Upper and extra-motoneuron involvement in early motoneuron disease: a diffusion tensor imaging study.

Motoneuron disease is a term encompassing three phenotypes defined largely by the balance of upper versus lower motoneuron involvement, namely amyotrophic lateral sclerosis, primary lateral sclerosis and progressive muscular atrophy. However, neuroradiological and pathological findings in these phenotypes suggest that degeneration may exceed the neuronal system upon which clinical diagnosis is based. To further delineate the phenotypes within the motoneuron disease spectrum, this controlled study assessed the upper- and extra-motoneuron white matter involvement in cohorts of patients with motoneuron disease phenotypes shortly after diagnosis by comparing diffusion tensor imaging data of the different cohorts to those of healthy controls and directly between the motoneuron disease phenotypes (n = 12 for each cohort). Furthermore, we acquired follow-up data 6 months later to evaluate fractional anisotropy changes over time. Combined use of diffusion tensor tractography of the corticospinal tract and whole-brain voxel-based analysis allowed for comparison of the sensitivity of these techniques to detect white matter involvement in motoneuron disease. The voxel-based analysis demonstrated varying extents of white matter involvement in different phenotypes of motoneuron disease, albeit in quite similar anatomical locations. In general, fractional anisotropy reductions were modest in progressive muscular atrophy and most extensive in primary lateral sclerosis. The most extensive patterns of fractional anisotropy reduction were observed over time in the voxel-based analysis, indicating progressive extra-motor white matter degeneration in limb- and bulbar onset amyotrophic lateral sclerosis and in progressive muscular atrophy. The observation of both upper motor and extra-motoneuron involvement in all phenotypes of motoneuron disease shortly after diagnosis suggests that these are all part of a single spectrum of multisystem neurodegenerative disease. Voxel-based analysis was more sensitive to detect longitudinal changes than diffusion tensor tractography of the corticospinal tract. Voxel-based analyses may be particularly valuable in the evaluation of motor and extra-motor white matter involvement in the early symptomatic stages of motoneuron disease, and for monitoring the spread of pathology over time.

The meaning of distal sensory loss and absent ankle reflexes in relation to age: a meta-analysis.

CONTEXT: Polyneuropathy is a common disease and is more prevalent (at least 3 %) in elderly people. However, routine neurological examination of healthy elderly people may show distal sensory loss and absent tendon reflexes, which can obscure the distinction from polyneuropathy. OBJECTIVE: To investigate the relation between age and the prevalence of distal sensory loss, absent tendon reflexes, or muscle weakness, and to ascertain above which age these neurological signs could be considered as normal in ageing. DATA SOURCES: PubMed, Embase, the Cochrane Library, and Current Contents from 1960 until 2004. Reference lists of relevant studies were searched for additional studies, reviews or textbooks. STUDY SELECTION: Studies reporting on neurological signs upon routine neurological examination in generally healthy adult persons were considered for inclusion. Two reviewers independently assessed study eligibility and performed study inclusion. Of 629 studies initially identified, 50 (8 %) met the inclusion criteria. DATA EXTRACTION: Two reviewers independently performed data extraction and assessed study quality based on study design and the rigour by which confounding co-morbidity was excluded. DATA SYNTHESIS: The 50 included studies comprised a total of 9,996 adult persons. Assuming heterogeneity between studies, the prevalence data from different studies were pooled for separate age groups with a random-effects model. In healthy persons older than 60 years the prevalence of absent vibration sense at the big toes (29 % [95 % CI 18 % to 38%]) or ankles (15 % [95 % CI 11 % to 20%]), and absent ankle reflexes (23 % [95 % CI 16 % to 30 %]) was increased. CONCLUSIONS: Self-declared healthy adult persons younger than 60 years do not have neurological signs. After the age of 60 absent vibration sense at the big toes or ankles, and absent ankle reflexes are more prevalent, although the majority does not have these neurological signs. It seems more appropriate to apply different diagnostic criteria for polyneuropathy in adult persons younger and older than 60 years.

Differentiation of hereditary spastic paraparesis from primary lateral sclerosis in sporadic adult-onset upper motor neuron syndromes.

OBJECTIVE: To study whether clinical characteristics can differentiate sporadic presentations of hereditary spastic paraparesis (HSP) from primary lateral sclerosis (PLS). Differentiation between these diseases is important for genetic counseling and prognostication. DESIGN: Case series. SETTING: Tertiary referral center. PATIENTS: One hundred four Dutch patients with an adult-onset, sporadic upper motor neuron syndrome of at least 3 years' duration. Hereditary spastic paraparesis was genetically confirmed in 14 patients (7 with SPG4 and 7 with SPG7 mutations). RESULTS: All 14 patients with the SPG4 or SPG7 mutation had symptom onset in the legs, and 1 of the patients with the SPG7 mutation also developed symptoms in the arms. Of the other 90 patients, 78 (87%) had symptom onset in the legs. Thirty-six patients developed a PLS phenotype (bulbar region involvement), 15 had a phenotype that was difficult to classify as similar to HSP or PLS (involvement of legs and arms only), and 39 continued to have a phenotype similar to typical HSP (involvement of the legs only). Median age at onset was lower in patients with the SPG4 or SPG7 mutation (39 [range, 29-69] years), but there was considerable overlap with patients with the PLS phenotype (52 [range, 32-76] years). No differences were found in the features used by previous studies to distinguish HSP from PLS, including evidence of mild dorsal column impairment (decreased vibratory sense or abnormal leg somatosensory evoked potentials), symptoms of urinary urgency, or mild electromyographic abnormalities. CONCLUSIONS: In most patients with a sporadic adult-onset upper motor neuron syndrome, differentiation of sporadic presentations of HSP from PLS based on clinical characteristics is unreliable and therefore depends on results of genetic testing.

Spastin mutations in sporadic adult-onset upper motor neuron syndromes.

Mutation of the spastin gene is the single most common cause of pure hereditary spastic paraparesis. In patients with an unexplained sporadic upper motor neuron (UMN) syndrome, clinical distinction between primary lateral sclerosis and sporadic hereditary spastic paraparesis may be problematic. To investigate whether spastin mutations are present in patients with primary lateral sclerosis and sporadic hereditary spastic paraparesis, we screened the spastin gene in 99 Dutch patients with an unexplained, apparently sporadic, adult-onset UMN syndrome. We found 6 mutations, of which 4 were novel, in the subgroup of 47 patients with UMN symptoms restricted to the legs (13%). Another novel spastin mutation was found in a patient with a rapidly progressive spinal and bulbar UMN syndrome that progressed to amyotrophic lateral sclerosis. In the patients with arm or bulbar UMN symptoms and slow progression, no spastin mutations were found. Our study shows that spastin mutations are a frequent cause of apparently sporadic spastic paraparesis but not of primary lateral sclerosis.