Sharon Abrahams

EFNS guidelines on the clinical management of Amyotrophic Lateral Sclerosis (MALS) - revised report of an EFNS task force

Background:  The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak.

Verbal fluency and executive dysfunction in amyotrophic lateral sclerosis (ALS)

Neuropsychological investigations of amyotrophic lateral sclerosis (ALS) patients have revealed variable results on specific tests, despite a similar overall cognitive profile of predominantly executive dysfunction with some evidence of memory impairment. The most striking and consistent deficit is found using tests of verbal fluency. The current investigation explored why verbal fluency is particularly sensitive to the impairment in ALS, by investigating some of the underlying cognitive processes: (i) intrinsic response generation; (ii) phonological loop functions; and (iii) simple word retrieval. Twenty-two ALS patients and 25 healthy controls were investigated. The battery included: (i) written and spoken letter-based fluency, category fluency, design fluency; (ii) the Phonological Similarities effect and Word Length Effect; and (iii) computerised sentence completion and confrontational naming. The tests were designed to control for motor speed and to accommodate for the range of disabilities that are present in ALS patients. Significant impairments were found on some tests of intrinsic response generation, namely the Written Verbal Fluency Test, Category Fluency Test (generation of animal names) and Design Fluency Test. Phonological loop functions appeared to be intact with evidence of both the Phonological Similarities and Word Length Effects, but the ALS patients displayed significantly reduced working memory capacity. No deficits were found on tests of simple word retrieval. The findings indicate that verbal fluency impairments in ALS patients result from a higher order dysfunction, implicating deficits in the supervisory attentional system or central executive component of working memory, and are not caused or exaggerated by an impairment in phonological loop functions or in primary linguistic abilities. The study also demonstrates the importance of controlling for differences in motor speed, which may have served to exaggerate the presence of cognitive deficits in ALS patients reported by some other studies.

Spatial memory deficits in patients with unilateral damage to the right hippocampal formation

Patients with unilateral temporal lobe damage resulting from intractable temporal lobe epilepsy (TLE, n = 30) or from temporal lobe resection (temporal lobectomy, TLR, n = 47) were investigated on the Nine-box Maze. The task, analogous to the radial arm maze, was designed to compare spatial mapping and working memory theories of the functions of the hippocampus. The task provides measures of spatial, object, working and reference memory, incorporated into a within subjects design. The spatial component was designed to encourage the formation of allocentric rather than egocentric spatial representations. Spatial memory deficits were found (across working and reference memory components) in both TLE and TLR patients with right temporal lobe damage, with intact spatial memory in patients with corresponding left temporal lobe damage. Performance on the matched non-spatial (object) working memory component was equal to healthy controls for all groups. However all patient groups showed a deficit on object reference memory. These findings are discussed in relation to the underlying temporal lobe pathology and particularly atrophy of the hippocampal formation. Overall, the results support the cognitive mapping theory of hippocampal function, with the demonstration of a selective (and probably allocentric) spatial memory deficit in patients with right hippocampal damage.

Relation between cognitive dysfunction and pseudobulbar palsy in amyotrophic lateral sclerosis.

OBJECTIVES: To examine the relation between cognitive dysfunction and pseudobulbar features in patients with amyotrophic lateral sclerosis (ALS). METHODS: The performance of two patient groups, ALS with pseudobulbar palsy (n = 24) and ALS without pseudobulbar palsy (n = 28), was compared with 28 healthy age matched controls on an extensive neuropsychological battery. Tests used were the national adult reading test, short form of the WAIS-R, recognition memory test, Kendrick object learning test, paired associate learning, Wisconsin card sorting test, verbal fluency, Stroop and negative priming tests, a random movement joystick test, and a computerised Tower of Hanoi test. RESULTS: Tests of executive function showed a pronounced deficit on written verbal fluency in both ALS groups in comparison to controls, which tended to be more prominent in patients with ALS with pseudobulbar palsy. The random movement joystick test (a non-verbal test of intrinsic movement generation) showed an impairment in the generation of random sequences in patients with pseudobulbar palsy only. The computerised Tower of Hanoi showed a subtle planning impairment (shorter planning times) in all the patients with ALS compared with controls on trials requiring more complex solutions. In addition the pseudobulbar patients displayed shorter planning times on complex trials, and tended to solve these trials less accurately. There was also evidence of a deficit for all patients with ALS in comparison with controls on total errors and number of categories achieved on the Wisconsin card sorting test and a strong tendency towards an impairment on a task of selective attention and cognitive inhibition (negative priming). A word recognition memory deficit was showed across both ALS groups. CONCLUSIONS: This study elicited cognitive deficits (involving predominantly executive processes, with some evidence of memory impairment) in patients with ALS and further strengthened the link between ALS and frontal lobe dysfunction, this being more prominent in patients with pseudobulbar palsy. However, cognitive impairments suggestive of extramotor cortical involvement were not exclusive to this subgroup.

Frontotemporal white matter changes in amyotrophic lateral sclerosis

AbstractCognitive dysfunction can occur in some patients with amyotrophic lateral sclerosis (ALS) who are not suffering from dementia. The most striking and consistent cognitive deficit has been found using tests of verbal fluency. ALS patients with verbal fluency deficits have shown functional imaging abnormalities predominantly in frontotemporal regions using positron emission tomography (PET). This study used automated volumetric voxel-based analysis of grey and white matter densities of structural magnetic resonance imaging (MRI) scans to explore the underlying pattern of structural cerebral change in nondemented ALS patients with verbal fluency deficits. Two groups of ALS patients, defined by the presence or absence of cognitive impairment on the basis of the Written Verbal Fluency Test (ALSi, cognitively impaired, n = 11; ALSu, cognitively unimpaired n = 12) were compared with healthy age matched controls (n = 12). A comparison of the ALSi group with controls revealed significantly (p < 0.002) reduced white matter volume in extensive motor and non–motor regions, including regions corresponding to frontotemporal association fibres. These patients demonstrated a corresponding cognitive profile of executive and memory dysfunction. Less extensive white matter reductions were revealed in the comparison of the ALSu and control groups in regions corresponding to frontal association fibres. White matter volumes were also found to correlate with performance on memory tests. There were no significant reductions in grey matter volume in the comparison of either patient group with controls. The structural white matter abnormalities in frontal and temporal regions revealed here may underlie the cognitive and functional imaging abnormalities previously reported in non–demented ALS patients. The results also suggest that extra–motor structural abnormalities may be present in ALS patients with no evidence of cognitive change. The findings support the hypothesis of a continuum of extra–motor cerebral and cognitive change in this disorder.

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. Coordinated 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. Here, 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. View this table: Table 1 Clinical syndromes of MND (ALS—amyotrophic lateral sclerosis) and related disorders (modified from Kato et al , 2003*, with permission) The 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 …

Screening for cognition and behaviour changes in ALS.

Abstract This study presents the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), developed for ALS patients with physical disability for use by health care professionals. The screen is designed to detect the specific profile of cognition and behaviour changes in ALS and to differentiate it from other disorders. Forty-eight ALS patients (none with evident dementia), 40 healthy controls and 20 carers were recruited. The ECAS, a 15–20-min screen, includes an ALS-Specific score (executive functions and social cognition; fluency; language); an ALS Non-specific score (memory; visuospatial functions); and a carer behaviour screen of five domains characteristic of frontotemporal dementia (FTD). Data from healthy controls produced abnormality cut-offs of 77/100 ALS-Specific score; 24/36 ALS Non-specific score; 105/136 ECAS Total. Twenty-nine percent of patients showed abnormal ALS-Specific scores, and 6% also showed abnormal ALS Non-specific scores. The most prevalent deficit occurred in language functions (35%) followed by executive functions and fluency (23% each). Forty percent of carers reported behaviour change in at least one domain, while 15% met criteria for possible FTD. In conclusion, the ECAS is an effective within-clinic assessment for ALS that determines the presence, severity and type of cognitive and/or behavioural changes, an essential first step to managing these symptoms.

Visual short-term memory binding deficits in familial Alzheimer’s disease

Short-term memory binding is a memory function that underpins the temporary retention of complex objects (e.g. shapes with colours). In the verbal domain, this function has been found to be impaired in sporadic Alzheimers disease. Whether short-term memory binding is also impaired in familial Alzheimers disease, whether this impairment extends to the visual domain and whether it could be detected earlier than other cognitive deficits are issues yet to be investigated. Twenty two patients with familial Alzheimers disease caused by the E280A single presenilin-1 mutation, thirty carriers of the mutation who did not meet Alzheimers disease criteria (asymptomatic carriers) and 30 healthy relatives (non-carrier healthy controls) were assessed with a visual short-term memory task and a neuropsychological battery. The short-term memory task assessed the recognition of shapes, colours or shape-colour bindings presented in two consecutive arrays (i.e. study and test). Changes, which always occurred in the test array, consisted of new features replacing studied features (single feature conditions) or of features swapping across items (the binding condition). The neuropsychological battery comprised tests of associative and non-associative memory, attention, language, visuospatial and executive functions. Patients with Alzheimers disease and asymptomatic carriers performed significantly worse than healthy controls in the feature binding condition only. Group comparisons between asymptomatic carriers and healthy controls on standard neuropsychological tasks revealed no significant differences. Classification and area under the curve analyses confirmed that the binding task combines more sensitivity and specificity for patients with Alzheimers disease and most notably for asymptomatic carriers of the mutation than other traditional neuropsychological measures. This suggests that visual short-term memory binding deficits may be a preclinical marker for familial Alzheimers disease.

Deficits in Emotional and Social Cognition in Amyotrophic Lateral Sclerosis

OBJECTIVE These studies investigated whether non-demented ALS patients display impairments on tests of emotional decision making and social and emotional cognition, sensitive to frontal variant Frontotemporal Dementia (fvFTD). Previous studies have shown predominant executive dysfunction and dorsolateral prefrontal involvement in ALS, but evidence of other prefrontal dysfunction implicated in fvFTD is sparse. METHOD In Study A, 19 ALS patients and 20 healthy controls undertook a test of affective decision making, modified Iowa Gambling Task (IGT). Behavioral measures included the Frontal Systems Behavior Scale. In Study B, 14 ALS patients and 20 controls undertook tests of social and emotional cognition (Judgment of Preference based on eye gaze, the Mind in the Eyes, recognition of Facial Expressions of Emotion). RESULTS In Study A, ALS patients demonstrated a significantly different performance profile from healthy controls on the IGT and did not learn to avoid the disadvantageous stimuli (Block 3, d = 0.60, Block 4 days = 0.68). Behavior ratings showed increased apathy from premorbid levels. In Study B, ALS patients were impaired on attentionally demanding (d = 3.12) and undemanding (d = 7.52) conditions of the Judgment of Preference task, despite many showing intact executive functions. A smaller subset showed impaired emotion recognition. Behavior change was also evident. CONCLUSIONS The findings reveal a Theory of Mind deficit on a simple test that was dissociated from the presence of executive dysfunction and suggests a profile of cognitive and behavioral dysfunction indicative of a subclinical fvFTD syndrome. The relative contribution of prefrontal pathways to the cognitive profile in ALS is considered.

Prevalence of depression in a 12-month consecutive sample of patients with ALS

There is an impression both in clinical practice and in research literature that patients with amyotrophic lateral sclerosis (ALS) possess ‘heroic stoicism with a low frequency of depression’. Reliance on specific interview methods may have contributed to differing estimates of mood disorder in people with ALS. The objective of the current study was to compare prevalence rates of depression and anxiety in ALS using different assessment tools. The Beck Depression Inventory (BDI), The Hospital Anxiety and Depression Scale (HADS) and the Spielberger State‐Trait Anxiety Inventory (STAI) were sent to a 12‐month consecutive sample of 190 patients with ALS attending a tertiary referral clinic in the UK. Data were collected from 104 patients with ALS. Using BDI scores, 44% were categorized as not depressed, 37% were mild‐moderately depressed, 13% were moderately‐severely depressed, and 6% were severely depressed. In contrast, the HADS depression subscale identified 75% as not depressed, 13% were in the borderline range, and 13% were categorized as meeting ‘caseness’ for depression. Twenty‐five percent of the patients were using antidepressant medication. The estimated prevalence of mood disorder amongst patients with ALS may vary significantly depending on the measure used.