P N Leigh

Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study.

Microglial activation is implicated in the pathogenesis of ALS and can be detected in animal models of the disease that demonstrate increased survival when treated with anti-inflammatory drugs. PK11195 is a ligand for the peripheral benzodiazepine binding site expressed by activated microglia. Ten ALS patients and 14 healthy controls underwent [(11)C](R)-PK11195 PET of the brain. Volumes of interest were defined to obtain [(11)C](R)-PK11195 regional binding potential values for motor and extra-motor regions. Significantly increased binding was found in motor cortex (P = 0.003), pons (P = 0.004), dorsolateral prefrontal cortex (P = 0.010) and thalamus (P = 0.005) in the ALS patients, with significant correlation between binding in the motor cortex and the burden of upper motor neuron signs clinically (r = 0.73, P = 0.009). These findings indicate that cerebral microglial activation can be detected in vivo during the evolution of ALS, and support the previous observations that cerebral pathology is widespread. They also argue for the development of therapeutic strategies aimed at inflammatory pathways.

Diffusion tensor MRI assesses corticospinal tract damage in ALS

Background: A number of neurophysiologic and neuroimaging techniques have been evaluated in the research setting to assess upper motor neuron (UMN) damage in ALS. Changes in tissue structure in the CNS modify the diffusional behavior of water molecules, which can be detected by diffusion tensor MRI. Objectives: To explore the hypothesis that degeneration of the motor fibers in ALS would be reflected by changes in the diffusion characteristics of the white matter fibers in the posterior limb of the internal capsule and that these changes could be detected by diffusion tensor MRI. Methods: We studied 22 patients with El Escorial definite, probable, or possible ALS—11 with limb onset (mean age 54.5 ± 10.7 years) and 11 with bulbar onset (mean age 49.6 ± 11.7 years)—and compared them with 20 healthy, age-matched controls (mean age 46.0 ± 12.6 years). We assessed central motor conduction time (CMCT), threshold to stimulation, and silent period using transcranial magnetic stimulation. Diffusion tensor MRI was performed using a 1.5-T GE Signa system (Milwaukee, WI) fitted with Advanced NMR hardware and software capable of producing echo planar MR images. Data were acquired from seven coronal slices centered to include the posterior limb of the internal capsule. Maps of the mean diffusivity, fractional anisotropy, and T2-weighted signal intensity were generated. Results: There were no differences between the subject groups on measures of CMCT, threshold to stimulation, and silent period. However, the CMCT correlated with clinical measures of UMN involvement. We found a significant increase in the mean diffusivity and reduction in fractional anisotropy along the corticospinal tracts between the three subject groups, most marked in the bulbar-onset group. The fractional anisotropy correlated with measures of disease severity and UMN involvement, whereas the mean diffusivity correlated with disease duration. Conclusion: The results support the use of diffusion tensor MRI in detecting pathology of the corticospinal tracts in ALS.

EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives

Despite being one of the most devastating diseases known, there is little evidence for diagnosing and managing patients with amyotrophic lateral sclerosis (ALS). Although specific therapy is lacking, correct early diagnosis and introduction of symptomatic and specific therapy can have a profound influence on the care and quality of life of the patient and may increase survival time. This document addresses the optimal clinical approach to ALS. The final literature search was performed in the spring of 2005. Consensus recommendations are given graded according to the EFNS guidance regulations. Where there was lack of evidence but consensus was clear we have stated our opinion as good practice points. People affected with possible ALS should be examined as soon as possible by an experienced neurologist. Early diagnosis should be pursued and a number of investigations should be performed with high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. PEG is associated with improved nutrition and should be inserted early. The operation is hazardous in patients with vital capacity <50%. Non‐invasive positive pressure ventilation improves survival and quality of life but is underused. Maintaining the patients ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end of life care are important and should be fully discussed early with the patient and relatives respecting the patients social and cultural background.

Volumetric analysis reveals corticospinal tract degeneration and extramotor involvement in ALS

Background: Pathologic changes in the motor cortex and corticospinal tracts in ALS may be reflected by abnormal signal intensities on conventional MRI. The sensitivity of these changes in detecting underlying pathology remains unclear. Method: The authors used automated image analysis to quantify volumes of cerebral gray and white matter in 16 patients with ALS (eight limb onset, eight bulbar onset) and eight normal controls. Previously they had demonstrated a reduction in N-acetyl aspartate/creatine + phosphocreatine (NAA/[Cr + PCr]) measured by 1H-MRS in the subcortical white matter in the motor cortex region in the patients with bulbar-onset ALS. To determine whether this resulted from axonal degeneration, they also compared gray and white matter volumes in the patients with limb- and bulbar-onset ALS. Results: There were no differences in the total brain volumes of gray or white matter for the three subject groups (p > 0.23). Comparison of the total ALS group and controls revealed localized deficits in gray matter volume centered on Brodmann areas 8, 9, and 10 bilaterally. Comparison of the patients with limb- and bulbar-onset ALS revealed deficits in the white matter volume in the bulbar-onset group, extending bilaterally from the precentral gyrus into the internal capsule and brainstem, consistent with the course of the corticospinal tract. There was no loss in gray matter volume in the precentral gyri. Conclusions: The loss of gray matter in the frontal regions (total ALS group) provides further support that ALS is a multisystem disorder. In addition, there is in vivo evidence of axonal degeneration in the subcortical white matter in the motor region in patients with bulbar-onset ALS. This is consistent with a “dying back” process affecting cortical motoneurons in bulbar-onset ALS.

The management of motor neurone disease

The management of motor neurone disease (MND) has evolved rapidly over the last two decades. Although still incurable, MND is not untreatable. From an attitude of nihilism, treatments and interventions that prolong survival have been developed. These treatments do not, however, arrest progression or reverse weakness. They raise difficult practical and ethical questions about quality of life, choice, and end of life decisions.nnCoordinated multidisciplinary care is the cornerstone of management and evidence supporting this approach, and for symptomatic treatment, is growing.1–3 Hospital based, community rehabilitation teams and palliative care teams can work effectively together, shifting emphasis and changing roles as the needs of the individuals affected by MND evolve. In the UK, MND care centres and regional networks of multidisciplinary teams are being established. Similar networks of MND centres exist in many other European countries and in North America.nnHere, we review current practice in relation to diagnosis, genetic counselling, the relief of common symptoms, multidisciplinary care, the place of gastrostomy and assisted ventilation, the use of riluzole, and end of life issues.nnnnnnView this table:nn Table 1 nClinical syndromes of MND (ALS—amyotrophic lateral sclerosis) and related disorders (modified from Kato et al , 2003*, with permission)nnnnThe average delay from onset of symptoms to diagnosis is about 14 months, about one third of expected survival. Occasionally, survival following diagnosis may be less than six months. The patient may already suspect the diagnosis …

Natural history and clinical features of the flail arm and flail leg ALS variants

Objective: We sought to define the significance of brachial amyotrophic diplegia (flail arm syndrome [FA]) and the pseudopolyneuritic variant (flail leg syndrome [FL]) of amyotrophic lateral sclerosis (ALS; motor neuron disease). Methods: We analyzed survival in clinic cohorts in London, UK (1,188 cases), and Melbourne, Australia (432 cases). Survival from disease onset was analyzed using the Kaplan- Meier method and Cox proportional hazards model. Results: In the London cohort, the FA syndrome represented 11% and the FL syndrome 6% of the sample. Median survival was 35 months for limb onset and 27 months for bulbar onset ALS, whereas this was 61 months for FA syndrome (p < 0.001) and 69 months for FL syndrome (p < 0.001). Five-year survival in this cohort was 8.8% for bulbar onset, 20% for limb onset, 52% for FA syndrome, and 64% for FL syndrome. The ratio of men to women was 4:1 in the FA group compared to 2:1 in other limb onset cases. Excluding lower motor neuron FA and FL cases, progressive muscular atrophy comprised 4% of the sample and had a prognosis similar to typical limb onset ALS. In the Melbourne cohort, median survival for limb onset ALS was 31 months, bulbar onset 27 months, FA syndrome 66 months (p < 0.001), and FL syndrome 71 months (p = 0.001). Conclusions: The flail arm (FA) and flail leg (FL) syndromes had significantly better survival than typical amyotrophic lateral sclerosis (ALS) or progressive muscular atrophy cases that were not classified as FA or FL. Our findings underline the clinical and prognostic importance of the FA and FL variants of ALS.

Good practice in the management of amyotrophic lateral sclerosis : clinical guidelines. An evidence-based review with good practice points. EALSC Working Group.

The evidence base for diagnosis and management of ALS is still weak, and curative therapy is lacking. Nonetheless, early diagnosis and symptomatic therapy can profoundly influence care and quality of life of the patient and relatives, and may increase survival time. This review addresses the current optimal clinical approach to ALS. The literature search is complete to December 2006. Where there was lack of evidence but consensus was clear we have stated our opinion as good practice points. We conclude that a diagnosis of ALS can be achieved by early examination by an experienced neurologist. The patient should be informed of the diagnosis by the consultant. Following diagnosis, a multi‐diciplinary care team should support the patient and relatives. Medication with riluzole should be initiated as early as possible. PEG is associated with improved nutrition and should be inserted early. The operation is hazardous in patients with VC <50%: RIG may be a better alternative. Non‐invasive positive pressure ventilation improves survival and quality of life but is underused in Europe. Maintaining the patients ability to communicate is essential. During the course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end of life care are important and should be discussed early with the patient and relatives if they so wish.

An estimate of amyotrophic lateral sclerosis heritability using twin data

Background Causative gene mutations have been identified in about 2% of those with amyotrophic lateral sclerosis (ALS), often, but not always, when there is a strong family history. There is an assumption that there is a genetic component to all ALS, but genome-wide association studies have yet to produce a robustly replicated result. A definitive estimate of ALS heritability is therefore required to determine whether ongoing efforts to find susceptibility genes are worth while. Methods The authors performed two twin studies, one population- and one clinic-based. The authors used structural equation modelling to perform a meta-analysis of data from these studies and an existing twin study to estimate ALS heritability, and identified 171 twin pairs in which at least one twin had ALS. Results and discussion Five monozygotic twin pairs were concordant-affected, and 44 discordant-affected. No dizygotic twin pairs were concordant-affected, and 122 discordant-affected. The heritability of sporadic ALS was estimated as 0.61 (0.38 to 0.78) with the unshared environmental component 0.39 (0.22 to 0.62). ALS has a high heritability, and efforts to find causative genes should continue.

The effect of non-invasive positive pressure ventilation (NIPPV) on cognitive function in amyotrophic lateral sclerosis (ALS): a prospective study

OBJECTIVES Neuropsychological investigations have shown a degree of cognitive dysfunction in a proportion of non-demented patients with ALS. Respiratory muscle weakness in ALS can lead to nocturnal hypoventilation, resulting in sleep disturbance and daytime somnolence. Sleep deprivation of this type may cause impairments in cognitive function, but this has not been formally evaluated in ALS. METHODS Cognitive functioning was evaluated in nine patients with ALS with sleep disturbance caused by nocturnal hypoventilation (NIPPV group), and in a comparison group of 10 similar patients without ventilation problems (control group). The NIPPV group then started non-invasive positive pressure ventilation (NIPPV) at night. After about 6 weeks, change in cognitive function was evaluated. RESULTS Statistically significant improvement in scores on two of the seven cognitive tests was demonstrated in the NIPPV group postventilation, and a trend towards significant improvement was found for two further tests. Scores in the control group did not improve significantly for these four tests, although an improvement was found on one other test. CONCLUSIONS Nocturnal hypoventilation and sleep disturbance may cause cognitive dysfunction in ALS. These deficits may be partially improved by NIPPV over a 6 week period. This has important implications for investigations of both cognitive dysfunction in non-demented patients with ALS, and the effect of ventilation on quality of life.

Measuring brain stem and cerebellar damage in parkinsonian syndromes using diffusion tensor MRI

Objective: To use diffusion tensor MRI to quantify and compare degeneration of the pons and cerebellar peduncles in multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and Parkinson disease (PD) and to relate changes in diffusion measures to clinical features and localized atrophy. Methods: We used a region-of-interest approach to measure changes in fractional anisotropy and mean diffusivity in the middle cerebellar peduncles, decussation of the superior cerebellar peduncles, and pons in 17 patients with MSA, 17 with PSP, 12 with PD, and 12 healthy volunteers. We also evaluated atrophy of the cerebellar peduncles and pons on T2-weighted magnetic resonance images in patients with MSA and PSP. Results: In MSA, fractional anisotropy was markedly reduced in the middle cerebellar peduncles, and mean diffusivity increased both here and in the pons compared with other groups, whereas in PSP, mean diffusivity was strikingly increased in the decussation of superior cerebellar peduncles. Cerebellar ataxia was related to mean diffusivity in the middle cerebellar peduncles (r = 0.71, p = 0.001) and pons (r = 0.60, p = 0.01) in MSA. Diffusion measures were related to localized atrophy in both MSA and PSP. Conclusions: Diffusion tensor MRI can be used to quantify neurodegenerative processes in different brain stem and cerebellar structures in multiple system atrophy and progressive supranuclear palsy during life, and may have diagnostic value. Larger studies of early, undifferentiated parkinsonian syndromes are indicated to provide estimates of the relative diagnostic value of diffusion measures, atrophy measures, and visual assessment of scans.