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

University of Milan, Milano, Lombardy, Italy
Journal of the Neurological Sciences (Impact Factor: 2.47). 01/2007; 250(1-2):45-9. DOI: 10.1016/j.jns.2006.06.027
Source: PubMed


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.
Identify risk factors for delay in the diagnosis and trial exclusion.
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.
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.
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.

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    • "Bulbar presentation was associated with a shorter time to diagnosis [4] [8] [9]. We suggest that this implies recognition that bulbar symptoms are not derived from spinal cord or root lesions; indeed, neurologists associate progressive bulbar weakness as typically suggestive of ALS. "
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    ABSTRACT: We studied the limitations to early diagnosis in amyotrophic lateral sclerosis (ALS). The diagnostic process was assessed in 120 consecutive patients, including onset, interval to diagnosis, investigations, specialist assessment and pre-diagnostic management. Times from onset to first consultation (T1), second consultation (T2) and diagnosis (TD) were considered. Predictors of diagnostic delay were determined by multivariate logistic regression, adjusted for gender, age, clinical manifestations, and specialism of the first and second consultants. There were 101 consecutive ALS patients with complete datasets (69% men; median age at diagnosis 61.5 years). The mean TD and median TD were respectively 10.1 and 9.5 months. In 55%, the first consultant was a general practitioner (GP), in 16% a neurologist and in 14% an orthopedist. The diagnosis of ALS was made by non-neurologists in 9 patients. The odds of delayed diagnosis (≥ 12 months) were higher (1.56; 0.19–12.56) in younger patients (≤ 45 years) (p < 0.05). Female gender (0.56; 0.29–1.70) and bulbar-onset (0.56; 0.29–1.70) were independently associated with earlier diagnosis (p < 0.05). Assessment by a neurologist at the first (0.32; 0.19–2.46) or second consultation (0.87; 0.21–1.21) was associated with a shorter diagnosis time (< 12 months) (p < 0.05). We conclude that diagnostic delay mainly resulted from delayed referral from non-neurologist physicians to a neurologist. Moreover, incomplete neurophysiological investigation had a relevant impact.
    Full-text · Article · Aug 2014 · Journal of the Neurological Sciences
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    • "Signs of central motor neuron degeneration are often difficult to detect in clinical practice, justifying the interest for objective neuroimaging markers of upper motor neuron (UMN) involvement. It has been estimated that clinical UMN signs are absent at first examination in 7 to 10% of patients who further develop full-blown ALS [3, 4]. The diagnostic delay is increased in patients who present isolated lower motor neuron (LMN) signs [3]. "
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    ABSTRACT: Neuroimaging allows investigating the extent of neurological systems degeneration in amyotrophic lateral sclerosis (ALS). Advanced MRI methods can detect changes related to the degeneration of upper motor neurons but have also demonstrated the participation of other systems such as the sensory system or basal ganglia, demonstrating in vivo that ALS is a multisystem disorder. Structural and functional imaging also allows studying dysfunction of brain areas associated with cognitive signs. From a biomarker perspective, numerous studies using diffusion tensor imaging showed a decrease of fractional anisotropy in the intracranial portion of the corticospinal tract but its diagnostic value at the individual level remains limited. A multiparametric approach will be required to use MRI in the diagnostic workup of ALS. A promising avenue is the new methodological developments of spinal cord imaging that has the advantage to investigate the two motor system components that are involved in ALS, that is, the lower and upper motor neuron. For all neuroimaging modalities, due to the intrinsic heterogeneity of ALS, larger pooled banks of images with standardized image acquisition and analysis procedures are needed. In this paper, we will review the main findings obtained with MRI, PET, SPECT, and nuclear magnetic resonance spectroscopy in ALS.
    Full-text · Article · Apr 2014 · BioMed Research International
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    • "However, because NIV is established in palliative care in ALS [9,10], ethical aspects have to be considered in randomized study designs, especially if the initiation of NIV is somehow blinded. Moreover, the diagnosis of ALS is often delayed and the patients often have reduced ventilation capacity at the time of diagnosis [22,25]. We saw this in our patients as the median time from the first symptoms until diagnosis ranged from 11 to 13 months (Table 1). "
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    ABSTRACT: Background Hypoventilation due to respiratory insufficiency is the most common cause of death in amyotrophic lateral sclerosis (ALS) and non-invasive ventilation (NIV) can be used as a palliative treatment. The current guidelines recommend performing spirometry, and recording nocturnal oxyhemoglobin saturation and arterial blood gas analysis to assess the severity of the hypoventilation. We examined whether the respiratory rate and thoracic movement were reliable preliminary clinical signs in the development of respiratory insufficiency in patients with ALS. Methods We measured the respiratory rate and thoracic movement, performed respiratory function tests and blood gas analysis, and recorded subjective hypoventilation symptoms in 42 ALS patients over a 7-year period. We recommended NIV if the patient presented with hypoventilation matching the current guidelines. We divided patients retrospectively into two groups: those to whom NIV was recommended within 6 months of the diagnosis (Group 1) and those to whom NIV was recommended 6 months after the diagnosis (Group 2). We used the Mann Whitney U test for comparisons between the two groups. Results The mean partial pressure of arterial carbon dioxide in the morning in Group 1 was 6.3 (95% confidence interval 5.6–6.9) kPa and in Group 2 5.3 (5.0–5.6) kPa (p = 0.007). The mean respiratory rate at the time of diagnosis in Group 1 was 21 (18–24) breaths per minute and 16 (14–18) breaths per minute in Group 2 (p = 0.005). The mean thoracic movement was 2.9 (2.2–3.6) cm in Group 1 and 4.0 (3.4–4.8) cm in Group 2 (p = 0.01). We observed no other differences between the groups. Conclusions Patients who received NIV within six months of the diagnosis of ALS had higher respiratory rates and smaller thoracic movement compared with patients who received NIV later. Further studies with larger numbers of patients are needed to establish if these measurements can be used as a marker of hypoventilation in ALS.
    Full-text · Article · Dec 2012 · BMC Palliative Care
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