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Background

This is a devastating neurodegenerative disorder characterized by progressive and insidious loss of motor function. Although Lou Gehrig was not the first patient afflicted with this disease, his plight first drew serious attention from the public.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/Immunohistochemistry/Electron Microscopy  
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS Lou Gehrig's Disease

Genetics of ALS in Italian families.

Gellera C.

Division of Biochemistry and Genetics, National Neurological Institute-IRCCS, Carlo Besta, Milan, Italy.

Amyotroph Lateral Scler Other Motor Neuron Disord 2001 Mar;2 Suppl 1:S43-6 Abstract quote

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons.

The majority of the patients are sporadic cases (SALS), while 10-15% of patients has a family history of ALS (familial ALS or FALS). Mutations in the gene coding for cytoplasmic Cu/Zn superoxide dismutase (SOD1) have been identified in 20% of FALS. We found SOD1-gene mutations in 7 of 36 unrelated FALS and in 3 of 48 SALS patients. Four FALS patients carried previously described mutations, the A4V (2 cases), the L84F mutations (1 case), and the G93D (1 case), while three FALS patients carried new missense mutations: the G12R mutation, the F45C mutation and the V47F mutation, respectively. Two SALS patients carried previously reported mutations: the homozygous D90A and the heterozygous I113T mutation, respectively. In addition, in one SALS patient we identified an apparently non-pathogenic SOD1 variant: the A95T mutation.

Our study contributes to expand the number of ALS-associated SOD1 gene mutations.

 

DISEASE ASSOCIATIONS CHARACTERIZATION

Amyotrophic lateral sclerosis associated with sarcoidosis.

Saiki S, Yoshioka A, Yamaya Y, Hirose G.

Department of Neurology, Kanazawa Medical University, Uchinada, Ishikawa.

Intern Med 2001 Aug;40(8):822-5 Abstract quote

We report a rare association of amyotrophic lateral sclerosis (ALS) with incidental pulmonary and muscle sarcoidosis.

A 63-year-old woman presented with slowly progressive weakness and atrophy of the extremities starting from the left leg. The biopsy of a small mass in the left gastrocnemius revealed a typical sarcoid nodule. She was treated with corticosteroid for possible sarcoid neuromyopathy. In spite of the treatment, her clinical course was relentlessly progressive and she died of bulbar palsy.

Autopsy revealed a loss of motor neurons in the anterior horn, vacuolar degeneration of the lateral funiculus, and noncaseating granulomas in paratracheal lymph nodes and lungs. No granulomatous lesion or cellular infiltration was found in the spinal cord.

 

PATHOGENESIS CHARACTERIZATION
CHROMOSOMAL ABNORMALITIES

Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical region at chromosome 2q33-q34: candidate genes for ALS2.

Hadano S, Yanagisawa Y, Skaug J, Fichter K, Nasir J, Martindale D, Koop BF, Scherer SW, Nicholson DW, Rouleau GA, Ikeda J, Hayden MR.

NeuroGenes, International Cooperative Research Project, Japan Science and Technology Corporation, Isehara, 259-1193, Japan

Genomics 2001 Jan 15;71(2):200-13 Abstract quote

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that manifests as selective upper and lower motor neuron degeneration. The autosomal recessive form of juvenile amyotrophic lateral sclerosis (ALS2) has previously been mapped to the 1.7-cM interval flanked by D2S116 and D2S2237 on human chromosome 2q33-q34.

We identified three novel full-length transcripts encoded by three distinct genes (HGMW-approved symbols ALS2CR1, ALS2CR2, and ALS2CR3) within the ALS2 critical region. The intron-exon organizations of these genes as well as those of CFLAR, CASP10, and CASP8, which were previously mapped to this region, were defined. These genes were evaluated for mutations in ALS2 patients, and no disease-associated sequence alterations in either exons or intron-exon boundaries were observed. Sequence analysis of overlapping RT-PCR products covering the whole coding sequence for each transcript revealed no aberrant mRNA sequences.

These data strongly indicate that ALS2CR1, ALS2CR2, ALS2CR3, CFLAR, CASP10, and CASP8 are not causative genes for ALS2.

A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.

Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz DA, Kwiatkowski T, Hosler BA, Sagie T, Skaug J, Nasir J, Brown RH Jr, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE.

NeuroGenes, International Cooperative Research Project, Japan.

Nat Genet 2001 Oct;29(2):166-73 Abstract quote

Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2.

These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF.

Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.

Mechanisms of neurodegeneration in amyotrophic lateral sclerosis.

Cluskey S, Ramsden DB.

Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, UK.

Mol Pathol 2001 Dec;54(6):386-92 Abstract quote

Amyotrophic lateral sclerosis (ALS) is the most common variant of motor neurone disease affecting adults that usually strikes during mid to late life. Its aetiology is still poorly understood, although a major breakthrough came with the discovery that mutations in the Cu/Zn superoxide dismutase (SOD1) gene affect approximately 20% of patients with familial ALS.

Experiments using both transgenic mice and ALS tissues have been useful in delineating other genetic defects in ALS. However, because only a subset of cases can be attributed to one particular molecular defect (such as mutation of SOD1 or the gene encoding neurofilament H), the aetiology of ALS is likely to be multifactorial.

This review discusses the major mechanisms of neurodegeneration in ALS, such as oxidative stress, glutaminergic excitotoxicity, damage to vital organelles, and aberrant protein aggregation.

The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.

Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T.

Department of Neurology, Northwestern University Medical School, Chicago, Illinois, USA.

Nat Genet 2001 Oct;29(2):160-5 Abstract quote

Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system.

We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin.

The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs).

OTHER MECHANISMS

Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients.

Shibata N, Nagai R, Uchida K, Horiuchi S, Yamada S, Hirano A, Kawaguchi M, Yamamoto T, Sasaki S, Kobayashi M.

Department of Pathology, Tokyo Women's Medical University, Kawada-cho 8-1, Shinjuku-ku, 162-8666, Tokyo, Japan

Brain Res 2001 Oct 26;917(1):97-104 Abstract quote

For determining whether both the spinal cord motor neurons and glial cells are exposed to increased oxidative stress in amyotrophic lateral sclerosis (ALS), we performed an immunohistochemical investigation of end products of lipid peroxidation and protein glycoxidation in spinal cords from seven sporadic ALS patients and seven age-matched control individuals.

In the ALS spinal cords, immunoreactivities for adducts of 4-hydroxy-2-nonenal-histidine and crotonaldehyde-lysine as markers of lipid peroxidation, N(epsilon)-(carboxymethyl)lysine as a marker of lipid peroxidation or protein glycoxidation, and pentosidine as a marker of protein glycoxidation were localized in the gray matter neuropil and almost all of the motor neurons, reactive astrocytes and microglia/macrophages, whereas none of the immunoreactivities for N(epsilon)-(carboxyethyl)lysine or argpyrimidine as markers of protein glycoxidation or enzymatic glycolysis, or pyrraline or imidazolone as markers of nonoxidative protein glycation were detectable. The control spinal cords displayed no significant immunoreactivities for any of these examined products.

Our results indicate that in sporadic ALS, both lipid peroxidation and protein glycoxidation are enhanced in the spinal cord motor neurons and glial cells, and suggest that the formation of certain products in these abnormal reactions is implicated in motor neuron degeneration.

Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: associated mutations develop motor neuron disease.

Nagai M, Aoki M, Miyoshi I, Kato M, Pasinelli P, Kasai N, Brown RH Jr, Itoyama Y.

Department of Neuroscience, Division of Neurology, Institute for Experimental Animals, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.

J Neurosci 2001 Dec 1;21(23):9246-54 Abstract quote

Some cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding cytosolic, copper-zinc superoxide dismutase (SOD1).

We report here that rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. As in the human disease and transgenic ALS mice, pathological analysis demonstrates selective loss of motor neurons in the spinal cords of these transgenic rats. In spinal cord tissues, this is accompanied by activation of apoptotic genes known to be activated by mutant SOD1 protein in vitro and in vivo.

These animals provide additional support for the proposition that motor neuron death in SOD1-related ALS reflects one or more acquired, neurotoxic properties of the mutant SOD1 protein. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies).

Effect of Creatine Supplementation on Metabolite Levels in ALS Motor Cortices.

Vielhaber S, Kaufmann J, Kanowski M, Sailer M, Feistner H, Tempelmann C, Elger CE, Heinze HJ, Kunz WS.

Department of Neurology II, University of Magdeburg Medical Center, Leipziger Strasse 44, Magdeburg, D-39120

Exp Neurol 2001 Dec;172(2):377-82 Abstract quote

Mitochondrial pathology is an early observation in motor neurons and skeletal muscle of patients with amyotrophic lateral sclerosis (ALS).

To clarify the relevance of this finding, we determined the effects of a 1-month oral administration of creatine on (1)H NMR-visible metabolites in the motor cortices of 15 controls and 15 patients with sporadic ALS, most of whom had mitochondrial pathology in skeletal muscle. In the motor cortex of the ALS group the N-acetylaspartate (NAA)/creatine (Cr(t)) metabolite ratio was lower than in our control group, indicating NAA loss. Upon creatine supplementation we observed in the controls a decline in the NAA/Cr(t), NAA/choline (Cho), glutamate + glutamine (Glx)/Cr(t), and Glx/Cho metabolite ratios. In contrast, in the ALS patient group the NAA/Cr(t) and the NAA/Cho metabolite ratios remained unchanged, while the Glx/Cr(t) and Glx/Cho metabolite ratios decreased.

These data are compatible with the interpretation that creatine supplementation causes an increase in the diminished NAA levels in ALS motor cortex as well as an increase of choline levels in both ALS and control motor cortices. Because NAA is synthesized by mitochondria in an energy-dependent manner and the NAA/Cho metabolite ratios in the ALS motor cortices were found to be correlated to the degree of mitochondrial pathology in ALS skeletal muscle, our results can be explained by a deficiency of enzymes of mitochondrial respiratory chain in the ALS motor cortex which might affect motor neuron survival.

 

LABORATORY/RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
RADIOLOGIC  

Clinical neurophysiology of ALS.

Eisen A, Swash M.

Neuromuscular Diseases Unit, Vancouver General Hospital, 1st Floor Willow Pavillion, 855 West 12th Avenue, British Columbia, V5Z 1M9, Vancouver, Canada

Clin Neurophysiol 2001 Dec;112(12):2190-2201 Abstract quote

The neurophysiology of amyotrophic lateral sclerosis is important not only in relation to diagnosis, but also in the development of methods to follow progress, and the effects of putative therapies, in the disease.

Quantitative techniques can be applied to the measurement of reinnervation using needle electromyogram. The methodology of motor unit number estimation may be useful in measuring loss of functioning motor units in groups of patients but variability in the measurement using current methods limits its sensitivity in the evaluation of individual patients. Conventional neurophysiological measurements, expressed as a multimetric index, may be useful in assessing progress. The cortical and upper motor neuron system can be assessed using transcortical magnetic stimulation protocols, and cortical excitability may be measured by the peristimulus histogram method.

In this review the advantages, limitations and promise of these various methods is discussed, in order to indicate the direction for further neurophysiological studies in this disorder.

LABORATORY MARKERS  

Plasma superoxide dismutase and glutathione peroxidase activity in sporadic amyotrophic lateral sclerosis.

Moumen R, Nouvelot A, Duval D, Lechevalier B, Viader F.

Equipe d'Universite Hydrolases et cytotoxicite, Universite de Caen, France.

J Neurol Sci 1997 Oct 3;151(1):35-9 Abstract quote

To determine the possible role of oxydative stress in the pathology of amyotrophic lateral sclerosis (SALS), we measured the plasma activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX), together with GPX and malone dialdehyde (MDA, a marker of lipoperoxydation) plasma concentrations in a sample of 21 SALS patients and 7 normal control (NC) subjects.

MDA concentration and SOD activity were significantly higher, whereas GPX activity was significantly lower in SALS patients than in NC. Increased MDA concentration provides indirect confirmation of excess lipoperoxydation.

Increased plasma SOD activity might reflect the involvement of extra-cellular SOD (SOD3), a hitherto unreported finding in SALS. Impaired GPX activity, which has already been found in red blood cells and brain tissue of SALS patients, might play a part in the pathogenesis of this disease.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL  
VARIANTS  

Laryngeal dysfunction in Amyotrophic Lateral Sclerosis: a review and case report.

Watts CR, Vanryckeghem M.

Department of Speech Pathology & Audiology, University of South Alabama, Mobile, AL, USA.

BMC Ear Nose Throat Disord 2001;1(1):1 Abstract quote

BACKGROUND: Laryngeal dysfunction can be a salient feature in the clinical symptomatology of speakers diagnosed with Amyotrophic Lateral Sclerosis (ALS). In addition to dysphonia, swallowing function is also disrupted. This paper reviews what is known about laryngeal dysfunction resulting from ALS.

RESULTS: Presented is a case report of a female, diagnosed with ALS, whose initial symptoms were caused by laryngeal bulbar involvement that was characterized by dysphonia and dysphagia.

CONCLUSIONS: In bulbar forms of ALS, voice and/or swallowing difficulties are often the initial signs of disease. Careful examination of the muscles innervated by bulbar nerves, and tracking the rate of progressive deficit in the affected muscles, will help to solidify an accurate diagnosis. With therapy, the ability to swallow safely may still be maintained even when voice and articulation abilities are such that oral communication is inefficient.

Does primary lateral sclerosis exist? A study of 20 patients and a review of the literature.

Le Forestier N, Maisonobe T, Piquard A, Rivaud S, Crevier-Buchman L, Salachas F, Pradat PF, Lacomblez L, Meininger V.

Federation Mazarin de Neurologie Professeurs Delattre et Meininger, Hopital de la Salpetriere, Paris, France.

Brain 2001 Oct;124(Pt 10):1989-99 Abstract quote

The question of whether primary lateral sclerosis (PLS) is a nosological entity distinct from amyotrophic lateral sclerosis (ALS) has been the subject of controversy since it was first described in the nineteenth century. PLS has been defined as a rare, non-hereditary disease characterized by progressive spinobulbar spasticity, related to the selective loss of precentral pyramidal neurones, with secondary pyramidal tract degeneration and preservation of anterior horn motor neurones. In the recent clinical literature, the frontier between ALS and neurodegenerative disease remains poorly defined.

We studied 20 patients with a diagnosis of PLS. We carried out a variety of tests in order to determine the presence of a more diffuse neurodegenerative process. We also performed a longitudinal electrophysiological evaluation.

Our clinical, electrophysiological and pathological investigations provide evidence that the disease has a heterogeneous clinical presentation and that degeneration is not restricted to the central motor system.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL  

Recent advances in research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations: neuronal Lewy body-like hyaline inclusions and astrocytic hyaline inclusions.

Kato S, Saito M, Hirano A, Ohama E.

Division of Neuropathology, Faculty of Medicine, Tottori University, Yonago, Japan.

Histol Histopathol 1999 Jul;14(3):973-89 Abstract quote

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. Of all patients with ALS, approximately 5%-10% of them are familial and most of the others are sporadic. Superoxide dismutase 1 (SOD1) gene mutations are shown to be associated with about 20% of familial ALS (FALS) patients. FALS is neuropathologically classified into two subtypes: classical FALS in which degeneration is restricted to only motor neurons and FALS which is characterized by the degeneration of the posterior column in addition to the lesion of the motor neuron system.

The neuronal Lewy body-like hyaline inclusion (LBHI) is a characteristic neuropathological marker of mutant SOD1-linked FALS with posterior column involvement. Inclusions similar to the neuronal LBHIs have been discovered in astrocytes in certain patients with FALS exhibiting SOD1 gene mutations. The purpose of this review is to discuss the novel neuropathological significance of the astrocytic hyaline inclusions (Ast-HIs) and neuronal LBHIs in brain tissues from individuals with the posterior-column-involvement-type FALS with SOD1 gene mutations. In hematoxylin and eosin preparations, both Ast-HIs and neuronal LBHIs are eosinophilic inclusions and sometimes show eosinophilic cores with paler peripheral halos. Immunohistochemically, both inclusions are intensely positive for SOD1. At the ultrastructural level, both inclusions consist of approximately 15-25 nm-sized granule-coated fibrils and granular materials. Immunoelectron microscopically, these abnormal granule-coated fibrils and granular materials are positive for SOD1.

Therefore, the FALS disease process originating from SOD1 gene mutations occurs in astrocytes as well as neurons and is involved in the formation of both inclusions.

New consensus research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 (SOD1) gene mutations: inclusions containing SOD1 in neurons and astrocytes.

Kato S, Takikawa M, Nakashima K, Hirano A, Cleveland DW, Kusaka H, Shibata N, Kato M, Nakano I, Ohama E.

Division of Neuropathology, Faculty of Medicine, Tottori University, Yonago, Japan.

Amyotroph Lateral Scler Other Motor Neuron Disord 2000 Jun;1(3):163-84 Abstract quote

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. Approximately 5-10% of ALS is familial. Superoxide dismutase 1 (SOD1) gene mutations are shown to be associated with about 20% of familial ALS (FALS) patients. The neuronal Lewy-body-like hyaline inclusion (LBHI) and astrocytic hyaline inclusion (Ast-HI) are morphological hallmarks of certain SOD1-linked FALS patients with SOD1 gene mutant and transgenic mice expressing human SOD1 with G85R mutation. From the detailed immunohistochemical analyses, the essential common protein of both inclusions is SOD1.

Ultrastructurally, both inclusions consist of granule-coated fibrils 15-25 nm in diameter. Based on the immuno-electron microscopical finding that these abnormal granule-coated fibrils are positive for SOD1, the formation (or aggregation) of the abnormal fibrils containing SOD1 would be essential evidence in diseases caused by various SOD1 mutations. The granule-coated fibrils are also modified by advanced glycation end products (AGEs).

The AGEs themselves are insoluble molecules with direct toxic effects on cells. AGE formation of SOD1 composing the granule-coated fibrils (probable AGE-modified mutant SOD1) may amplify their aggregation and produce a more marked toxicity.

Pathological study of the diffuse myelin pallor in the anterolateral columns of the spinal cord in amyotrophic lateral sclerosis.

Hayashi S, Sakurai A, Amari M, Okamoto K.

Department of Neurology, Gunma University School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan.

Neurol Sci 2001 Jul 15;188(1-2):3-7 Abstract quote

An immunohistochemical study using a monoclonal antibody against macrophage (Ki-M1p) was performed to examine which fiber tracts are affected in the spinal cords and brainstems of ALS patients.

In 21 out of 30 ALS patients, various degrees of macrophage infiltration were observed diffusely in the anterolateral columns beyond the corticospinal tracts. On the other hand, a few macrophages were scattered in 20 non-ALS patients in the anterolateral columns outside the corticospinal tracts. In ALS brainstems, the macrophages were mainly localized in the corticospinal tracts. The result suggests that the diffuse myelin pallor in the anterolateral columns beyond the corticospinal tracts may be derived from intrinsic spinal cord lesions. Quantitative investigation using a monoclonal antibody against phosphorylated neurofilaments (SMI-31) revealed that the decrease in the numbers of small fibers would induce the diffuse myelin pallor in anterolateral columns of ALS patients.

From these findings, we propose that the propriospinal bundles are candidates for the degenerating fibers in the anterolateral columns of ALS.

VARIANTS  

Atypical amyotrophic lateral sclerosis with dementia mimicking frontal Pick's disease: a report of an autopsy case with a clinical course of 15 years.

Tsuchiya K, Ikeda K, Haga C, Kobayashi T, Morimatsu Y, Nakano I, Matsushita M.

Department of Laboratory Medicine and Pathology, Tokyo Metropolitan Matsuzawa Hospital, Japan.

Acta Neuropathol (Berl) 2001 Jun;101(6):625-30 Abstract quote

This report concerns an autopsy case of atypical amyotrophic lateral sclerosis (ALS) with dementia mimicking frontal Pick's disease.

The patient was a Japanese woman without hereditary burden who was 45 years old at the time of death. She developed abnormal behavior and amnesia at age 30, followed by disinhibition, aspontaneity, urinary incontinence, abulia, and rectal incontinence. Neurological signs compatible with ALS developed about 14 years after the disease onset. No respirator was used throughout the clinical course. Macroscopically, neuropathological examination showed atrophy of the frontotemporal lobes with accentuation in the convexities of the frontal lobes.

Histologically, there was neuronal loss in the cerebral cortex, parahippocampal gyrus, amygdala, caudate nucleus, substantia nigra, brain stem motor nuclei, and anterior horns of the spinal cord, in addition to marked degeneration of the pyramidal tracts. Ubiquitin-immunoreactive neuronal inclusions were present in the frontotemporal cortical layer II neurons and motor neurons in the brain stem and spinal cord. In the hippocampal dentate granular cells, many ubiquitin-immunoreactive neurites were present without ubiquitin-immunoreactive intraneuronal inclusions.

Based on these clinicopathological findings and a review of the literature, we concluded that our case was atypical ALS with dementia of long disease duration. We also note the possibility that motor neuron disease-inclusion dementia with a long clinical course may develop into ALS in the final stage of the illness.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
SPECIAL STAINS  
IMMUNOPEROXIDASE  

Copper chaperone for superoxide dismutase co-aggregates with superoxide dismutase 1 (SOD1) in neuronal Lewy body-like hyaline inclusions: an immunohistochemical study on familial amyotrophic lateral sclerosis with SOD1 gene mutation.

Kato S, Sumi-Akamaru H, Fujimura H, Sakoda S, Kato M, Hirano A, Takikawa M, Ohama E.

Division of Neuropathology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Yonago, Japan.

Acta Neuropathol (Berl) 2001 Sep;102(3):233-8 Abstract quote

The copper chaperone for superoxide dismutase (CCS) interacts with Cu/Zn-binding superoxide dismutase 1 (SOD1) specifically and delivers copper to SOD1.

To determine the role of the CCS-SOD1 interaction in the pathogenesis of SOD1-mutated familial amyotrophic lateral sclerosis (FALS) patients, we produced an affinity-purified rabbit antibody against CCS and investigated the immunohistochemical localization of both CCS and SOD1 in neuronal Lewy body-like hyaline inclusions (LBHIs) in the spinal cords of two FALS patients with a two-base pair deletion at codon 126 in the SOD1 gene and three FALS patients with an Ala to Val substitution at codon 4. The LBHIs in anterior horn cells from the five FALS patients showed identical immunoreactivities for CCS: the reaction product deposits with the antibody against CCS were generally restricted to the periphery of the core and halo-type LBHIs. The localizations of the immunoreactivities for CCS and SOD1 were similar in the inclusions: both CCS and SOD1 colocalized in neuronal LBHIs in the five mutant SOD1-linked FALS patients.

Our results suggest that the specific interaction and aggregation of CCS-SOD1 (probably CCS-mutant SOD1) in SOD1-mutated FALS patients may amplify the formation of inclusions and emphasize a more marked mutant SOD1-mediated toxicity.

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

Inclusion body myositis mimicking motor neuron disease.

Dabby R, Lange DJ, Trojaborg W, Hays AP, Lovelace RE, Brannagan TH, Rowland LP.

Neurological Institute, Columbia-Presbyterian Medical Center, Box 150, 710 W 168th St, New York, NY 10032, USA.

Arch Neurol 2001 Aug;58(8):1253-6 Abstract quote

OBJECTIVE: To describe the clinical and electrophysiologic features of patients with inclusion body myositis that was misinterpreted as motor neuron disease.

PATIENTS AND METHODS: We retrospectively retrieved the medical records of 70 patients with a pathologic diagnosis of inclusion body myositis. From this group, we selected those who had been first diagnosed as having motor neuron disease or amyotrophic lateral sclerosis. We reviewed the clinical, electrophysiologic, laboratory, and morphologic studies.

RESULTS: Nine (13%) of 70 patients with inclusion body myositis had been diagnosed as having motor neuron disease. Six of the 9 patients had asymmetric weakness; in 4 the distal arm muscles were affected. Eight patients had finger flexor weakness. Tendon reflexes were preserved in weak limbs in 6, hyperactive in 2, and absent in 1. Four patients had dysphagia. Fasciculation was seen in 2 patients. None had definite upper motor neuron signs or muscle cramps. Routine electromyographic studies showed fibrillation potentials and positive sharp waves in all 9. Fasciculation potentials were seen in 7 and long-duration polyphasic motor unit potentials were seen in 8. There was no evidence of a myogenic disorder in these 9 patients. Muscle biopsy was done because of slow progression or prominent weakness of the finger flexors and was diagnostic of inclusion body myositis. A quantitative electromyogram was myopathic in 4 of the 5 patients studied.

CONCLUSIONS: Inclusion body myositis may mimic motor neuron disease. Muscle biopsy and quantitative electromyographic analysis are indicated in patients with atypical motor neuron disease, especially those with slow progression or early and disproportionate weakness of the finger flexors.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSTIC FACTORS  

Respiratory muscle strength and ventilatory failure in amyotrophic lateral sclerosis.

Lyall RA, Donaldson N, Polkey MI, Leigh PN, Moxham J.

Respiratory Muscle Laboratory, Guys, Kings and St Thomas' School of Medicine, London UK.

Brain 2001 Oct;124(Pt 10):2000-13 Abstract quote

Although ventilatory failure is the most common cause of death in amyotrophic lateral sclerosis (ALS) and measurement of respiratory muscle strength (RMS) has been shown to have prognostic value, no single test of strength can predict the presence of hypercapnia reliably. RMS was measured in 81 ALS patients to evaluate the relationship between tests of RMS and the presence of ventilatory failure, defined as a carbon dioxide tension > or = 6 kPa.

We studied the predictive value of vital capacity (VC), static inspiratory and expiratory mouth pressures (MIP, MEP), maximal sniff oesophageal (sniff P(oes)), transdiaphragmatic (sniff P(di)) and nasal (SNP) pressure, cough gastric (cough P(gas)) pressure and transdiaphragmatic pressure after bilateral cervical magnetic phrenic nerve stimulation (CMS P(di)) to identify the risk of ventilatory failure in the whole group and in subgroups of patients with and without significant bulbar involvement. For patients without significant bulbar involvement, sniff P(di) had greatest predictive power [odds ratio (OR) 57] with specificity, sensitivity and positive and negative predictive values (PPV, NPV) of 87, 90, 74 and 95%, respectively Of the less invasive tests, per cent predicted SNP had greater overall predictive power (OR 25, specificity 85%, sensitivity 81%) than per cent predicted VC (9, 89%, 53%) and per cent predicted MIP (6, 83%, 55%). No test had significant predictive power for the presence of hypercapnia when used to measure RMS in a subgroup of patients with significant bulbar weakness. Thirty-five patients underwent polysomnography. CMS P(di), sniff P(di) and per cent predicted SNP were significantly correlated with the apnoea/hypopnoea index (AHI) (P = 0.035, 0.042 and 0.026, respectively). The correlations between AHI and per cent predicted MIP and VC were less strong (both non-significant).

In ALS patients without significant bulbar involvement, novel tests of RMS have greater predictive power than conventional tests to predict hypercapnia. In particular, the non-invasive SNP is more sensitive than VC and MIP, suggesting that it could usefully be included in tests of respiratory muscle strength in ALS and will be helpful in assessing the risk of ventilatory failure. In patients with significant bulbar involvement, tests of respiratory muscle strength do not predict hypercapnia. Sleep-disordered breathing is correlated with RMS and the novel tests of RMS having the strongest relationship with the degree of sleep disturbance.

TREATMENT  

Marijuana in the management of amyotrophic lateral sclerosis.

Carter GT, Rosen BS.

Muscular Dystrophy Association (MDA), Neuromuscular Disease Clinic, Department of Rehabilitation Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

Am J Hosp Palliat Care 2001 Jul-Aug;18(4):264-70 Related Articles, Books, LinkOut Marijuana in the management of amyotrophic lateral sclerosis. Carter GT, Rosen BS. Muscular Dystrophy Association (MDA), Neuromuscular Disease Clinic, Department of Rehabilitation Medicine, University of Washington School of Medicine, Seattle, Washington, USA. Marijuana has been proposed as treatment for a widening spectrum of medical conditions. Marijuana is a substance with many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, marijuana has now been shown to have strong antioxidative and neuroprotective effects, which may prolong neuronal cell survival. In areas where it is legal to do so, marijuana should be considered in the pharmacological management of ALS. Further investigation into the usefulness of marijuana in this setting is warranted.

The pathogenesis of ALS: implications for treatment strategies.

Silani V, Braga M, Cardin V, Scarlato G.

Institute of Neurology, University of Milan, Medical School, IRCCS Maggiore Hospital, Milano, Italy.

Neurol Neurochir Pol 2001;35(1 Suppl):25-39 Abstract quote

Besides the free radical hypothesis raised by the identification of Superoxide Dismutase I mutations in a subset of familiar Amyotrophic Lateral Sclerosis (ALS) patients, three etiopathogenic hypotheses for sporadic ALS, namely autoimmune, neurofilament, and glutamate toxicity, have attracted interest in the last few years.

The role of autoimmunity in ALS has been seriously questioned. The excitotoxic hypothesis for ALS spurred two clinical trials with riluzole. The results of both studies showed a modest benefit in prolonging survival that was statistically significant. Riluzole was the first drug made available for ALS patients. It began a new era in both basic and clinical research.

Various human recombinant neurotrophic molecules (CNTF, BDNF, IGF-I) were administered to ALS patients. IGF-I slowed the progression of functional impairment in patients with ALS with no adverse effects. The recent demonstration of the specific viral echovirus 7 RNA sequences in the spinal cord of ALS patients refocused research on the viral hypothesis of the disease and antiviral drugs are ready to be used in clinical settings.

New treatment strategies are today under study: intrathecal infusion with BDNF, intrathecal capsules for neurotrophic factor secretion or in vivo gene therapy using viral vectors. New research findings are, more than for other diseases, immediately transferred to clinical ground for the desperate need of a curative treatment of the patients affected by ALS.

Pharmacological treatment of ALS.

Munch C, Ludolph AC.

Department of Neurology, University of Ulm, Germany.

Neurol Neurochir Pol 2001;35(1 Suppl):41-50 Abstract quote

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from chronic and selective loss of motor neurons in the brain and spinal cord. In 1993, the etiology of ALS has been clarified for a small sub-group of patients with an autosomal-dominant form of this disease. About 10 percent of familial ALS patients have been associated with more than 50 mutations of the gene of the Cu/Zn superoxide dismutase (SOD1). Mutations in the SOD1 gene account for 1 percent of all ALS patients and have therefore limited epidemological and clinical relevance; however, they are of fundamental importance for the understanding of the ALS pathogenesis, and the development of neuroprotective strategies.

In two double-blind and placebo-controlled studies the membrane stabilisator riluzole has been shown to be the first neuroprotective compound with a significant effect on survival of ALS patients. The neuroprotective approach reduced therapeutic nihilism in ALS and is a first step in the treatment of this devastating disease.

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Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.


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Basic Principles of Disease
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