C37 REGIONAL DIFFERENCES BETWEEN LONG AND SHORT SURVIVORS IN ALS
Katz JS1, Malone SL3, Oore DH2, Anderson F3, Miller RG1 & CARE Study Group ALS1
1California Pacific Medical Center, San Francisco, 2University of California San Francisco, San Francisco, and 3Univeristy of Massachusetts School of Medicine, Worcester, USA
E‐mail address for correspondence: [email protected]
Background: Prognostic factors known to predict poor survival in ALS include older age, bulbar onset, reduced forced vital capacity, low scores on ALSFR‐S, and short time period from symptom onset to diagnosis. In contrast, predictors of long survival are not well‐characterized. Discussion of longer survival has generally been limited to reports of specific regional presentations, such as in brachial amyotrophic diplegia, where long‐term survival can occur.
Objectives: To characterize features of long and short survivors in ALS using a large North American patient database.
Methods: The ALS Patient Care Database is the largest prospectively designed, clinically confirmed database of patients with ALS. It was created, in part, to measure outcomes in this disorder. For this study, we defined short survival in ALS as death within one year of symptom onset and long survival as death more than five years after symptom onset (without requiring ventilator support) or patients who are still alive, without ventilator support more than five years after onset. We queried the database to determine clinical features as close to the time of presentation as possible. Thus, we excluded long survivors who did not have at least one available data form from within two years after disease onset. We compared the clinical features of short survivors (SS) and long survivors (LS) and characterized key features of the long survivors.
Results: Of 5877 patients in the database, 1809 were known to have died as of the index date. Approximately 6% (101 patients) had survived for less than one year of onset and 18% more than five years. After the addition of still‐surviving patients and exclusions, there were 86 long survivors (5.1–8.8 years). LS were more likely to have possible ALS by El Escorial criteria (LS: 15.4%, SS: 2.2%). Among LS, difficulty with climbing stairs was the most common functional abnormality (ALSFR‐S), followed by difficulty walking and dressing. In contrast, more than 90% of the longest survivors reported little or no difficulty using BiPAP and swallowing. Short survivors were older (SS: 66.5, LS 54.6 years); had decreased FVC (SS: 56% of predicted, LS: 87%); and had lower ALSFR‐S scores (SS: 26.5/40, LS 33/40). No differences were found in gender, chance of having only UMN symptoms, or having only LMN symptoms.
Conclusions: A new finding of this study is that among LS, difficulty climbing stairs and walking, along with consistently normal bulbar function and swallowing may indicate relatively isolated lower limb involvement. The high frequency of possible ALS in this group also points to a favourable prognosis for isolated regional presentations. Our findings also confirm earlier studies showing respiratory dysfunction, low ALSFR‐S scores, and older age is associated with short survival. Prospective studies will determine how strongly these findings predict long survival in other patient cohorts. Future studies on prognosis may benefit from a focus on the rate of spread between regions in addition to the rate of progression.
C38 KENNEDY'S DISEASE: A CLINICAL AND FUNCTIONAL STUDY IN 44 PATIENTS
Salachas F1, Jafari‐Schluep H1, Maisonobe T1, Pradat PF1, Bruneteau G1, Le Forestier N1, Cymard B1, Leguern E1, Camu W2 & Meininger V1
1Hopital de la Salpetriere, Paris, and 2CHU, Montpellier, France
E‐mail address for correspondence: [email protected]
Background: Kennnedy's disease is a lower motor neuron disease which is recessively inherited, in male patients, due to an abnormal expansion of CAG repeat in the first exon of the androgen receptor gene located on the X chromosome. Since the description of bulbo‐spinal muscular atrophy in 1968 by Kennedy et al., the clinical hallmarks of this slowly progressing sensori‐motor neuronopathy have been better characterized. However, little is known about disease onset modalities, functional status, rate of increasing weakness and life expectancy.
Objectives: To present clinical, functional, biological and neurophysiological data of 44 patients with Kennedy's disease (KD).
Methods: Forty‐four patients seen in the Paris ALS centre have been extensively studied. They underwent neurological examination, functional rating, neuropsychological testing, biological and electrophysiological studies and molecular analysis. Statistical analysis was performed to look for relationships between time of onset, muscle function decline and size of CAG repeat.
Results: Mean age at the time of diagnosis was 56.8 years. The mean age at onset was 45.4 years. The main symptoms leading the patient to see their physician were lower limb muscle weakness and cramps; 74.2% of patients had abnormal sensory nerve potentials. No correlation was observed between the age of onset, disease duration, and the size of the polyglutamine tract. The functional rating scales routinely used in ALS therapeutic trials such as the ALSFR‐S were not appropriate in this disease because of the slow rate of decline in muscle function. Other scales used in multiple sclerosis have been used to monitor the progression of the disease.
Discussion and conclusions: KD is a rare, slowly progressive, motor neuron disease whose natural history remains unclear. Collecting data on muscle function decline is a first step in disease understanding and will help to design appropriate therapeutic trials.
C39 EARLY‐ONSET ALS WITH ‘SPASTIC PHENOTYPE’: A DISTINCT ENTITY?
Sabatelli M, Conte A, Madia F, Mereu ML, Loria G & Tonali P
Catholic University, Rome, Italy
E‐mail address for correspondence: [email protected]
Background and objectives: Although the great majority of ALS patients disclose a stereotyped clinical picture, noticeable heterogeneity exists regarding the age of onset, initial clinical manifestations and outcome. Most studies show that the age‐specific incidence in sporadic ALS is very low in the third and forth decades and then markedly increases reaching a peak between 55 and 75 years. ALS occurs predominantly in males, with a male to female ratio of 1.4–1.7, but in ALS patients with onset of the disease before the age of 40 years this ratio is strikingly higher. Age of onset represents an important prognostic factor, survival being significantly longer in those patients with onset age less than 50 years compared to those with onset age in the sixth‐eighth decades. Better prognosis in younger patients is explained on the basis of greater neuronal reserve with respect to older patients. There are very few reports in the literature concerning early‐onset ALS. The aim of our study was to investigate the clinical features and the long‐term follow‐up of a group of ALS patients with an onset before the age of 40 years in order to establish whether early‐onset represents a distinctive feature of an ALS subtype.
Methods: Three hundred and eighty‐six ALS patients were observed in our Neurological Institute from 1987 to 2005. Forty‐five ALS patients (11%) had an onset of the disease before the age of 40 years and were included in the study. These patients were followed for a mean period of 52.4 months (range 7–146 months)
Results: The age of onset ranged from 22 to 40 years. There were 37 males and eight females with a male to female ratio of 4.6:1. Seventeen of the 45 patients (38%) had the ‘classic’ clinical pattern with predominant lower motor neuron (LMN) signs and moderate pyramidal signs. The male to female ratio was 18:1. Eight patients died or underwent tracheostomy after a mean period of 47.2 months (range 18–106 months) from the onset. Nine patients are alive with a mean duration of disease of 34 months (range 7–91 months).
The remaining 28 patients (62%) disclosed a quite distinct clinical picture characterized, in the initial phases of the disease, by the following features: 1) Pyramidal signs were a striking feature, with a marked spastic paraparesis, brisk reflexes, pseudobulbar speech; 2) LMN signs (weakness, atrophy and fasciculations) were noticeable in the forearms and hands on both sides, but were scanty in the proximal upper limb muscles and in the lower limbs; 3) Respiratory muscles were involved late in the course of the disease. The male to female ratio was 13:1. All patients showed a clearly progressive course: 12 patients died or underwent tracheostomy after a mean of 53 months (range 14–74) from the onset. Sixteen patients are still alive with a mean duration of disease of 64.8 months (range 9–146 months). In the late stages of the disease LMN signs were clearly present in all four limbs and in the tongue
Conclusions: Patients with young‐onset ALS show two different phenotypes. In a first group of patients' clinical manifestations, male/female ratio and outcome are similar to those observed in the ‘classic’ form. A second group of patients has a stereotyped clinical picture, which appears to be an intermediate form between primary lateral sclerosis and classic ALS. These patients represent the majority of early‐onset ALS (62%) and disclose an unusual male predominance. The duration of the disease is significantly longer than that observed in ALS with an onset after 40 years. Based on these data the hypothesis that young‐onset ALS with the ‘spastic phenotype’ is a distinct entity should be taken in account.
C40 FURTHER INSIGHTS INTO HSP AND SPASTIN: SEVERE COMPLICATED PHENOTYPES, DOUBLE MUTATIONS AND EVIDENCE OF LOWER MOTOR NEURON DYSFUNCTION
McDermott CJ1, Burness CE1, Rao G1, Kirby J1, Dalton A2 & Shaw PJ1
1Academic Neurology Unit, University of Sheffield, Sheffield, and 2North Trent Molecular Genetics Service, Sheffield, UK
E‐mail address for correspondence: [email protected]
Background: Mutations in the spastin gene are the commonest cause of hereditary spastic paraparesis (HSP) accounting for approximately 40% of autosomal dominant cases. The phenotype associated with HSP due to mutation in the spastin gene (SPG4) tends to be of pure HSP. At least 107 different mutations have been identified scattered along the length of spastin initially suggesting haploinsufficiency may be the pathogenic mechanism. However, recent work in cell models has suggested that in some cases an abnormal gain of function mechanism may occur.
Objectives: To characterize SPG4 genetically and phenotypically.
Methods: Sheffield offers an international screening service for mutations in the spastin gene. Patients were identified who had tested positive for spastin mutations using a direct sequencing approach of all exons. Clinical details were readily available for those seen in the South Yorkshire region who had been assessed by PJS or CJM. Clinical details for patients from other centres were collected by use of a proforma sent to the referring neurologist.
Results: In 61 patients we have identified 47 different spastin mutations of which 25 are novel. Twenty missense, three nonsense, 12 frameshift and nine splicing changes were identified. These mutations were scattered throughout the gene with a particular hot spot in exon 1. Three patients were identified with two separate mutations within the spastin gene. The phenotype in the majority of patients was of pure HSP. However in two individuals the phenotype stood out as being particularly severe and unusual. In one, progressive bulbar dysfunction and respiratory insufficiency requiring overnight non‐ invasive ventilation complicated a severe spastic quadraparesis. In a second individual severe contractures, scoliosis and bulbar dysfunction complicated a spastic quadraparesis. A further observation in three individuals was the presence of denervation on neurophysiological assessment indicating lower motor neuron involvement.
Discussion: These findings add to the number of spastin mutations identified and demonstrate the importance of screening the whole gene given the possibility of double mutations. The hot spot for spastin mutation identified in exon 1 suggests an important functional role for this region of spastin which requires further investigation. The identification of the complicated phenotypes has important implications for patients in whom spastin screening should be considered. The presence of lower motor neuron dysfunction in a group of patients supports pathological evidence of lower motor neuron involvement, indicating that the cellular dysfunction in SPG4 extends beyond the axonal projections of upper motor neurons and ascending sensory pathways.