Leo Davies

BOTULINUM TOXIN A FOR TREATMENT OF UPPER LIMB SPASTICITY FOLLOWING STROKE: A MULTI-CENTRE RANDOMIZED PLACEBO- CONTROLLED STUDY OF THE EFFECTS ON QUALITY OF LIFE AND OTHER PERSON-CENTRED OUTCOMES

OBJECTIVE Botulinum toxin is known to relieve upper limb spasticity, which is a disabling complication of stroke. We examined its effect on quality of life and other person-centred perspectives. DESIGN A multi-centre, randomized, double-blind, placebo-controlled study. PATIENTS Ninety-six patients were randomized (mean age 59.5 years) at least 6 months post-stroke. Mean time since stroke was 5.9 years. METHODS Patients received either botulinum toxin type A or placebo into the affected distal upper limb muscles on 2 occasions, 12 weeks apart. Assessment was undertaken at baseline, 8, 12, 20 and 24 weeks. The primary outcome measure was the Assessment of Quality of Life scale (AQoL). Secondary outcome assessments included Goal Attainment Scaling (GAS), pain, mood, global benefit, Modified Ashworth Scale (MAS), disability and carer burden. RESULTS The groups did not differ significantly with respect to quality of life, pain, mood, disability or carer burden. However, patients treated with botulinum toxin type A had significantly greater reduction in spasticity (MAS) (p < 0.001), which translated into higher GAS scores (p < 0.01) and greater global benefit (p < 0.01). CONCLUSION Although no change in quality of life was demonstrated using the AQoL, botulinum toxin type A was found to be safe and efficacious in reducing upper limb spasticity and improving the ability to achieve personal goals.

GOAL ATTAINMENT SCALING IN THE EVALUATION OF TREATMENT OF UPPER LIMB SPASTICITY WITH BOTULINUM TOXIN: A SECONDARY ANALYSIS FROM A DOUBLE-BLIND PLACEBO-CONTROLLED RANDOMIZED CLINICAL TRIAL

OBJECTIVE To examine goal attainment scaling for evaluation of treatment for upper limb post-stroke spasticity with botulinum toxin-A. DESIGN Secondary analysis of a multi-centre double-blind, placebo-controlled randomized clinical trial. SETTING Six outpatient clinics in Australia. PARTICIPANTS Patients (n=90) completing per protocol 2 cycles of treatment/placebo. Mean age 54.5 (standard deviation 13.2) years. Mean time since stroke 5.9 (standard deviation 10.5) years. INTERVENTIONS Intramuscular botulinum toxin-A (Dysport 500-1000U) or placebo given at 0 and 12 weeks. Measurement points were baseline, 8 and 20 weeks. MAIN OUTCOME MEASURES Individualized goal attainment and its relationship with spasticity and other person-centred measures - pain, mood, quality of life and global benefit. RESULTS A significant treatment effect was observed with respect to goal attainment (Mann-Whitney z=-2.33, p< or = 0.02). Goal-attainment scaling outcome T-scores were highly correlated with reduction in spasticity (rho=0.36, p=0.001) and global benefit (rho=0.45, p<0.001), but not with other outcome measures. Goal-attainment scaling T-scores were lower than expected (median 32.4, interquartile range 29.6-40.6). Goals related to passive tasks were more often achieved than those reflecting active function. Qualitative analysis of goals nevertheless demonstrated change over a wide area of patient experience. CONCLUSION Goal-attainment scaling provided a responsive measure for evaluating focal intervention for upper limb spasticity, identifying outcomes of importance to the individual/carers, not otherwise identifiable using standardized measures.

Paraneoplastic brain stem encephalitis in a woman with anti-Ma2 antibody

A woman developed brain stem encephalopathy in association with serum anti-Ma2 antibodies and left upper lobe lung mass. T2 weighted MRI of the brain showed abnormalities involving the pons, left middle and superior cerebellar peduncles, and bilateral basal ganglia. Immunohistochemical analysis for serum antineuronal antibodies was confounded by the presence of a non-neuronal specific antinuclear antibody. Immunoblot studies showed the presence of anti-Ma2 antibodies. A premortem tissue diagnosis of the lung mass could not be established despite two CT guided needle biopsies, and the patient died as a result of rapid neurological deterioration. The necropsy showed that the lung lesion was an adenocarcinoma which expressed Ma2 immunoreactive protein. Neuropathological findings included prominent perivascular inflammatory infiltrates, glial nodules, and neuronophagia involving the brain stem, basal ganglia, hippocampus and the dentate nucleus of the cerebellum. Ma2 is an autoantigen previously identified in patients with germ cell tumours of the testis and paraneoplastic brain stem and limbic encephalitis. Our patients clinical and immunopathological findings indicate that this disorder can affect women with lung adenocarcinoma, and that the encephalitic changes predominate in those regions of the brain known to express high concentrations of Ma proteins.

Corticobasal syndrome with tau pathology.

Six cases with a clinical corticobasal syndrome (progressive asymmetric apraxia and parkinsonism unresponsive to levodopa) and tau pathology were selected from 97 brain donors with parkinsonism. Postmortem volumetric measures of regional brain atrophy (compared with age/sex‐matched controls) were correlated with clinical features and the degree of underlying cortical and subcortical histopathology. At death, no significant asymmetry of pathology was detected. All cases had prominent bilateral atrophy of the precentral gyrus (reduced by 22–54%) with other cortical regions variably affected. Subcortical atrophy was less severe and variable. Two cases demonstrated widespread atrophy of basal ganglia structures (44–60% atrophy of the internal globus pallidus) and substantial subcortical pathology consistent with a diagnosis of progressive supranuclear palsy (PSP). The remaining four cases had typical pathology of corticobasal degeneration. In all cases, neuronal loss and gliosis corresponded with subcortical atrophy, while the density of cortical swollen neurons correlated with cortical volume loss. Atrophy of the internal globus pallidus was associated with postural instability, while widespread basal ganglia histopathology was found in cases with gaze palsy. This study confirms the involvement of the precentral gyrus in the corticobasal syndrome and highlights the variable underlying pathology in these patients.

Ubiquitin-positive achromatic neurons in corticobasal degeneration

A 66-year-old woman presented with an alien limb syndrome without dementia. The course of her illness was unremitting and at autopsy 6 years later her diagnosis was confirmed as corticobasal degeneration without Alzheimer-type pathology. Although the presence of ballooned achromatic cortical neurons and cell loss from the substantia nigra distinguishes such patients, the site and density of achromatic neurons has not previously been quantified. We show that immunohistochemistry for the cell stress protein ubiquitin selectively stains these achromatic neurons, whereas they do not stain for abnormally phosphorylated tau protein. Phosphorylated neurofilament antibodies recognise both ballooned and non-ballooned neurons. In this case, high densities of ubiquitin-positive ballooned neurons were found in frontal cortical regions with the highest densities in layers V and VI of the anterior cingulate cortex. In addition, high densities of ubiquitin-positive ballooned neurons were found in the insular cortex, claustrum and amygdala. These results confirm past reports of frontal pathology, but show that there is also considerable pathology in insular and parahippocampal cortical regions and some subcortical regions. Our findings suggest that the distribution and staining characteristics of ballooned neurons in corticobasal degeneration may help to differentiate these cases pathologically, while the absence of dementia appears to be an important clinical criterion.

Reversible delayed leukoencephalopathy following intravenous heroin overdose.

We present serial neuropsychological, magnetic resonance (MR) imaging and EEG changes in a case of widespread CNS myelinopathy due to intravenous heroin overdose complicated by a period of prolonged unconsciousness. Following recovery from the acute overdose, the subject had the delayed onset of akinetic mutism with urinary incontinence. Sequential formal neuro-psychological assessments over 9 months showed evolution from severe global cerebral dysfunction to moderate disturbance of frontal lobe function. Almost complete resolution of diffuse white matter signal changes, accompanied by the development of a degree of volume loss, was evident on serial MR imaging over the same period, and generalized arrhythmic delta-range slowing on the EEG evolved int o a near normal pattern.

Posterior semicircular canal nystagmus is conjugate and its axis is parallel to that of the canal

Article abstract A patient with a postoperative fistula of the left posterior semicircular canal is presented. Negative pressure in the external ear canal produced upbeat-torsional nystagmus, which was recorded in three dimensions using binocular scleral search coils. The nystagmus was conjugate, without skew deviation, and its trajectory corresponded to the anatomic axis of the left posterior canal. The current study helps validate Ewald’s first law in humans: the axis of nystagmus should match the anatomic axis of the semicircular canal that generated it. This law is clinically useful in diagnosing pathology of the vestibular end-organ, such as benign paroxysmal positional vertigo or the superior semicircular canal dehiscence syndrome.

The clinical variability of the MECP2 duplication syndrome: description of two families with duplications excluding L1CAM and FLNA.

To the Editor: Mutations in the X-linked methyl CpG-binding protein 2 (MECP2) gene are associated with Rett syndrome in females (1) and a variety of generally severe phenotypes in males (2, 3). Males with duplications of MECP2 have a distinctive phenotype of X-linked mental retardation (XLMR), recurrent respiratory infections and progressive spasticity (4–7). We report two additional families withMECP2 duplications, extending the phenotype and reducing the minimum critical region. We used genomic real time quantitative PCR (qPCR) to screen 45 male subjects with a history consistent with XLMR, in many of whom a diagnosis of alpha-thalassemia–mental retardation (ATRX) was being considered. We found duplications encompassing MECP2 in two individuals. Patient 1 was an 8-year-old boy with severe intellectual disability, ataxia, lower limb hypertonia, discoordinate swallowing and recurrent aspiration pneumonia. His mother had mild learning difficulties, longstanding hypertension, simple migraine and type 2 diabetes. Aged 31 years, she had an unusual cluster of synchronous strokes for which no cause could be identified. In particular, she had no embolic focus identifiable, and no evidence of a prothrombotic state. Magnetic resonance imaging (MRI) showed multiple areas of restricted diffusion consistent with cerebral infarction. In DNA extracted from blood, she had evidence of complete skewing of X-inactivation at the HUMARA locus. However, in hair roots, the ratio was 74:26%, raising the possibility that skewing is also not complete in her brain and that her strokes may have been connected with heterozygosity for the duplication. To our knowledge, X-inactivation studies in tissues other than blood have not previously been reported in women heterozygous for a MECP2 duplication. Her brother, the proband’s maternal uncle, was also hemizygous for the duplication. He had severe developmental delay, seizures and truncal hypotonia. He followed a neurodegenerative course, with stepwise deteriorations associated with episodes of pneumonia. At best, he could speak 25 words and could walk independently. Shortly before his death at 11 years of age, he was severely ataxic and could not walk or speak. Cerebral CT scan was normal at 8 years but showed generalized cerebral atrophy at 11 years. Patient 2 was a 43-year-old man. He was 187 cm tall and was macrocephalic (occipitofrontal circumference 59.5 cm) but not otherwise dysmorphic. He walked at the age of 5, and at 45, he remained ambulant with an unsteady gait and frequent falls. Lower limb hypertonia was not progressive, and he had no regression of skills. He had medically controlled seizures and a history of unexplained febrile episodes. Cerebral MRI showed bilaterally increased signal in the posterior periventricular white matter. The proband’s mother was heterozygous for the duplication. She had complete skewing at the HUMARA locus in blood DNA. She had a history of five miscarriages (sex unknown), but there was no other family history of note. We used qPCR and multiplex ligation-dependent probe amplification (MLPA) to delineate the size of the duplications. In both families, the duplication excluded both L1CAM and FLNA (Fig. 1). Previously reported deletions have involved duplication of one or both of these genes, each of which is known to play a role in preand post-natal CNS development. In both patients, MLPA analysis shows that IRAK1 is

Autonomic and peripheral neuropathy in endstage liver disease and following liver transplantation

Severe chronic liver disease may be associated with a peripheral somatic and an autonomic neuropathy. There are only a limited number of reports on the incidence and features of these neuropathies. In addition the effects of liver transplantation on these neuropathies have not been well studied. We examined peripheral somatic and autonomic nerve function in 42 patients with endstage liver disease prior to transplantation and also examined the effect of liver transplantation on these neuropathies in 14 patients. Peripheral somatic neuropathy (93%) and autonomic neuropathy (50%) were common in patients with endstage liver disease and were more frequent than previously reported. Abnormalities improved in some patients after liver transplantation, particularly if there was return of normal hepatic function. Muscle Nerve 28: 595–600, 2003

Conduction block in vasculitic neuropathy

Vasculitis involving peripheral nerves usually presents as an acute asymmetrical axonal neuropathy. We report a 67‐year‐old man with a symmetrical subacute neuropathy in which nerve conduction studies showed prominent conduction block, a finding indicative of demyelination. Sural nerve biopsy showed a vasculitic neuropathy with invasion of blood vessel walls by inflammatory cells and a mixture of nerve fiber loss and demyelination. The demyelination in this case was presumably a consequence of subinfarctive nerve ischemia.