Proton magnetic resonance spectroscopy and transcranial magnetic stimulation for the detection of upper motor neuron degeneration in ALS patients

Transcranial magnetic stimulation (TMS) was compared to proton magnetic resonance spectroscopy (¹H-MRS) for the detection of upper motor neuron loss or dysfunction in 49 ALS patients classified according to the El Escorial criteria. Abnormal NAA/Cho ratios were detected in 53% of ALS patients. Abnormal TMS results (i.e. cortical inexcitability or prolonged CMCT's) were obtained in 63% of ALS patients. If one or both methods were considered for diagnosis of upper motor neuron degeneration/dysfunction, the percentage of abnormal findings was 77%, whilst in 39% of all patients both methods produced abnormal results. Compared to TMS, ¹H-MRS detected more patients with upper motor neuron involvement in the suspected El Escorial subgroup (42% versus 25%), whereas TMS detected more patients with upper motor neuron involvement in the possible (81% versus 50%), probable (71% versus 57%) and definite El Escorial subgroup (71% versus 64%). We conclude that the combined use of ¹H-MRS and TMS increases diagnostic accuracy for the detection of upper motor neuron involvement in ALS patients.     

Clinically definite ALS presenting weeks after mild electric injury: causality or coincidence?

Motor neuron syndromes including typical ALS develop very rarely after electrotrauma, with possible causality discussed but not confirmed. We report on a 44-year-old male who developed clinically definite ALS by the revised El Escorial criteria with onset weeks after mild electric injury. He presented with asymmetric upper limb amyotrophy and weakness beginning around the entry point of the current. Over 1?year he developed generalized wasting, weakness and fasciculations, including the bulbar and thoracic muscles, with prominent spasticity and pyramidal tract signs. Electrodiagnostic studies confirmed widespread denervation, very unstable neurogenic motor units in the bulbar, cervical, thoracic and lumbosacral segments with normal motor velocities and normal sensory parameters. This is a well-documented case of fast-progressive ALS that seems related to electric injury.     

Electrodiagnostic criteria for diagnosis of ALS.

A consensus meeting was held to determine the best use and interpretation of electrophysiological data in the diagnosis of ALS. The utility of needle EMG and nerve conduction studies was affirmed. It is recommended that electrophysiological evidence for chronic neurogenic change should be taken as equivalent to clinical information in the recognition of involvement of individual muscles in a limb. In addition, in the context of a suspected clinical diagnosis of ALS, fasciculation potentials should be taken as equivalent to fibrillation potentials and positive sharp waves in recognising denervation. The importance of searching for instability in fasciculation potentials and in motor unit potentials in ALS is stressed. These changes in the interpretation of electrophysiological data render obsolete the category Probable Laboratory-Supported ALS in the modified El Escorial diagnostic criteria for ALS. Methods for detection of upper motor neuron abnormality appear sensitive but require further study, particularly regarding their value when clinical signs of upper motor neuron lesion are uncertain.     

Predictors of delay in the diagnosis and clinical trial entry of amyotrophic lateral sclerosis patients: a population-based study

BACKGROUND: The El Escorial and the revised Airlie House diagnostic criteria for amyotrophic lateral sclerosis (ALS) were introduced to select patients for clinical trials. Heterogeneity of clinical presentation at onset and delay in diagnosis may decrease the likelihood for trial entry. OBJECTIVE: Identify risk factors for delay in the diagnosis and trial exclusion. METHODS: ALS incident cases were identified with El Escorial (EEC) and Airlie House criteria (AHC) through a population-based registry established in Puglia, Southern Italy, in the years 1998-99. RESULTS: 130 ALS incident cases were diagnosed with a median interval between onset of symptoms and diagnosis of 9.3 months and not different across both EEC and AHC categories. Twenty percent of cases were not eligible for clinical trials according to the AHC. About 5% of subjects in this series died with only lower motor neuron signs. Predictors for delay in the diagnosis were age between 65 and 75 years and spinal onset while fasciculations and cramps as first symptoms were predictors of exclusion from trials. CONCLUSIONS: In this population-based series, diagnostic delay was longer in subjects with spinal onset and age between 65 and 75 and fasciculation as first symptoms. About 80% of incident cases were trial eligible with AHC criteria. However, a significant number of subjects with ALS, characterized by a limited spread of signs, were not trial eligible while alive.     

p.N345K mutation in TARDBP in a patient with familial amyotrophic lateral sclerosis: An autopsy case

We report the neuropathology of a patient with a family history of amyotrophic lateral sclerosis (ALS) and a p.N345K mutation in the transactivation response DNA‐binding protein 43 kDa (TDP‐43) gene (TARDBP). A 62‐year‐old man had bulbar palsy with progressive weakness in the extremities. Neurological examination revealed evident upper motor neuron signs and lower motor neuron involvement corroborated by needle electromyography. The patient was diagnosed as having probable ALS according to the revised El Escorial diagnostic criteria and was eventually diagnosed with familial ALS. At 65 years of age, respiratory failure became critical, and artificial ventilation was initiated. At 70 years of age, the patient died from a urinary tract infection. Histopathological investigation showed Bunina bodies in the remaining motor neurons and anterolateral funicular myelin pallor in the spinal cord. TDP‐43‐positive cytoplasmic inclusions were quite rare in the spinal cord motor neurons, being predominantly present in the glial cells (especially astrocytes) of the spinal cord anterior horn. Although the reason for the preferential vulnerability of spinal glial cells to TARDBP mutations remains unclear, our findings indicate that TARDBP p.N345K mutation could have an influence on the topography of TDP‐43 aggregation.     

Upper motor neuron involvement in amyotrophic lateral sclerosis evaluated by triple stimulation technique and diffusion tensor MRI

The objective of this study was to evaluate the diagnostic value of triple stimulation technique (TST) and diffusion tensor imaging (DTI) tractography as markers of upper motor neuron (UMN) degeneration in amyotrophic lateral sclerosis (ALS). Fourteen ALS patients fulfilling the El Escorial criteria and 30 control subjects participated in the study. TST amplitude and area ratio were used as an estimate of the degree of central motor conduction failure. DTI fractional anisotropy was used as a quantitative measure of the structural integrity of the corticospinal tract and the posterior limb of the internal capsule. Mean TST amplitude and area ratio were lower in patients than controls, while there were no differences in mean fractional anisotropy of the corticospinal tract or the posterior limb of the internal capsule. TST was abnormal in 7/13 patients (sensitivity 54 %) and DTI was abnormal in 3/12 (sensitivity 25 %). Combining TST and DTI disclosed abnormalities in 8/11 patients (sensitivity 73 %). TST confirmed UMN degeneration in one of every 2.25 patient in the diagnostic categories lower than ‘probable’ ALS. Using results from TST as a criterion for UMN degeneration, four patients in diagnostic categories lower than ‘probable’ ALS and without clinical signs of UMN degeneration in the cervical region increased in diagnostic category. Our findings indicate that TST has a significant diagnostic value as an early objective marker of UMN degeneration in ALS, while the value of DTI analysis seems limited.     

Amyotrophic lateral sclerosis associated with extrapyramidal symptoms or signs]

This investigation was conducted to clarify the frequency and characteristics of ALS associated with extrapyramidal symptoms or signs in Wakayama prefecture. The questionnaires to survey ALS cases were mailed to all medical centers in Wakayama prefecture. A total of 252 cases were found to have motor neuron diseases. Among them, 204 cases fulfilled probable or definite according to El Escorial Criteria. In 10 of them, extrapyramidal signs were identified as follows: rigidity 50%, tremor 40% and akinesia 10%. Family history of ALS in these cases (20%) is higher than expected in usual ALS, and all of them are negative for SOD-1 mutation. Dementia and autonomic nervous symptoms were observed in several cases. Incidence of extrapyramidal signs in ALS resulted in 4.8%. The incidence of extrapyramidal signs is more frequent than expected by chance, suggesting that the degeneration of basal ganglia and/or substantia nigra may not be so rare in ALS.     

Challenges in diagnosis of motor neuron disease: A case series of ALS mimic syndromes

Amyotrophic lateral sclerosis (ALS) is most often a sporadic disorder that affects both upper and lower motor neurons. Because the prognosis of ALS is uniformly poor compared to other motor neuron disorders, defining the diagnosis can help guide appropriate clinical management and improve quality of life for patients. However, the diagnosis of ALS is often challenging and there may be overlapping clinical features with other rare diseases. We present four patients who were referred to our center because of the clinical suspicion of ALS, in whom more detailed assessments revealed an alternative diagnosis, and we discuss the limitations of the modified-El Escorial criteria.     

The role of cranial and thoracic electromyography within diagnostic criteria for amyotrophic lateral sclerosis

Introduction: The contribution of cranial and thoracic region electromyography (EMG) to diagnostic criteria for amyotrophic lateral sclerosis (ALS) has not been evaluated. Methods: Clinical and EMG data from each craniospinal region were retrospectively assessed in 470 patients; 214 had ALS. Changes to diagnostic classification in Awaji‐Shima and revised El Escorial criteria after withdrawal of cranial/thoracic EMG data were ascertained. Results: Sensitivity for lower motor neuron involvement in ALS was highest in the cervical/lumbar regions; specificity was highest in cranial/thoracic regions. Cranial EMG contributed to definite/probable Awaji‐Shima categorization in 1.4% of patients. Thoracic EMG made no contribution. For revised El Escorial criteria, cranial and thoracic data reclassified 1% and 5% of patients, respectively. Conclusion: Cranial EMG data make small contributions to both criteria, whereas thoracic data contribute only to the revised El Escorial criteria. However, cranial and thoracic region abnormalities are specific in ALS. Consideration should be given to allowing greater diagnostic contribution from thoracic EMG. Muscle Nerve 54 : 378–385, 2016     

Primary lateral sclerosis: further clarification

Primary lateral sclerosis (PLS) has been defined as a rare. Non-hereditary disease characterized by progressive spinobulbar spasticity, related to the exclusive involvement of precentral pyramidal neurons, with secondary pyramidal tract degeneration and a preservation of anterior horn motor neurons, the latter allowing PLS to be distinguish from amyotrophic lateral sclerosis (ALS). However, a clear distinction between the two diseases remains a subject of debate. With this in mind, we assessed patients with meeting the previously published criteria for PLS in a prospective, longitudinal study.At regular intervals, we analyzed various clinical and electrophysiological parameters in nine patients with a diagnosis of PLS. We made a deltoid muscle biopsy and PET study.Our results provide evidence that degeneration in PLS is not restricted to the upper motor neurons but also affects the lower motor neurons. The distinction between ALS and PLS is related to the degree and stability of lower motor neuron involvement.In view of the similarities with ALS, we consider that PLS may represent a slowly progressive syndrome closely related to this disease.     

Reliability of the El Escorial diagnostic criteria for amyotrophic lateral sclerosis

BACKGROUND: The El Escorial diagnostic criteria are the most commonly used in clinical studies and therapeutic trials in patients with amyotrophic lateral sclerosis (ALS). The accuracy of the El Escorial criteria was tested in clinical practice, but the reliability is unknown when the diagnosis of ALS must be assessed on the basis of medical records. OBJECTIVE: To assess the reliability of the El Escorial criteria for the diagnosis of ALS in different settings. DESIGN AND METHODS: Semistructured forms were used to include the main diagnostic information on 20 patients with definite (n = 6), probable (n = 6), possible (n = 6), and suspected ALS (n = 2) and 19 patients with clinical conditions considered in the differential diagnosis. Agreement was tested by comparing the diagnosis made by the attending physician (the 'gold standard') with that of 4 raters with different backgrounds: a teaching neurologist with research and practical experience in the field of motor neuron disorders, a neurologist with specific interest in motor neuron disorders and neurophysiological background, a neurophysiologist, and a general neurologist with only occasional ALS patients. Sources of disagreement were discussed and the agreement was tested further on the medical records of 98 additional cases taken from an ongoing ALS registry. Eight additional cases (ALS: 4; other conditions: 4) were examined directly by the 4 raters. RESULTS: The interrater agreement on the medical records was poor (overall kappa 0.05-0.29). When the differential diagnosis was made between ALS (all diagnostic levels) and other conditions, interrater agreement was at best modest, with moderate variations when raters were compared in pairs (kappa 0.03-0.58) and when each rater was compared with the physician (kappa 0.27-0.51). Agreement was higher after direct examination of the patients (kappa 0.33-1) and increased significantly on the medical records after training (overall kappa 0.52-0.79). However, concordance was low (overall kappa 0.08-0.36), even after training, at the lowest diagnostic level (definite to suspected ALS vs. other conditions). CONCLUSIONS: The El Escorial criteria are a poor diagnostic indicator when patients' records are examined. Although medical education significantly improves the reliability of the criteria, concordance is still modest when the diagnosis includes suspected ALS.     

Parkinsonism and motor neuron diseases: Twenty‐seven patients with diverse overlap syndromes

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 forparkinsonism. A prospective study may elucidate this possibility. © 2010 Movement Disorder Society.     

Early diagnosis of ALS: the search for signs of denervation in clinically normal muscles

AIM AND METHODS: We prospectively investigated whether early diagnosis of amyotrophic lateral sclerosis (ALS) could be facilitated by demonstrating signs of denervation in a muscle of a clinical and electromyographical unaffected region. Muscle fibre conduction velocity (MFCV) was determined in 18 patients in whom the diagnosis ALS was considered but not established beyond a level of clinically possible ALS according to the revised El Escorial criteria. A muscle biopsy was obtained from the same muscle, to demonstrate neurogenic changes. The study followed the guidelines from the STARD initiative. RESULTS AND CONCLUSION: Results were analysed with respect to the final diagnosis. After a mean follow-up of 16 months, 9 patients developed probable or definite ALS. Sensitivity of abnormal MFCV for developing ALS was 89%. Muscle biopsy confirmed that denervation was the cause of abnormal MFCV. We concluded that MFCV can be used to detect denervation in muscles that show no clinical or electromyographical signs of lower motor neuron disease, and thus may contribute to early diagnosis of probable laboratory-supported ALS.     

Amyotrophic lateral sclerosis with prolonged survival and degeneration of the spinocerebellar tracts,substantia nigra and dentatorubral system

We report on a case of sporadic amyotrophic lateral sclerosis (ALS) with prolonged, respirator-assisted survival and clinical signs limited to the upper and lower motor neuron systems. Autopsy revealed degeneration of the upper and lower neuron systems and Bunina bodies, both characteristic of ALS. In addition, we found degeneration of the spinocerebellar tracts, the substantia nigra and the dentatorubral system. Our case is an additional example of multisystem degeneration in ALS associated with prolonged, respirator-assisted survival. These findings suggest that sporadic ALS comprises heterogeneous subgroups with patterns of degeneration that depend, in part, on survival time.     

Les critères d’Awaji : les nouveaux critères diagnostiques de la sclérose latérale amyotrophique

Amyotrophic lateral sclerosis is the most common motor neuron disorder in adults. Although the diagnosis appears obvious in theory, clinical practice shows the contrary as diagnosis is delayed in many patients; the average time between symptom onset and diagnosis can reach 12 months. The delay can be explained by the variability of the clinical presentation and by the absence of diagnostic markers. In order to standardize diagnosis for enrolment in clinical research, diagnostic criteria for ALS were created and revisited during the last 20 years. In 2006, the Awaji criteria for the diagnosis of ALS were proposed, adding two major points to the diagnostic criteria: electromyography is considered equivalent to clinical examination for the identification of LMN signs and fasciculation potentials resume their prominent place in the diagnosis. Comparisons of the accuracy of the revisited El Escorial and Awaji criteria support improved diagnostic sensitivity without any effect on specificity with the new classification. The only weakness of the new classification involves patients with UMN signs in one region and LMN in two regions; these patients were previously classified as laboratory-supported probable ALS and currently as possible ALS, a lower level of diagnostic certainty. In all other instances the accuracy appears to be improved by the Awaji criteria. Nevertheless, there is a body of evidence suggesting the need for a revision of these new criteria, giving more weight to clinical and complementary findings of UMN involvement. The need to diagnose and treat ALS quickly could be facilitated by the inclusion of complementary investigations that detect UMN signs.     

Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP-43 proteinopathy

Motor neuron disease (MND) may present as an isolated lower motor neuron (LMN) disorder. Although the significance of pathological 43 kDa transactive responsive sequence DNA binding protein (TDP-43) for amyotrophic lateral sclerosis (ALS) was appreciated only recently, the topographical distribution of TDP-43 pathology in MND clinically isolated to the LMN versus normal controls (COs) is only incompletely described. Therefore, we performed longitudinal clinical evaluation and retrospective chart review of autopsied patients diagnosed with isolated LMN disease. Cases with a disease duration over 4 years were designated as progressive muscular atrophy (PMA), and those with a more rapid course as MND/LMN. Immunohistochemistry was employed to identify neuronal and glial TDP-43 pathology in the central nervous system (CNS) in patients and COs. We examined 19 subjects including six patients (i.e., four with MND/LMN and two with PMA) and 13 COs. All patients showed significant TDP-43 linked degeneration of LMNs, and five cases showed a lesser degree of motor cortex degeneration. Additional brain areas were affected in varying degrees, ranging from predominantly brainstem pathology to significant involvement of the whole CNS including neocortical and limbic areas. Pathological TDP-43 was present only rarely in the CO group. We conclude that MND limited to the LMN and PMA is part of a disease continuum that includes ALS and FTLD-TDP, all of which are characterized by widespread TDP-43 pathology. Hence, we suggest that the next revision of the El Escorial criteria for the diagnosis of ALS include MND patients with disease clinically limited to the LMN and PMA as variants of ALS, which like classical ALS, are TDP-43 proteinopathies.     

Upper motor neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis: A clinical and brain imaging review

There is an ongoing discussion whether ALS is primarily a disease of upper motor neurons or lower motor neurons. We undertook a review to assess how new insights have contributed to solve this controversy. For this purpose we selected relevant publications from 1995 onwards focussing on (1) primary targets and disease progression in ALS and variants of ALS, (2) brain imaging markers for upper motor neuron lesion, and (3) evidence for ALS being a multisystem disorder. Clinically, upper motor and lower motor neuron symptoms can occur in any order over time. Brain imaging markers show upper motor neuron involvement in early disease. Overlap syndromes of ALS and dementia, and involvement of autonomic and sensory nerves occur frequently. PET/SPECT scans, functional MRI and voxel based morphometry studies clearly show abnormalities in extra-motor areas of the brain. Pathologically, the 43 kDa TAR DNA-binding protein (TDP-43) provides a clue to these overlapping disorders. In conclusion, evidence accumulates that ALS is a multisystem disorder rather than a pure lower and/or upper motor neuron disorder.     

Motor neuron disease with predominantly upper extremity involvement: a clinicopathological study

We report two autopsy cases of motor neuron disease (MND) patients with an unusual type of muscular atrophy predominantly affecting the shoulder girdle and the upper extremities with proximal dominance. Both patients are considered to be clinically categorized into the El Escorial suspected form of amyotrophic lateral sclerosis (ALS). At autopsy, they showed marked loss of spinal anterior horn cells accompanied by astrogliosis positively immunostained with anti-glial fibrillary acidic protein antibody at the cervical level. At the lumbosacral level, anterior horn neurons were relatively well preserved and Bunina bodies, ubiquitin-positive skein-like inclusions and Lewy body-like inclusions were observed in the remaining neurons. In one patient, brain stem motor neurons (nerves V, VII, XII) and motor cortex, including Betz cells, were also affected and the corticospinal tracts were degenerated at the level of the thoracic and lumbar spinal cord. Pathological findings of this patient are consistent with those of ALS. In the other patient, the motor cortex, brain stem motor nuclei and the corticospinal tracts were well preserved, which is pathologically compatible with progressive spinal muscular atrophy. These patients with such a peculiar pattern of progressive muscular atrophy should be placed in a subgroup of ALS. Received: 14 January 1999 / Revised, accepted: 6 April 1999     

Lowered cerebral glucose utilization in amyotrophic lateral sclerosis

Regional cerebral metabolic rates for glucose (rCMRGlc) were analyzed in 19 studies of 12 patients with amyotrophic lateral sclerosis (ALS) by positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose. In the 8 ALS patients with upper motor neuron signs, the mean cortical rCMRGlc was significantly lower than in 11 age-matched control subjects (p less than 0.01). The degree of hypometabolism correlated with the duration of the clinical signs and extended throughout the cortex and basal ganglia, but not to the cerebellum. Of the 4 such patients who had repeat PET scans, 3 demonstrated significant subsequent reduction in the rCMRGlc, corresponding to the worsening of the clinical picture. In contrast, 4 ALS patients with disease confined to lower motor neurons and 3 patients with lower motor neuron disease from old paralytic poliomyelitis had normal or near-normal rCMRGlc throughout the brain. Because histological evidence shows no generalized neuronal cell loss in the cortex of ALS patients, including in some cases the primary motor regions, the demonstration of severe generalized hypometabolism in structurally normal cortex indicates that some cortical neurons exist in a state of neuronal nonfunction, rather than cell death, and that anatomoclinical correlations may be more complex. The data also indicate that ALS with upper motor neuron involvement extends beyond the corticospinal tracts and differs in cortical function from the ALS confined to lower motor neurons or the other lower motor neuron disorders.