX) activity and had reduced mtDNA-encoded COX subunits. By single-fiber polymerase chain reaction analysis, COX-negative fibers contained a low number of wild-type or duplicated mtDNA molecules (ie, nondeleted). In situ hybridization demonstrated that the abnormal fibers contained increased amounts of mtDNA compared with normal fibers and that most of the genomes were deleted. We concluded that deleted mtDNA molecules were primarily responsible for the phenotype in this patient.

Rifkin, Stimulants. Quitkin, Taylor, Antidepressants. Bowden, Antimanic Agents. Heyer, Sedative-Hypnotics. Kane, Antipsychotic Agents. Sellers, Antianxiety Agents: Benzodiazepine Derivatives. Index. Index of Proprietary Names. Index of FDA-Approved Indications. Index of Off-Label Indications.

To promote clinical and patient oriented research, as part of the Second International ALS Conference in Tarrytown, NY, USA, seven pairs of clinicians and scientists were asked to lead discussions with meeting attendees on six major topics (one of which was discussed by two groups); each one the focus of a 90-min Breakout Session. Approximately 25 meeting attendees participated in each session. The Breakout Sessions considered six major themes: 1) Approaches to encourage clinicians to engage in more clinical research to discover the pathogenesis and cause of ALS; 2) Exploring avenues to build more effective partnerships between basic scientists and ALS physicians; 3) Increasing patient interest and commitment to participating in non-trial clinical research; 4) Brainstorming about factors that are most critical to the discovery of the pathogenesis and cause of ALS; 5) Finding ways to incorporate clinical research projects into clinical trials; and 6) Developing state-of-the-art epidemiological studies to solve the mystery of ALS. In this paper, we present the reports from each of the Breakout Sessions; and we provide a wrap-up of the entire conference.

Some have suggested that nonfamilial motor neuron disease (MND) may be autoimmune, and the neurological disorder may benefit from immunotherapy. There have been reports of over 30 cases of lymphoproliferative disease (lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia) with MND, and these patients might he offered immunosuppressive therapy. Bone marrow examination might increase the sensitivity of the diagnostic workup for lymphoma and other lymphoproliferative disorders. We examined the bone marrow in our first evaluation of 161 patients with MND seen at Columbia-Presbyterian Medical Center during 1991-1994. Four of 161 patients (2.5%) had lymphoproliferative disease in the marrow; only 1 of these had a monoclonal paraprotein. Routine bone marrow examination of patients with MND increases the diagnostic yield of lymphoproliferative diseases. The frequency of these bone marrow abnormalities in comparison with a group of age-matched control subjects should be studied further.

Preface Part I. Overview of Pathologic and Pathogenic Comparison Between Sporadic Inclusion-Body Myositis and Hereditary Inclusion-Body Myopathies: 1. Newest approaches to diagnosis and pathogenesis of sporadic inclusion-body myositis and hereditary inclusion-body myopathies, including molecular-pathologic similarities to Alzheimer disease Part II. Historical Perspective: 2: Evolving concepts of inclusion-body myositis Part III. Sporadic Inclusion-Body Myositis - Clinical and Diagnostic Considerations: 3: Sporadic inclusion-body myositis: Clinical and laboratory features and diagnostic criteria 4: Inclusion-body myositis: natural history 5: Uncommon clinico-pathological forms of sporadic inclusion-body myositis: Report of four cases 6: Inclusion-body myositis: pathological changes 7: Unusual pathological forms of inclusion-body myositis, and neuromuscular disorders with IBM-like changes 8: Electrophysiological findings in inclusion-body myositis 9: Genetic factors in sporadic inclusion-body myositis Part IV. Hereditary Inclusion-Body Myopathies - Clinical and Diagnostic Considerations: 10: Hereditary inclusion-body myopathy in Jews of Persian origin: Clinical and laboratory data 11. Hereditary inclusion-body myopathy (h-IBM) with quadriceps sparing: epidemiology and genetics 12: Familial autosomal-recessive inclusion-body myositis with asymptomatic leukoencephalopathy 13: Welander distal myopathy - clinical, pathophysiological, and molecular aspects 14. Tibial muscular dystrophy - clinical, genetic, and morphological characteristics 15. Distal myopathy with rimmed vacuoles, inclusion-body myositis and related disorders in Japan 16. Inclusion-body myopathies 17. Is the muscle fiber in inclusion body-myositis an antigen-presenting cell of an innocent bystander? 18. Viruses, immunodeficiency and inclusion-body myositis 19. Myonuclear abnormalities may play a central role in the pathogenesis of muscle fiber damage in inclusion-body myositis 20. Nuclear degeneration and rimmed vacuole formation in neuromuscular disorders 21. Mitochondrial alterations in sporadic inclusion-body myositis 22. mtDNA analysis in muscle of patients with sporadic inclusion-body myopathy Part V. Treatment: 23. Evaluation of treatment for sporadic inclusion-body myositis 24. Personal experience in treating sporadic inclusion-body myositis Subject index.