C9 MONOMELIC MOTOR NEURON DISEASE IN EUROPE: PROGRESSIVE AND NON‐PROGRESSIVE FORMS
De Carvalho M1, Swash M2
1Department of Neurology, Hospital de Santa Maria, Neuromuscular Unit, Institute of Molecular Medicine, Lisbon, Portugal, 2Department of Neurology, Royal London Hospital, Queen Mary School of Medicine, University of London, London, UK
E‐mail address for correspondence: [email protected]
Background: There are many reports of patients with motor neuron disease (MND) with single limb involvement, including some in Western countries. In Asia, Hirayama disease has been separately defined as a distinct entity. Generally, monomelic MND is a benign condition with no clinical progression over time. No particular initial signs have been described that might indicate a risk of progression when a patient is first observed.
Objectives: To describe a population of 17 patients regularly followed in order to ascertain findings which could imply a progressive disorder.
Methods: A group of 17 patients (14 males, aged from 25 to 60 years at disease onset) were selected, in accordance with the following inclusion criteria: presentation with painless and insidious onset of focal weakness and wasting of one limb, of neurogenic cause; a history of progression over a period of at least three years without clinical involvement of any other limb or body region; pure motor features without sensory symptoms or signs; no other disease and no familial history; normal neuroimaging and somatosensory evoked potentials; normal CSF and blood investigations. After inclusion, the patients were followed for a minimum of three years (three to eight years) and underwent periodic clinical and neurophysiological assessment (EMG and transcranial magnetic stimulation – TMS).
Results: There were two clinical syndromes at presentation, an upper limb (seven patients) and a lower limb disorder. Four patients showed clinical and neurophysiological progression to other regions. In two cases more severe weakness developed in the arm muscles initially affected, with progression to more proximal muscles, opposite limb, and lower limb and neck muscles. In two cases progression evolved to homologous segments in the opposite leg and proximal muscles of the first affected leg. In the other cases there was no clinical or neurophysiological progression. Progression was a feature only of those patients who presented with distal weakness, whether in the upper or lower limb. Those presenting with proximal weakness never showed progression after the initial period of development of the syndrome. One patient developed multifocal conduction block, responsive to immunotherapy. Brisk reflexes in wasted muscles (p = 0.32) or EMG abnormality in the opposite limb at presentation were of no prognostic value in predicting the later development of clinical progression (p = 0.67). On the other hand, abnormal TMS at presentation was a useful predictor of subsequent progression (p<0.019).
Conclusion: Patients with monomelic MND affecting proximal segments have a benign course. Patients with distal weakness may slowly experience progression to other regions. Abnormal TMS can identify upper motor neuron involvement and suggest potential progression (ALS patients with slow progression).
C10 THE INFLUENCE OF RARE AMYOTROPHIC LATERAL SCLEROSIS (ALS) PHENOTYPES ON SURVIVAL
Tomik B, Partyka D, Pasternak K, Szczudlik A
Department of Neurology, Krakow, Poland
E‐mail address for correspondence: [email protected]
Background: ALS clinical heterogeneity is known and can be confusing. There may be predominance of the peripheral or central signs of motor neuron involvement, or a predominant initial involvement of one region: bulbar (progressive bulbar palsy), upper limbs (‘flail arm’ syndrome, FA), lower limbs (‘flail leg’ syndrome, FL), one limb (monomelic amyotrophy) and unilateral limbs (hemiplegic type). In addition, a number of epidemiological studies have reported clinical, molecular and geographical ALS risk factors and these results also lack uniformity. In this context, the recognition of ALS subforms may have significance for ALS differential diagnosis, prognosis and survival.
Objective: To estimate the occurrence of FA and FL phenotypes and their influence on survival in ALS individuals.
Methods: We carried out a retrospective study on 288 sporadic ALS patients seen at the Krakow MND Centre between January 2002 and January 2006. All participants were classified according to El Escorial Criteria. From ALS patients, FA and FL individuals were selected. FA was defined as a predominantly proximal LMN of the upper limbs in a more or less symmetric manner, without significant functional involvement of other regions at clinical presentation. FL was defined as a predominantly distal LMN of the lower limbs, without significant functional involvement of other regions at clinical presentation. The patients' demographic characteristics were compared between groups.
Results: FA phenotype (n = 19) is more common than FL (n = 14) in ALS patients studied. There is predominance of males. The male to female ratio was, in FA, 5.3:1, FL, 3.6:1 and in remaining ALS cases 1.5:1, respectively.
There was a difference between the mean duration of the disease in studied groups: FA, 74.2, FL, 53.1, limb onset ALS, 58.2, bulbar onset ALS, 42.1 months, respectively. During the time of observation four FA and three FL individuals died compared to 33 out of 288 individuals who died from the remaining ALS patients. The mean survival of those FA patients that had died was: 34.5, FL: 29, bulbar onset ALS: 28.7 and limb onset ALS: 43.7 months, respectively.
Detailed analysis of progression of the disease in FA and FL individuals demonstrated that the location of the second sign (i.e. in the trunk in FA cases, proximally in the upper limbs in FL cases) was associated with shorter survival because of accompanying progressive respiratory failure.
Conclusions: FA and FL phenotypes occurred in less than 10% of ALS patients, with predominance of males. The mean duration of ALS is usually longer in FA and FL individuals compared to classic ALS cases. However, the survival in FA and FL cases could be dramatically shortened when second signs of disease have occurred in a specific location. What determines this factor is unknown and requires further study, including larger groups of patients.
C11 ALS AT THE ONSET: TOPOGRAPHY OF UPPER AND LOWER MOTOR NEURON WEAKNESS
Ravits J, Paul P, Jorg C
Virginia Mason Medical Center, Seattle, WA, USA
E‐mail address for correspondence: [email protected]
Background: Weakness in ALS is characteristically focal and contiguous early in the disease. Its upper motor neuron (UMN) and lower motor neuron (LMN) components are poorly characterized.
Objective: To separately characterize UMN and LMN components of weakness early after the onset of ALS.
Methods: We undertook a retrospective cross‐sectional chart review of 100 ALS patients seen early in their course. We quantified severities of UMN and LMN abnormalities for all body regions with a simple ordinal scale. We indexed these to body region of first symptoms and analysed relative to this region. We evaluated indices of relative and absolute severities and onset progression rates. We correlated findings with survival data, available in 73% of patients.
Results: Mean age was 62 years (range 26–85 years). Fifty‐eight per cent of patients were men and 42% were women. Ninety‐two per cent had sporadic ALS and 8% had familial ALS. The average duration of symptoms prior to evaluation was 11 months (range 3–36 months).
Weakness was focal and contiguous in 98% of patients. Virtually any region of the body could be abnormal: 29% had bulbar onset; 34% had arm onset – right arm in 24% and left arm in 10%; 6% had truncal or respiratory onset; and 29% had leg onset – right leg in 13%, left leg in 15%, and both in 1%. Motor abnormalities were diffuse or of uncertain origination in the remaining 2%.
UMN and LMN components of the weakness were severest in the index regions and decreased radially away from these regions. Contiguity of body regions for UMN and LMN levels was similar except in the arms, where contiguity at UMN level was with the ipsilateral leg, but contiguity at LMN level was with the contralateral arm (consistent with somatotopic anatomy).
Both UMN and LMN weakness preferentially spread to caudal regions over rostral regions. Severity of UMN and LMN involvement varied widely and varied independently of each other. Onset progression rates were established early, varied widely, and correlated with survival. Patients with highest progression rates had a 50‐50 mix of UMN/LMN involvement but those with 50‐50 mix did not necessarily have high progression rates. Onset progression rates were higher in patients with bulbar and arm onset than in patients with truncal or respiratory and leg onset. Patients with truncal or respiratory onset had the shortest survival even though they had the slowest progression rates.
Discussion and conclusions: These features suggest motor neuron degeneration in ALS: 1) is a focal process for both UMN and LMN; 2) advances contiguously and independently for both UMN and LMN and creates graded abnormalities radially away from their respective onset foci; 3) has variable rates of progression that are established early; and 4) summates at the UMN and LMN levels as the disease progresses until it ultimately involves the respiratory system, at which time it appears to be diffuse.
C12 MND/DEMENTIA IS A UNIQUE NOSOLOGICAL ENTITY AND NOT JUST AN OVERLAP BETWEEN MND AND FRONTOTEMPORAL DEMENTIA
Bak TH, Xuereb J, Hodges JR
MRC Cognition and Brain Sciences Unit, Cambridge, UK
E‐mail address for correspondence: [email protected]
Background: The occurrence of cognitive and behavioural symptoms reminiscent of the fronto‐temporal dementia (FTD) in a subgroup of patients with motor neuron disease (MND) has been increasingly recognized in recent years. However, it remains unclear whether motor neuron disease/dementia syndrome (MND/D) constitutes simply an unusually frequent combination of MND and FTD, or a separate disease entity with its own characteristics. Moreover, many studies do not separate symptoms characteristic for the three subgroups of FTD: the frontal variant (fv), non‐fluent‐progressive aphasia (NFPA) and sementic dementia (SD).
Objectives: To determine the specific behavioural, cognitive and pathological features of MND/D and compare them with the typical features of the three subgroups of FTD.
Method: We followed up prospectively 15 patients with the clinical MND/D syndrome. In 10 patients we were able to perform a pathological examination of the brain. We compared the clinical and pathological results with those of patients belonging to all three FTD subtypes.
Results: The pattern of behavioural and cognitive changes in MND/D was in many aspects different from that of FTD. The psychiatric picture was characterized by early florid psychotic prodromal stage with delusions and hallucinations, although such symptoms can occur in fvFTD. Their severity and frequency would be unusual, particularly at an early stage. Another consistent feature was a severe progressive non‐fluent aphasia with a consistent impairment in word and action processing. Again, the clinical picture does show some similarities to NFPA, but also significant differences. Pathologically, all examined MND/dementia cases were associated with ubiquitin‐positive inclusions. Such inclusions were also observed in some FTD patients, but the pathological changes in this group were much more heterogeneous.
Discussion and conclusions: Both in terms of the clinical presentation and pathology MND/D constitutes a remarkably homogenous group, characterized by frequent occurrence of psychosis and aphasia as well as the consistent presence of ubiquitin‐positive inclusions. It shares some features with FTD, particularly with the fvFTD and NFPA. In contrast, we have never observed a combination of SD and MND. We postulate, therefore, that MND/dementia should be considered as a separate entity within the spectrum of the ‘Pick complex’.
C13 MOTOR FINDINGS PREDOMINATE IN FRONTOTEMPORAL DEMENTIA
Lomen‐Hoerth C, Langmore S, Boxer A, Seeley B, Miller B
UCSF, San Francisco, USA
E‐mail address for correspondence: [email protected]
Objective: To determine the extent to which Parkinsonism and motor neuron disease are present, clinically and pathologically, in patients with dementia.
Background: Frontotemporal dementia (FTD) is a progressive dementia condition characterized by selective degeneration of the frontal and anterior temporal lobes, whereas ALS is a motor neuron disease with progressive loss of upper and lower motor neurons. Because these diseases attack different parts of the brain, the specialists caring for patients with the two conditions have vastly different areas of expertise and interests. However, recent reports suggest that the two disorders often develop together in the same patients. Motor findings in dementia may have different diagnostic utility, but the prevalence of specific motor features in dementia subtypes has not been studied prospectively.
Methods: Prospectively, 107 patients with dementia and 11 healthy controls underwent a detailed neurological examination and electromyography (EMG) of four limbs and tongue. All patients were enrolled in an autopsy programme and 15 of the patients studied had autopsies performed. A speech pathologist performed a clinical assessment with tongue strength and swallowing measures using fiberoptic endoscopic evaluation of swallowing (FEES) in a subset of patients. Clinical diagnoses included frontotemporal dementia known to have MND at the time of referral (FTD‐MND, n = 7), FTD (n = 37), progressive supranuclear palsy (PSP, n = 8), progressive non‐fluent aphasia (PA, n = 7), corticobasal degeneration (CBD, n = 14), semantic dementia (SD = 15), and Alzheimer's disease (AD, n = 19). El Escorial criteria for an ALS diagnosis were used.
Results: Of the 37 FTD patients, 11 had abnormal EMG studies and clinically one had bulbar onset MND. Five had new diagnoses of ALS based on the EMG study and six had more subtle EMG abnormalities concerning MND. In one patient there was a diagnosis of a non‐specific myopathy. Of the seven PA patients, just one had an abnormal EMG and met criteria for a diagnosis of ALS. Of the 15 SD patients, one had EMG abnormalities in one limb which will be followed over time to look for development of MND. Among the 19 AD patients, 8 PSP patients, 14 CBD patients, and 11 controls, only one patient with an atypical form of AD had EMG abnormalities in one limb. Parkinsonism and/or supranuclear gaze palsy was present in all CBD/PSP, six PA, and two FTD‐MND patients, but few FTD, AD or SD patients. Swallowing abnormalities were present to some degree in all groups and were not predictive of motor neuron disease. Similarly, there have been no autopsy cases in this cohort of MND associated with any form of dementia other than FTD. Cases with associated motor neuron disease have ubiquitin‐positive, tau‐negative pathology.
Conclusions: The prevalence of motor neuron abnormalities in patients with FTD may exceed 30% at the time of presentation, which significantly impacts predicted survival. Owing to the low rates of MND in other dementia subtypes, clinical or EMG findings that suggest MND should heighten suspicion for FTD. Swallowing abnormalities are not specific for MND, and EMG is necessary to determine the true etiology.
Reference
- Brooks BR, Miller RG, Swash M, et al, for the World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293–8.
C14 BEHAVIOURAL CHANGE IN PATIENTS WITH AND WITHOUT COGNITIVE IMPAIRMENT IN ALS
Woolley‐Levine S, Miller R, Katz J
Forbes Norris ALS Center, San Francisco, CA, USA
E‐mail address for correspondence: [email protected]
Background: Frontal lobe pathology can cause either cognitive or behavioural impairments, and profound behavioural change is the hallmark of frontotemporal dementia (FTD). While frontotemporal pathology occurs in ALS, little is known about the significance of behavioural changes in this population.
Objective: To examine and compare the frequency, type and degree of behavioural changes in cognitively impaired and cognitively normal patients with ALS.
Methods: We initially evaluated 47 patients with ALS for the presence of cognitive impairment. Patients with scores 1.5 standard deviations below the mean for age and education‐matched norms on two or more of the following measures were classified as cognitively impaired: Trail Making Test, Verbal Fluency, Design Fluency, Color‐Word Interference, Digit Span, and Mental Control. Behavioural changes were assessed using the Frontal Systems Behaviour Scale (FrSBe), a questionnaire completed by a caregiver. We compared premorbid with current behaviour to define a change score. New onset behavioural impairment was defined as a 2‐standard deviation (SD) change from premorbid levels on either a FrSBe subscale (Apathy, Executive Dysfunction or Disinhibition) or the Total score. Patients with significant head injury, pre‐existing dementia or major depression were excluded.
Results: Twenty‐three patients were cognitively impaired (CI) and 24 were cognitively normal (CN). The groups did not differ demographically or in relation to disease factors (FVC, ALSFRS scores, site of onset, or duration of symptoms). Behavioural change associated with the onset of ALS was reported in 56% of CI and in 58% of CN. Apathy was the most prevalent abnormality in both groups. The CI groups showed a mean increase in apathy of 3 SD versus 2 SD for CN patients. The CI group demonstrated, on average, a 1.5 SD increase in executive dysfunction, with no change in the CN group. Neither group revealed significant changes in disinhibition. Total scores increased by 2 SD in the CI group but only 1 SD in the CN group. Scores on the executive dysfunction scale trended to correlate with cognitive impairment (p = 0.052) but apathy, despite the high prevalence, did not.
Discussions and conclusions: Caregivers commonly reported behavioural changes, particularly apathy, whether or not patients were cognitively impaired or cognitively normal. However, greater behavioural change occurred in patients with cognitive deficits, suggesting that some of the observed change relates to the ALS‐cognitive syndrome. Treatable factors such as hypoxia, sleep disturbance, and medication may also contribute to the high frequency of behavioural change. Additionally, standard behavioural questionnaires may not adequately control for disease‐specific factors such as motor weakness which may be misinterpreted by caregivers as apathy. These issues are worthy of further study.