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GB and PNL contributed equally to this paper.; International audience; AIM: To evaluate a standardised MRI acquisition protocol and a new image rating scale for disease severity in patients with progressive supranuclear palsy (PSP) and multiple systems atrophy (MSA) in a large multicentre study. METHODS: The MRI protocol consisted of two-dimensional sagittal and axial T1, axial PD, and axial and coronal T2 weighted acquisitions. The 32 item ordinal scale evaluated abnormalities within the basal ganglia and posterior fossa, blind to diagnosis. Among 760 patients in the study population (PSP = 362, MSA = 398), 627 had per protocol images (PSP = 297, MSA = 330). Intra-rater (n = 60) and inter-rater (n = 555) reliability were assessed through Cohen's statistic, and scale structure through principal component analysis (PCA) (n = 441). Internal consistency and reliability were checked. Discriminant and predictive validity of extracted factors and total scores were tested for disease severity as per clinical diagnosis. RESULTS: Intra-rater and inter-rater reliability were acceptable for 25 (78%) of the items scored (≥ 0.41). PCA revealed four meaningful clusters of covarying parameters (factor (F) F1: brainstem and cerebellum; F2: midbrain; F3: putamen; F4: other basal ganglia) with good to excellent internal consistency (Cronbach α 0.75-0.93) and moderate to excellent reliability (intraclass coefficient: F1: 0.92; F2: 0.79; F3: 0.71; F4: 0.49). The total score significantly discriminated for disease severity or diagnosis; factorial scores differentially discriminated for disease severity according to diagnosis (PSP: F1-F2; MSA: F2-F3). The total score was significantly related to survival in PSP (p

While patients with amyotrophic lateral sclerosis (ALS) may complain of fatigue, the underlying mechanisms appear complex, with dysfunction of central and peripheral nervous systems independently reported as contributing factors. The aim of the present study was to further delineate the mechanisms underlying increased fatigability in ALS by measuring activity dependent changes in axonal excitability following a maximum voluntary contraction (MVC).Nerve excitability changes were recorded before and after an MVC of the abductor pollicis brevis in 16 patients with ALS and 25 controls.In patients with ALS, there was a greater increase in threshold (36.5 (5.9)%; controls 19.6 (3.5)%; p0.05) as a result of MVC, with reduction in the amplitude of the compound muscle action potential generated by a submaximal stimulus (ALS 49 (7.6)%; controls 41.0 (5.4)%). These changes were associated with an increase in superexcitability (ALS 65.1 (25.4)%; controls 42.3 (5.7)%) and reduction in strength-duration time constant (ALS 20 (4.9)%; controls 10 (2.5)%; p0.01), indicative of axonal hyperpolarisation. The increase in threshold was more pronounced in patients with ALS with predominantly lower motor neuronal involvement.Higher firing rates of surviving motor axons attempting to compensate for neurogenic weakness are likely to explain the greater activity dependent changes in ALS. As such, the present study suggests a further peripheral factor underlying the development of fatigue in ALS.

Background: Horizontal gaze palsy and progressive scoliosis (HGPPS) is caused by mutations of the ROBO3 gene, which encodes a receptor associated with axonal guidance during development. Although there is evidence for uncrossed cuneatal and corticospinal tracts in HGPPS, it is unclear whether other central nervous system pathways are involved. Objective: To study two patients with HGPPS homozygotic for the ROBO3 E319K mutation using a variety of neurophysiological and neuropsychological tests. Methods: A battery of neuropsychological tests was applied to assess various cognitive and perceptual functions. The corticospinal, somatosensory and auditory pathways were evaluated using appropriate neurophysiological tests. To access motor pathways to the neck muscles, electromyographic recordings were obtained from the sternocleidomastoideus and splenius capitis muscle during active head rotation. Results: Both patients performed normally on manual dexterity, complex sensory and visuospatial functions, reading and general intelligence tests. Motor evoked potentials in both patients showed uncrossed corticospinal tracts for the extremities, although in one patient, electromyography indicated pyramidal tract crossing for the neck muscles. Although somatosensory evoked potentials showed uncrossed somatosensory fibres subserving proprioception and light touch, right median nerve somatosensory evoked potential in one patient indicated a partial lemniscal crossing. Sympathetic skin response and blink reflex showed a midline crossing of the spinothalamic and quintothalamic tracts. Brain stem auditory evoked potentials indicated a lack of crossing in the level of the trapezoid body. Conclusions: Our patients with the ROBO3 E319Κ mutation show normal perceptual and cognitive functions and have both crossed and uncrossed motor, sensory and auditory pathways.

The high coincidence of organic vestibular and somatoform vertigo syndromes has appeared to support pathogenic models showing a strong linkage between them. It was hypothesised that a persisting vestibular dysfunction causes the development of anxiety disorders.To determine the relation between vestibular deficits and somatoform vertigo disorders in an interdisciplinary prospective study.Participants were divided into eight diagnostic groups: healthy volunteers (n=26) and patients with benign paroxysmal positioning vertigo (BPPV, n=11), vestibular neuritis (n=11), Menière's disease (n=7), vestibular migraine (n=15), anxiety (n=23), depression (n=12), or somatoform disorders (n=22). Neuro-otological diagnostic procedures included electro-oculography with rotatory and caloric testing, orthoptic examination with measurements of subjective visual vertical (SVV) and ocular torsion, and a neurological examination. Psychosomatic diagnostic procedures comprised interviews and psychometric instruments.Patients with BPPV (35.3%) and with vestibular neuritis (52.2%) had pathological test values on caloric irrigation (p0.001). Otolith dysfunction with pathological tilts of SVV and ocular torsion was found only in patients with vestibular neuritis (p0.001). Patients with Menière's disease, vestibular migraine, and psychiatric disorders showed normal parameters for vestibular testing but pathological values for psychometric measures. There was no correlation between pathological neurological and pathological psychometric parameters.High anxiety scores are not a result of vestibular deficits or dysfunction. Patients with Menière's disease and vestibular migraine but not vestibular deficits showed the highest psychiatric comorbidity. Thus the course of vertigo syndromes and the possibility of a pre-existing psychopathological personality should be considered pathogenic factors in any linkage between organic and psychometric vertigo syndromes.

Background: Antipsychotic treatment in schizophrenia is frequently associated with extrapyramidal side effects. Objective behavioural measures to evaluate the severity of extrapyramidal side effects in the clinical setting do not exist. Objectives: This study was designed to investigate grasping movements in five drug naive and 13 medicated subjects with schizophrenia and to compare their performance with that of 18 healthy control subjects. Deficits of grip force performance were correlated with clinical scores of both parkinson-like motor disability and psychiatric symptom severity Methods: Participants performed vertical arm movements with a handheld instrumented object and caught a weight that was dropped into a handheld cup either expectedly from the opposite hand or unexpectedly from the experimenter’s hand. The scaling of grip force and the temporospatial coupling between grip and load force profiles was analysed. The psychiatric symptom severity was assessed by the positive and negative symptom score of schizophrenia and the brief psychiatric rating scale. Extrapyramidal symptoms were assessed by the unified Parkinson’s disease rating scale. Results: Drug naive subjects with schizophrenia performed similar to healthy controls. In contrast, medicated subjects with schizophrenia exhibited excessive grip force scaling and impaired coupling between grip and load force profiles. These performance deficits were strongly correlated with the severity of both extrapyramidal side effects related to antipsychotic therapy and negative symptoms related to the underlying pathology. Conclusions: These data provide preliminary evidence that deficits of sensorimotor performance in schizophrenia are, at least in part, related to the side effects of antipsychotic treatment. The investigation of grasping movements may provide a sensitive measure to objectively evaluate extrapyramidal side effects related to antipsychotic therapy.

Background: Adhesion molecules and matrix metalloproteinases (MMPs) are known to be relevant to the ongoing development and disappearance of areas of demyelination in the white matter of the CNS of multiple sclerosis (MS) patients. This study examined whether serum matrix metalloproteinase-3 (MMP-3) levels correlate with disease activity in MS. Methods: Serum MMP-3 levels in 47 consecutive patients with relapsing-remitting MS were measured by immunoassay every 4 weeks over a 15 month period. Results: During the study period, 48 clinical relapses occurred. Serum MMP-3 levels within 1 month of relapse were significantly higher than during the remission phase. Sequential analysis showed that serum MMP-3 levels had increased transiently at the time of clinical relapse but returned to the normal range within a month. Conclusions: Circulatory MMP-3 levels are correlated with disease activity in relapsing-remitting MS. This may contribute to the breakdown of the blood-brain barrier at the time of relapse.

We sought to determine the prevalence, clinical features, and laboratory characteristics of polyneuropathies in Waldenström's macroglobulinaemia (WM), a malignant bone marrow disorder with lymphocytes that produce monoclonal IgM.We prospectively studied 119 patients with WM and 58 controls. Medical history was taken, and neurological examinations, electrodiagnostic tests, and serum studies were performed by different examiners who were blinded to results except the diagnosis of WM.Polyneuropathy symptoms, including discomfort and sensory loss in the legs, occurred more frequently (p0.001) in patients with WM (47%) than in controls (9%). Patients with WM had 35% lower quantitative vibration scores, and more frequent pin loss (3.4 times) and gait disorders (5.5 times) than controls (all p0.001). Patients with IgM binding to sulphatide (5% of WM) had sensory axon loss; those with IgM binding to myelin associated glycoprotein (MAG) (4% of WM) had sensorimotor axon loss and demyelination. Patients with WM with IgM binding to sulphatide (p0.005) or MAG (p0.001) had more severe sensory axon loss than other patients with WM. Demyelination occurred in 4% of patients with WM with no IgM binding to MAG. Age related reductions in vibration sense and sural SNAP amplitudes were similar ( approximately 30%) in WM and controls.Peripheral nerve symptoms and signs occur more frequently in patients with WM than controls, involve sensory modalities, and are often associated with gait disorders. IgM binding to MAG or sulphatide is associated with a further increase in the frequency and severity of peripheral nerve involvement. Age related changes, similar to those in controls, add to the degree of reduced nerve function in patients with WM.

Background: Frontotemporal dementia (FTD) and Alzheimer's disease are clinically distinct disorders, yet neuropsychological studies have had variable success in distinguishing them. A possible reason is that studies typically rely on overall accuracy scores, which may obscure differences in reasons for failure. Objectives: To explore the hypothesis that analysis of qualitative performance characteristics and error types, in addition to overall numerical scores, would enhance the neuropsychological distinction between FTD and Alzheimer's disease. Methods: 38 patients with FTD and 73 with Alzheimer's disease underwent assessment of language, visuospatial abilities, memory, and executive function, using a neuropsychological screening instrument and standard neuropsychological tests. In each of these cognitive domains, performance characteristics and error types were documented, in addition to numerical scores on tests. Results: Whereas comparison of neuropsychological test scores revealed some group differences, these did not occur consistently across tests within cognitive domains. However, analysis of performance characteristics and error types revealed qualitative differences between the two groups. In particular, FTD patients displayed features associated with frontal lobe dysfunction, such as concrete thought, perseveration, confabulation, and poor organisation, which disrupted performance across the range of neuropsychological tests. Conclusions: Numerical scores on neuropsychological tests alone are of limited value in differentiating FTD and Alzheimer's disease, but performance characteristics and error types enhance the distinction between the two disorders. FTD is associated with a profound behavioural syndrome that affects performance on cognitive assessment, obscuring group differences. Qualitative information should be included in neuropsychological research and clinical assessments.

Objective: To clarify the progression of autonomic symptoms and functional deterioration in pure autonomic failure (PAF), particularly in comparison with multiple system atrophy (MSA). Methods: The investigation involved eight patients with PAF (M/F = 7/1; mean age at onset, 57 years) and 22 with probable MSA matched for age at onset (M/F = 14/8; onset 56 years). Subjects were followed up for neurological symptoms, activities of daily living, and autonomic function for more than seven years. Autonomic functional tests were carried out. Results: In PAF, fainting or sudomotor dysfunction occurred first, followed by constipation and syncope. Urinary dysfunction developed late, and respiratory dysfunction was not evident. This clinical course contrasted sharply with that in MSA, where early urinary dysfunction usually proceeded to sudomotor dysfunction or orthostatic hypotension (p = 0.004), followed by respiratory dysfunction (p = 0.0004). Results of pharmacological tests also distinguished PAF from MSA. Progression and prognosis in patients with PAF did not worsen, unlike the steady progressive autonomic dysfunction in MSA (p

Objective: To determine the sensitivity and specificity of clinical tests for detecting focal lesions in a prospective blinded study. Methods: 46 patients with a focal cerebral hemisphere lesion without obvious focal signs and 19 controls with normal imaging were examined using a battery of clinical tests. Examiners were blinded to the diagnosis. The sensitivity, specificity, and positive and negative predictive values of each test were measured. Results: The upper limb tests with the greatest sensitivities for detecting a focal lesion were finger rolling (sensitivity 0.33 (95% confidence interval, 0.21 to 0.47)), assessment of power (0.30 (0.19 to 0.45)), rapid alternating movements (0.30 (0.19 to 0.45)), forearm rolling (0.24 (0.14 to 0.38)), and pronator drift (0.22 (0.12 to 0.36)). All these tests had a specificity of 1.00 (0.83 to 1.00). This combination of tests detected an abnormality in 50% of the patients with a focal lesion. In the lower limbs, assessment of power was the most sensitive test (sensitivity 0.20 (0.11 to 0.33)). Visual field defects were detected in 10 patients with a focal lesion (sensitivity 0.22 (0.12 to 0.36)) and facial weakness in eight (sensitivity 0.17 (0.09 to 0.31)). Overall, the examination detected signs of focal brain disease in 61% of the patients with a focal cerebral lesion. Conclusions: The neurological examination has a low sensitivity for detecting early cerebral hemisphere lesions in patients without obvious focal signs. The finger and forearm rolling tests, rapid alternating movements of the hands, and pronator drift are simple tests that increase the detection of a focal lesion without greatly increasing the length of the examination.

Objectives: Since 1998, migraine with aura (MA) has been diagnosed according to the operational diagnostic criteria of the International Headache Society (ICHD-1). Here we present the data underlying the new criteria for MA in the ICHD-2 classification. Methods: Sensitivity of the new criteria was tested in patients with MA and specificity in patients with reversible non-aura visual disturbances. The diagnoses in both groups of patients were made in a validated semistructured physician-conducted interview. We tested five sets of criteria for sensitivity and specificity comparing with the diagnosis according to the ICHD-1 in 200 patients and the selected set of criteria in 274 additional patients. Results: Four sets of criteria had sensitivity/specificity of 46%/100%, 71%/100%, 62%/95%, and 99%/76%. Sensitivity of the selected set of criteria was 84% (95% CI 79% to 90%) and specificity 97% (95% CI 95% to 99%). According to these criteria at least two of the following should be fulfilled: homonymous visual or unilateral sensory symptoms; at least one aura symptom develops gradually over ⩾5 minutes and/or different symptoms occur in succession over ⩾5 minutes; each symptom lasts ⩾5 and ⩽60 minutes. In the additional sample sensitivity of the selected criteria was 90% (95% CI 86% to 94%) and specificity 96% (95% CI 91% to 100%). Conclusions: The diagnostic criteria for MA selected for ICHD-2 had high sensitivity and specificity. The ICHD-2 criteria are more operational and probably delineate a more homogeneous sample of patients than the ICHD-1. The ICHD-2 for MA is intended equally for research and clinical practice and can be used at different levels of specialisation.

Objectives: Anatomical evidence and lesion studies, as well as functional magnetic resonance imaging (fMRI) studies, indicate that the cerebellum contributes to higher cognitive functions. Cerebellar posterior lateral regions seem to be relevant for cognition, while vermal lesions seem to be associated with changes in affect. However, the results remain controversial. Deficits of patients are sometimes still attributed to motor impairment. Methods: We present data from a detailed neuropsychological examination of 21 patients with cerebellar lesions due to tumour or haematoma, and 21 controls matched for age, sex, and years of education. Results: Patients showed deficits in executive function, and in attentional processes such as working memory and divided attention. Further analysis revealed that patients with right-sided lesions were in general more impaired than those with left-sided lesions. Conclusions: Those hypotheses that suggest that lesions of the right cerebellar hemisphere lead to verbal deficits, while those of the left lead to non-verbal deficits, have in part been confirmed. The generally greater impairment of those patients with a right-sided lesion has been interpreted as resulting from the connection of the right cerebellum to the left cerebral hemisphere, which is dominant for language functions and crucial for right hand movements. Motor impairment was correlated with less than half of the cognitive measures, with no stronger tendency for correlation with cognitive tests that require motor responses discernible. The results are discussed on the basis of an assumption that the cerebellum has a predicting and preparing function, indicating that cerebellar lesions lead to a "dysmetria of thought."

Background: It is unclear whether contraction of the external anal sphincter (EAS) following a voluntary cough is an integral component of the cough response itself, or a reflex response to the abdominal and pelvic floor dynamics induced by the cough. Clinical experience suggests a reflex origin for this response. Objective: To compare motor latencies for intercostal, abdominal, and EAS muscle contraction after transcranial magnetic stimulation with those following voluntary coughing and sniffing. Methods: A needle electrode inserted into the EAS measured responses, which were confirmed by tonic electromyographic recording. Direct motor latencies from the cerebral cortex to the intercostal, rectus abdominis and EAS muscles were obtained using transcranial magnetic stimulation. Sniff and cough induced responses were also recorded in these muscles. Results: The results suggest that EAS responses following a voluntary cough or sniff represent a polysynaptic reflex. Conclusions: As the cough induced anal reflex response is consistent and easily elicited, its use in clinical neurological examination is appropriate.

Background: Anosognosia is a common manifestation of Alzheimer's disease. There is an association between impaired awareness and frontal-executive cognitive deficits. Anosognosia is also correlated with decreased metabolism in the right hemisphere, particularly in frontal lobe regions. Objective: To investigate pathological correlates of anosognosia in Alzheimer's disease. Design: 41 subjects followed longitudinally in the University of Pittsburgh memory disorders clinic and with necropsy verified Alzheimer's disease were divided into two groups, based on previous clinical assessment: +Aware (n = 23) and –Aware (n = 18). A subset analysis matching subjects for dementia severity using mini-mental state examination scores was also carried out (13 +Aware; 13 –Aware). Histopathological data from necropsy brain tissue consisted of senile plaque (SP) and neurofibrillary tangle (NFT) counts (regional density) from four different brain regions in the right and left hemispheres: superior and middle frontal gyri (SMF), superior temporal isocortex (ST), the prosubiculum of the hippocampus (PRO), and the entorhinal cortex (EC). Results: SP density was greater in the right PRO region of –Aware subjects (F = 6.54, p = 0.015) than +Aware subjects. Significant differences between SP or NFT density were not observed in any other regions. In the subset analysis matching for dementia severity, SP density was again greater in the right PRO region of –Aware subjects than in the other regions (F = 12.72, p = 0.002). Conclusions: Increased SP density in the right PRO region suggests that selective pathological involvement of this area contributes to awareness deficits in Alzheimer's disease. The putative role of the PRO in self appraisal may reflect its interconnections with other medial temporal and prefrontal regions.

Objective: To investigate a comprehensive battery of neurophysiological tests for objective evaluation of sensory neuropathies including fibre type involvement and severity, and to determine the relation between neurophysiological data and clinical examination. Methods: 45 patients referred for sensory neuropathy were studied using a standardised clinical evaluation of large and small fibre symptoms and an original neurophysiological battery. Clinical evaluation included: assessment of tactile, vibratory, and pin sensation; tendon reflexes; toe position sense; ataxia score; pain level; and presence of trophic, vasomotor, or sudomotor abnormalities. The neurophysiological battery included: recording of large fibre and small fibre components of the sural sensory nerve action potential; somatosensory evoked cortical potentials and soleus H reflex following tibial nerve electrical stimulation; laser evoked potentials following Nd:YAG laser stimulation of the foot; and plantar sympathetic skin response to median nerve stimulation. Neuropathy was classified according to the predominantly affected fibre type, and a severity score was established based on clinical and neurophysiological abnormalities. Results: On clinical examination there were 22 patients with large fibre sensory neuropathy (LFSN), 18 with mixed sensory neuropathy (MSN), and five with small fibre sensory neuropathy (SFSN). Neurophysiological classification identified 25 patients with LFSN, 13 with MSN, and seven with SFSN. Clinical and neurophysiological classifications and severity scores were correlated, whatever the type of neuropathy. Conclusions: The correlation between clinical examination and the results of an original neurophysiological test battery offers a comprehensive clinical and neurophysiological approach to the objective assessment of peripheral neuropathies according to fibre type involvement and overall severity.

Objective: To identify the presence of vestibulo-ocular arreflexia in patients with Machado-Joseph disease (MJD), which can easily be diagnosed at the bedside. Methods: Seven patients with MJD from five unrelated families and 11 patients with sporadic or hereditary cerebellar ataxia other than MJD underwent a detailed neuro-otological and oculomotor examination. Six MJD and five non-MJD patients also underwent electro-oculographic recordings and caloric tests. Results: Gaze evoked nystagmus, smooth pursuit, and saccade abnormalities were found in both MJD and non-MJD patients. However, in all seven MJD patients but in none of the non-MJD patients, sudden passively induced head thrust to both sides elicited pathological corrective catch-up saccades, indicating bilateral loss of the horizontal vestibulo-ocular reflex. This was further confirmed in six MJD patients who had absent vestibular response to both a standard caloric test and ice water ear irrigation. Nystagmus was induced by standard caloric irrigation in all non-MJD patients examined. There was no correlation between the loss of vestibular function and the severity of cerebellar impairment. Conclusions: The presence of vestibulo-ocular arreflexia, as measured by the head thrust test in a patient with dominant cerebellar ataxia, strongly suggests the diagnosis of MJD.

Objective: To describe the diagnostic yield and prognosis for patients with hemisensory syndrome. Background: The aetiology, utility of diagnostic procedures, and outcome of hemisensory syndrome in patients with exclusive hemibody complaints having only subjective sensory abnormalities on examination is unknown. Methods: Patients were prospectively identified with hemisensory syndrome in a tertiary care institution from 1998–2002. Diagnostic procedures were analysed for sensitivity and clinical follow up was performed. Results: Thirty four patients, 25 (74%) women, of age 35 (SD 11) years were identified. The hemisensory syndrome occurred on the left side in 23 (68%) cases. Neuroimaging of the brain demonstrated diagnostic abnormalities representing ischaemic aetiology in one case. Other diagnostic testing including cerebrospinal fluid examination, electrophysiological testing, carotid ultrasonography, echocardiography, and blood testing revealed no diagnostic abnormalities. Sixteen patients (47%) continued to complain of hemisensory difficulties after all investigations were completed at 9.6 (5.8) days. One patient with a history of systemic lupus erythematosus and positive antiphospholipid antibodies had a second event diagnosed as stroke seven months after presentation. Clinical follow up at 16 (7) months revealed persisting symptoms in 6 (20%) of 30 patients. Six (50%) of 12 patients agreeing to psychiatric assessment received diagnoses of personality or mood disorders. Conclusions: Diagnostic yield in hemisensory syndrome is low, and prognosis is almost always uniformly benign. The author advocates careful assessment of medical history and consideration for neuroimaging in this group of patients.

BACKGROUND: Myasthenia gravis is a potentially serious but treatable muscle disease caused by autoantibodies directed at the acetylcholine receptor (AChR) on the postsynaptic membrane of the neuromuscular junction. There is anecdotal evidence that the diagnosis is sometimes missed in older patients. OBJECTIVE: To examine the incidence and age distribution of positive AChR antibodies in samples referred to diagnostic laboratories in the UK, and the prevalence of positive AChR antibodies in samples from a cohort of older individuals. METHODS: Positive AChR antibody tests were identified from all UK centres registered for the assay with the European quality assurance scheme (EQAS) during 1997-99, and the age and sex specific incidence was calculated, based on the UK population. The prevalence of AChR antibodies in sera from a sample of 2000 individuals aged > or =60 years was determined. RESULTS: 3183 individuals had positive AChR antibody tests on routine screening during the years 1997 to 1999 in the UK, giving an annual incidence of 1.8/100 000. In both sexes, the age specific incidence rose steeply between the ages of 45 and 74, reaching 9.9/100 000 in men, and then fell, with a sharp decline above the age of 80. In the prevalence study, whereas only one serum from individuals aged 60-74 years was positive for AChR antibodies (0.12%), sera from eight individuals aged > or =75 years were positive (0.7%). Only one had a previous clinical diagnosis of myasthenia gravis but four others had histories of stroke or transient ischaemic attacks. CONCLUSIONS: The sharp fall in the incidence of clinically recognised myasthenia gravis in people over 80 years of age in our national AChR antibody incidence study, and the high prevalence of previously unrecognised positive AChR antibodies in those > or =75 years old, suggest that myasthenia gravis may be substantially underdiagnosed in older people.

Background: Hereditary spastic paraparesis (HSP) denotes a group of inherited neurological disorders with progressive lower limb spasticity as their clinical hallmark; a large proportion of autosomal dominant HSP belongs to HSP type 4, which has been linked to the SPG4 locus on chromosome 2. A variety of mutations have been identified within the SPG4 gene product, spastin. Objective: Correlation of genotype and electrophysiological phenotype. Material: Two large families with HSP linked to the SPG4 locus with a very similar disease with respect to age of onset, progression, and severity of symptoms. Methods: Mutation analysis was performed by PCR from genomic DNA and cDNA, and direct sequencing. The motor system was evaluated using transcranial magnetic stimulation. Results: Patients differ in several categories depending on the type of mutation present. Conclusions: For the first time in hereditary spastic paraparesis, a phenotypic correlate of a given genetic change in the spastin gene has been shown.

Objectives: To analyse the results of gamma knife radiosurgery (GKS) for the trreatment of intracranial meningiomas and to assess possible factors related to the outcome and complications of such treatment. Methods: The authors retrospectively reviewed the clinical and radiological data of 179 patients (194 lesions) treated with GKS for meningiomas between May 1992 and October 2000. The mean follow up duration was 37.3 months (range 6.4 to 86.3 months). The study determined the correlation between radiosurgical outcome including imaging changes after GKS and multiple factors such as tumour location and size, patient characteristics, venous sinus status, pre-GKS degree of oedema, other treatment modalities, and radiosurgical parameters. Results: The radiological control rate was 97.1%. Magnetic resonance imaging (MRI) showed complications after GKS in 35 lesions (25.0%) among the 140 lesions followed up with MRI. Complications were divided into peritumorous imaging changes (33 lesions; 23.6%) and transient cranial nerve dysfunction (two lesions; 1.4%). Radiation induced imaging changes were seen mostly in convexity, parasagittal, and falx meningiomas that were deeply embedded in the cortex. About 60% of these were asymptomatic and the overall rate of symptomatic imaging changes was 9.3%. Neurological deficit related to imaging changes developed in only three patients, and all the symptoms were transient. Conclusion: GKS for intracranial meningiomas seems to be a safe and effective treatment. However, meningiomas of the convexity, parasagittal region, or falx cerebri have a higher incidence of peritumorous imaging changes after GKS than those of the skull base. Therefore, the use of GKS needs to be considered very cautiously in cerebral hemispheric meningiomas, taking into consideration patient age and general condition, tumour size and location, pattern of cortical embedding, relation between the tumour and venous sinuses, presenting symptoms, and patient preference.

Objective: To undertake a prospective study of the long term neuropsychological outcome in patients with late onset idiopathic aqueduct stenosis (LIAS) after endoscopic third ventriculostomy. Methods: Six patients with LIAS were evaluated pre- and postoperatively using magnetic resonance imaging (MRI) and standardised psychometric testing procedures. Endoscopic third ventriculostomy was done using standard surgical techniques. The mean long term follow up was 81.2 weeks. Results: Preoperatively, all patients had cognitive impairment, four of them showing deficits in several cognitive domains. After endoscopic third ventriculostomy, all patients improved clinically and had ventricular size reduction on MRI. Postoperative neuropsychological testing showed that five patients achieved normal or near normal cognitive functions, and one improved moderately. Conclusions: Endoscopic third ventriculostomy caused a substantial improvement in the neuropsychological deficit of LIAS patients. This was also true for patients with enlarged ventricles that might be diagnosed radiologically as "arrested hydrocephalus."

Objectives: To determine the efficacy of a two week and a four week course of oral steroids in the conservative treatment of carpal tunnel syndrome. Methods: 109 patients with carpal tunnel syndrome were randomly divided into two treatment groups: (1) two weeks of prednisolone 20 mg daily followed by two weeks of prednisolone 10 mg daily (n = 53); (2) two weeks of prednisolone 20 mg daily and two weeks of placebo (n = 56). A symptom questionnaire was used to rate the five major symptoms of carpal tunnel syndrome (numbness, pain, weakness/clumsiness, tingling, and nocturnal awakening) on a scale of 0 (nil) to 10 (severe); the resulting global symptom score was used to evaluate the efficacy of treatment. Assessments were made at baseline and at one, three, six, nine, and 12 months. Electrodiagnosis was repeated at the end of the study to validate improvement. Results: In an intention to treat analysis at the end of the study, improvement in the four week treatment group was achieved in 66.0% of the patients after one month and in 49.0% at the end of the study; in the two week treatment group, the respective values were 48.2% and 35.7%. In the four week treatment group, 51% were considered treatment failures (including those lost to follow up, receiving surgery, or with mild or no improvement), compared with 64.3% for the two week group. Though the percentage improvement was higher in the four week group, the difference did not reach a statistical significance. Persistence of improvement was 74.2% in the four week group v 74.1% in the two week group, suggesting no difference in the long term effect. Efficacy analysis showed no significant difference in global symptom score reduction between the two groups. Follow up electrodiagnosis showed significant improvement in all measured variables except for the amplitude of compound muscle action potentials. Conclusions: Short term low dose oral steroid are effective treatment for carpal tunnel syndrome. The dose of steroids and the duration treatment are not key determinants of efficacy.

Aims: To evaluate micturition abnormalities in acute transverse myelitis and correlate these with evoked potentials, magnetic resonance imaging (MRI), and urodynamic findings. Setting: Tertiary care teaching hospital. Patients: 18 patients with acute transverse myelitis, aged 4–50 years; 15 had paraparesis and three quadriparesis. Methods: Patients with acute transverse myelitis had a neurological evaluation and tibial somatosensory and motor evoked potential studies in the lower limbs. Spinal MRI was carried out using a 1.5 T scanner. Urodynamic studies were done using Dantec UD 5500 equipment. Neurological outcome was determined on the basis of Barthel index score at six months as poor, partial, or complete. In some patients, urodynamic studies were repeated at six and 12 months. Results: Spinal MRI in 14 of the 18 patients revealed T2 hyperintense signal changes extending for at least three spinal segments in 13; one patient had normal MRI. In the acute stage, 17 patients had a history of urinary retention and one had urge incontinence. On follow up at six months two patients regained normal voiding, retention persisted in six, and storage symptoms developed in 10, of whom five also had emptying difficulties. Urodynamic studies showed an areflexic or hypocontractile bladder in 10, detrusor hyperreflexia with poor compliance in two, and detrusor sphincter dyssynergia in three. Early abnormal urodynamic findings commonly persisted at the six and 12 months examinations. Persistent abnormalities included detrusor hyperreflexia, dyssynergia, and areflexic bladder. The urodynamic abnormalities correlated with muscle tone and reflex changes but not with sensory or motor evoked potentials, muscle power, MRI signal changes, sensory level, or six months outcome. Conclusions: Bladder dysfunction is common in acute transverse myelitis and may be the only sequel. Urodynamic study is helpful in evaluating the bladder dysfunction and also in its management.

Objective: To evaluate patient characteristics, symptoms, and examination findings in the clinical diagnosis of lumbosacral nerve root compression causing sciatica. Methods: The study involved 274 patients with pain radiating into the leg. All had a standardised clinical assessment and magnetic resonance (MR) imaging. The associations between patient characteristics, clinical findings, and lumbosacral nerve root compression on MR imaging were analysed. Results: Nerve root compression was associated with three patient characteristics, three symptoms, and four physical examination findings (paresis, absence of tendon reflexes, a positive straight leg raising test, and increased finger-floor distance). Multivariate analysis, analysing the independent diagnostic value of the tests, showed that nerve root compression was predicted by two patient characteristics, four symptoms, and two signs (increased finger-floor distance and paresis). The straight leg raise test was not predictive. The area under the curve of the receiver-operating characteristic was 0.80 for the history items. It increased to 0.83 when the physical examination items were added. Conclusions: Various clinical findings were found to be associated with nerve root compression on MR imaging. While this set of findings agrees well with those commonly used in daily practice, the tests tended to have lower sensitivity and specificity than previously reported. Stepwise multivariate analysis showed that most of the diagnostic information revealed by physical examination findings had already been revealed by the history items.

Objectives: To evaluate the sensitivity of diffusion weighted magnetic resonance imaging (MRI) for the diagnosis of clinically suspected reversible ischaemic deficits of the brainstem. Methods: A total of 158 consecutive patients presenting with acute signs of brainstem dysfunction were investigated using EPI diffusion weighted MRI within 24 hours of the onset of symptoms. High resolution T1 and T2 weighted imaging was performed as a follow up after a median of six days Results: Fourteen of the 158 patients had a complete clinical recovery within 24 hours (transitory ischaemic attack (TIA)), and 19 patients recovered in less than one week (prolonged reversible neurological deficit (RIND)). Diffusion weighted MRI showed acute ischaemic deficits in 39% of patients with transient neurological deficits. The detection rate seemed to be higher in patients with longer lasting symptoms, but the difference between patients with TIA (29%) and RIND (47%) was not significant. Conclusions: Diffusion weighted MRI is a sensitive indicator of acute ischaemic brainstem deficits even in patients with reversible neurological deficit. Early identification of patients with TIA and increased risk of stroke may influence acute management and improve patient outcome.

Objectives: This study was undertaken to review the indications for surgical treatment of brain stem cavernomas and to develop strategies to minimise the complications of surgery. Patients and results: Twelve patients underwent surgical resection of a brain stem cavernoma due to symptoms caused by one or more haemorrhages. Age ranged from 18 to 47 years (mean 29.2 years). Long term follow up (mean 3.7 years) included a complete neurological examination and annual MRI studies. The annual haemorrhage rate was 6.8 %/patient/year and a rate of 1.9 rehaemorrhages/patient/year was found. Surgery was performed under microsurgical conditions with endoscopic assistance, use of neuronavigation, and neurophysiological monitoring. Navigation proved to be reliable when applied in an early stage of operative procedure with minimal brain retraction. Endoscopy was a useful tool in some cases to confirm complete resection of the lesion and to ascertain haemostasis. Ten patients had a new neurological deficit in the early postoperative period, nine of these were transient. At the last follow up the neurological state was improved in five patients, unchanged in six, and worse in one compared with the preoperative conditions. The preoperative average Rankin score was 2.2 points and had improved at the last follow up by 0.6 points to 1.6 points. Conclusions: Symptomatic brain stem cavernomas should be considered for surgical treatment after the first bleeding. Careful selection of the optimal operative approach and a meticulous microsurgical technique are mandatory. The additional use of modern tools such as neuronavigation, endoscopic assistance, and monitoring can contribute to the safety of the procedure.

Objective: To delineate the frequency and nature of dystonia in multiple system atrophy (MSA). Methods: a cohort of 24 patients with clinically probable MSA over the past 10 years were prospectively followed up. Motor features were either dominated by parkinsonism (MSA-P subtype, n=18) or cerebellar ataxia (MSA-C, n=6). Classification of dystonic features and their changes with time was based on clinical observation during 6–12 monthly follow up visits. Parkinsonian features and complications of drug therapy were assessed. Most patients (22/24) died during the observation period. Neuropathological examination was confirmatory in all of the five necropsied patients. Results: At first neurological visit dystonia was present in 11 (46%) patients all of whom had been levodopa naive at this time point. Six patients (25%) exhibited cervical dystonia (antecollis) (MSA-P n=4, MSA-C n=2), five patients (21%) showed unilateral limb dystonia (MSA-P n=4; MSA-C n=1). A definite initial response to levodopa treatment was seen in 15/18 patients with MSA-P, but in none of the six patients with MSA-C. A subgroup of 12 patients with MSA-P developed levodopa induced dyskinesias 2.3 years (range 0.5–4) after initiation of levodopa therapy. Most patients had peak dose craniocervical dystonia; however, some patients experienced limb or generalised dystonia. Isolated peak dose limb chorea occurred in only one patient. Conclusion: The prospective clinical study suggests that dystonia is common in untreated MSA-P. This finding may reflect younger age at disease onset and putaminal pathology in MSA-P. Levodopa induced dyskinesias were almost exclusively dystonic affecting predominantly craniocervical musculature. Future studies are required to elucidate the underlying pathophysiology of dystonia in MSA.

Objectives: The study aimed at addressing the issue of the precise nature of gait apraxia and the cerebral dysfunction responsible for it. Methods: The case of a patient, affected by a bilateral infarction limited to a portion of the anterior cerebral artery territory is reported. The patient's ability to walk was formally assessed by means of a new standardised test. Results: Due to an anomaly within the anterior cerebral artery system, the patient's lesion was centred on the supplementary motor regions of both hemispheres. He presented with clear signs of gait apraxia that could not be accounted for by paresis or other neurological deficits. No signs of any other form of apraxia were detected. Conclusions: The clinical profile of the patient and the analysis of 49 cases from previous literature suggest that gait apraxia should be considered a clinical entity in its own right and lesions to the supplementary motor areas are responsible for it.

OBJECTIVES—The pathophysiology of dysarthria can preferentially be studied in patients with the rare lacunar stroke syndrome of "isolated dysarthria". METHODS— A single study was carried out on seven consecutive patients with sudden onset of isolated dysarthria due to single ischaemic lesion. The localisation of the lesion was identified using MRI. The corticolingual, cortico-orofacial, and corticospinal tract functions were investigated using transcranial magnetic stimulation. Corticopontocerebellar tract function was assessed using 99mTc hexamethylpropylene amine oxime-single photon emission computerised tomography (HMPAO-SPECT) in six patients. Sensory functions were evaluated clinically and by somatosensory evoked potentials. RESULTS—Brain MRI showed the lesions to be located in the corona radiata (n=4) and the internal capsule (n=2). No morphological lesion was identified in one patient. Corticolingual tract function was impaired in all patients. In four patients with additional cortico-orofacial tract dysfunction, dysarthria did not differ from that in patients with isolated corticolingual tract dysfunction. Corticospinal tract functions were normal in all patients. HMPAO-SPECT showed no cerebellar diaschisis, suggesting unimpaired corticopontocerebellar tract function. Sensory functions were not affected. CONCLUSION—Interruption of the corticolingual pathways to the tongue is crucial in the pathogenesis of isolated dysarthria after extracerebellar lacunar stroke.

OBJECTIVE A previous study of botulinum toxin type F (BTX-F) treatment for torticollis had shown a dose of 520 MU to be effective, but for a much shorter duration than is usual with botulinum toxin type A (BTX-A). The objective was to assess the effect of a higher dose of BTX-F. METHODS Four of the previously treated patients, plus an additional patient, were treated with a higher dose of 780 MU BTX-F. All were secondary non-responders to BTX-A due to neutralising antibodies. A test injection of 40 MU BTX-F was also given into the extensor digitorum brevis muscle (EDB), to examine the time course of the biological effect of the toxin electrophysiologically. Patients were followed up at two, four, eight, and 12 weeks. RESULTS All patients reported subjective improvement lasting from seven to 11 (mean 8.6) weeks accompanied by a significant reduction in mean clinical severity scores at two weeks. Four patients had pain which was substantially reduced. The electrophysiological studies confirmed biological sensitivity to the toxin in all patients, showing a significant change beginning at two weeks and returning to baseline at 12 weeks. The time course of this effect paralleled roughly that of the clinical response. The four patients who had previously received 520 MU BTX-F reported that the response was better and longer in duration with 780 MU. Dysphagia was more common than reported with the lower dose. CONCLUSION Better results are possible with higher doses of BTX-F but the duration of benefit is still shorter than with BTX-A, seemingly due to a shorter duration of neuromuscular junction blockade.

Objective—The blink rate is an index which can be easily obtained during the clinical examination, but it has not yet been properly standardised. The present study was undertaken to collect data on the age dependent development of this index and on possible abnormalities in Parkinson’s disease and dystonia. Methods—The blink rate and the rate of perioral movements were measured in 156 normal controls, 51 patients with Parkinson’s disease, 48 patients with spasmodic torticollis, 14 patients with generalised dystonia, and 12 patients with focal hand or leg dystonias and have been correlated with the results of testing the orbicularis oculi reflex, the palmomental reflex, and the perioral reflex. Results—No age related eVects were found for the blink rate and perioral movements but all the reflexes showed age dependent variations. It is suYcient to measure the blink rate for one minute, provided standardised conditions are applied. Blink rate and perioral movement rate were positively correlated in patients and controls. The blink rate was significantly increased in spasmodic torticollis and decreased in Parkinson’s disease. In generalised dystonia the blink rate was increased but in hand and leg dystonia the blink rate was normal. The reflex tests did not significantly diVer between the subject groups except for the orbicularis oculi reflex, which was hyperexitable in Parkinson’s disease. Conclusion—Measuring the blink rate can assist the diagnosis of extrapyramidal disorders as a soft sign, but is not very sensitive. The group diVerences found indicate a decrease of the blink rate and perioral movements in hypokinetic and an increase in hyperkinetic extrapyramidal disorders such as spasmodic torticollis and generalised dystonias. This may be of interest for future pathophysiological studies. (J Neurol Neurosurg Psychiatry 1998;64:320‐324)

Marquardt et al describe the clinical course and long term outcome of 21 patients they diagnosed as having a perimesencephalic haemorrhage.1 The paper raises two questions. The first is an impression of an “emperor's new clothes syndrome” given by the first figure of the publication. This figure shows a slice of the CT made shortly after the initial episode of headache in the patient reported to have a recurrent episode of perimesencephalic haemorrhage. The legend of the figure states that the CT shows extravasated blood in the perimesencephalic subarachnoid space, but we fail to see any blood at all. Thanks to the electronic availability of the Journal we were able to review not only the paper version of the figure, but also an enlarged version on screen. Even after enlargement no blood was seen; the slice nicely shows the tentorium adjacent to the ambient cisterns, the proximal parts of the posterior cerebral arteries, and perfectly clear CSF in the perimesencephalic (chiasmatic and partly the ambient and quadrigeminal) cisterns and in the frontal interhemispheric and sylvian fissures. There are several explanations for this diagnostic mystery. Firstly, the authors may have submitted an inappropriate slice of the CT. In some patients with perimesencephalic haemorrhage, the prepontine cistern is the only site where CT shows blood.2 If blood was visible in the prepontine cistern in this particular patient, the authors have indeed found a patient with a perimesencephalic, non-aneurysmal haemorrhage with a recurrent haemorrhage. Given the unique character of this sequence of events, it would be fair to provide the appropriate slice to convince readers of the Journal . Secondly, if no evidence of blood is found even in the prepontine cistern, the patient may have had a CT negative subarachnoid haemorrhage. In patients with ruptured aneurysms CT can be … Dr G Marquardt

This paper has reviewed the techniques used for recording evoked potentials in the premature infant and the early developmental changes. The maturational changes in the evoked potentials, including morphological changes, and the very rapid latency changes within the first months of life, provide an invaluable means for assessing and monitoring development within the central nervous system. The maturational changes are such that normative values are requisite, and the norms must take into account both the infant's gestational age at birth as well as the postnatal age. These norms can then be used to aid in the assessment of gestational age, and whether there has or has not been normal maturational development, either in utero or during the postnatal preterm period. Evoked potentials are of increasing value clinically in preterm neonates, primarily because of the difficulty in obtaining reliable neurological evaluation of these infants. Median nerve SEPs may provide reliable information in preterm infants at risk of PVL, and when recorded in the second week of life, predict cerebral palsy. PTN SEPs seem to be even more reliable indicators of outcome, but the difficulty in obtaining them in preterm infants needs to be taken into consideration. Further study is needed in some areas, such as in apnoeic preterm babies clearly to establish the role that evoked potentials (in this case BAEPs) may have in understanding both the aetiology and the clinical course of this dysfunction. In other conditions, such as delayed intrauterine growth, that may lead to neurological sequelae, evoked potentials can provide objective CNS assessment. Evoked potentials may also prove useful in the monitoring of treatment modalities for preterm infants. The evoked potentials are a valuable adjunct in the assessment of preterm neonates and, as their value is recognised, we expect their use to increase.