The aim of this study was to evaluate cognitive impairment in patients with spinocerebellar ataxia type 6 (SCA6) and to verify the role of cerebellar involvement in intellectual abilities.
Cognitive function was examined in 18 patients with genetically confirmed SCA6 and in 21 age and education matched controls using a test battery for attention, verbal and visuospatial memory, as well as executive function.
Verbal fluency and immediate visual memory task were markedly impaired in SCA6 compared with the control group (p = 0.007, 0.004 and 0.014, respectively). The results of the Rule Shift Cards Test was reduced in patients with SCA6, but the reduction was not significant. These cognitive dysfunctions did not correlated with CAG repeat length, age at onset, ataxic motor dysfunctional scale or depression.
Our results demonstrate that specific cognitive deficits occur in patients with SCA6, independent of ataxic motor dysfunction. These deficits may reflect disruption of cortico-cerebellar circuits.
The ventrolateral (VL) nucleus of the thalamus is the commonly chosen target for deep brain stimulation (DBS) to alleviate tremor. However, it has a poor efficacy in alleviating proximal tremor and patients may develop tolerance to the action component of tremor. We performed bilateral stimulation of the caudal or motor part of the zona incerta nucleus (cZI) to determine its safety and efficacy in alleviating tremor.
5 patients with parkinsonian tremor and 13 with a range of tremors (Holmes (HT), cerebellar (CT), essential (ET), multiple sclerosis (MS) and dystonic tremor (DT)) affecting both the proximal and distal body parts underwent MRI guided, bilateral cZI DBS. Tremor was assessed by the Fahn–Tolosa–Marin (FTM) tremor scale at baseline and at a mean follow-up of 12 months.
Resting PD tremor improved by 94.8% and postural tremor by 88.2%. The total tremor score improved by 75.9% in 6 patients with ET. HT improved by 70.2%, proximal CT by 60.4% and proximal MS tremor by 57.2% in the total tremor rating score. In the single patient with DT, there was improvement in both the dystonia and the tremor. Patients required low voltages of high-frequency stimulation and did not develop tolerance to it. Stimulation-related side effects were transient.
This prospective study shows that the cZI may be an alternative target for the treatment of tremor with DBS. In contrast to bilateral DBS of the VL nucleus, it improves all components of tremor affecting both the distal and proximal limbs as well as the axial musculature.
We hypothesise that parkinsonian tremor arises when the caudal zona incerta (cZI) and subthalamic nucleus (STN) are deprived of dopamine and become increasingly responsive to motor cortical and β frequency oscillations. These oscillations are synchronised and amplified through the basal ganglia thalamocortical loop and entrained into the cerebello-thalamocortical loop via the cZI. On receiving potent -aminobutyric acid (GABA)-ergic and β frequency oscillations in cZI afferents, ventrolateral (VL) thalamocortical neurons become hyperpolarised and rebound burst fire, generating 4–6 Hz tremor oscillations. We test this hypothesis by stimulating the cZI at and β frequencies using deep brain stimulation (DBS) in non-tremulous parkinsonian patients to see whether a 4–6 Hz tremor can be induced.
This study included 11 patients with non-tremulous Parkinson’s disease (PD), who had DBS leads implanted in a range of targets, including the cZI, STN, VL nucleus, globus pallidus internus (GPi), centromedian and parafascicular nucleus (CM/Pf), and the pedunculopontine nucleus (PPN). All patients underwent stimulation of active contacts within their respective targets at a standard pulse width, with frequencies ranging from 5 to 80 Hz up to a maximum tolerated voltage. The frequency of the tremor induced in the hands was recorded by accelerometry.
Resting tremor in the 4–6 Hz range could be readily induced following stimulation of the cZI and the VL nucleus between 5 and 40 Hz. Tremor was also seen following STN stimulation; however, this was only at high stimulation voltages (>5 volts). No tremor could be induced following CM/Pf, PPN or GPi stimulation.
We discuss the implications of these findings and argue that resting tremor in PD is generated in the cortico-ZI-VL-thalamocortical loop rather than in the cortico-basal-ganglia-thalamocortical loop.
Motor deficits in Parkinson’s disease (PD) are reduced by deep brain stimulation (DBS) of the subthalamic nucleus (STN), but the impact of this therapy on dysarthrophonic problems in PD remains controversial. We therefore aimed to disentangle the effects of STN DBS on the speech skills of long-term treated patients.
Under continued medication, speech and motor functions of 19 patients with PD with bilateral STN DBS were studied when their therapeutic stimulation was active (STIM-ON) versus switched off (STIM-OFF). Per condition, perceptual speech ratings were given by: (i) the patients themselves, (ii) the treating physician, and (iii) professional speech therapists. Furthermore, single speech parameters were measured with a battery of technical exams in both STIM-ON and STIM-OFF.
STN DBS significantly worsened speech performance according to all perceptual rating methods applied. In contrast, technical measures showed DBS-induced improvements of single speech dimensions affected by the PD-specific motor disorder. These changes occurred independently of the reduction of motor impairment, which was consistently effectuated by STN DBS.
In parallel to the beneficial effects on the motor symptoms of PD, STN DBS reduces designated disease-inherent dysarthrophonic symptoms, such as glottic tremor. However, these actions on speech are predominantly outweighed by the general dysarthrogenic effects of STN DBS, probably based on a decline of complex (eg, prosodic) functions. Thus, stimulation-induced speech impairment should be considered a likely problem in the course of this treatment.
Predicting aphasia recovery after stroke has been difficult due to substantial variability in outcomes. Few studies have characterised the nature and extent of recovery, beginning with baselines at 24–72 hours after stroke onset.
To characterise the course of language recovery after first-time stroke.
Using our Performance and Recovery in Stroke Study (PARIS) database, we evaluated consecutive first-time stroke patients with aphasia and diffusion-weighted-image-positive lesions on admission and at 90 days.
Twenty-two of 91 patients had language disorders. Initial syndrome scores were positively correlated with 90-day scores (r = 0.60) and negatively correlated with the change in score from baseline to follow-up (r = –0.66). Neither lesion size, age nor education correlated with initial syndrome severity or with performance at 90 days. Level of education was not associated with degree of recovery. A multiple regression model that combined lesion size, age and initial syndrome was significant (p = 0.03) but only explained 29% of the variance. Patients with severe deficits at baseline in individual language domains could recover, improve to a less severe deficit or not improve at all.
There was significant variability in language recovery after first-time stroke, even in more severe, initial syndromes. Traditional predictors of post-stroke language outcomes did not reliably predict function at 90 days. These data suggest that other factors that account for functional stroke recovery have not yet been identified.
A transient leukoencephalopathy mimicking cerebrovascular accident has been described as a complication of chemotherapy, most commonly in recipients of intrathecal methotrexate for childhood leukaemia. Recently published neuroimaging data suggest a common pathophysiology associated with a variety of chemotherapy agents and modes of administration.
We reviewed the medical literature for single reports and case series of patients presenting with stroke-like episodes while receiving systemic or intrathecal chemotherapy. We only included studies providing detailed neuroimaging data. Patients with cerebrovascular accidents were excluded.
We identified 27 reports of toxic leukoencephalopathy in patients treated with methotrexate (intrathecal, systemic), 5-fluorouracil and its derivative carmofur, and capecitabine. Diffusion weighted imaging (DWI) of all patients revealed well demarcated hyperintense lesions within the subcortical white matter of the cerebral hemispheres and the corpus callosum, corresponding to areas of decreased proton diffusion on apparent diffusion coefficient (ADC) maps (available in 21/27 patients). Lesions exceeded the confines of adjacent vascular territories. Complete resolution of symptoms within 1–4 days was accompanied by normalisation of ADC abnormalities. However, fluid attenuated inversion recovery (FLAIR) sequences frequently revealed persistent white matter abnormalities.
Several pathophysiological models of delayed leukoencephalopathy after exposure to intrathecal or systemic chemotherapy have been proposed. DWI findings in this cohort are indicative of cytotoxic oedema within cerebral white matter and lend support to an at least partially reversible metabolic derangement as the basis for this syndrome.
To evaluate a new three dimensional (3D) MRI protocol for the reliable detection of aortic high risk plaques compared with transoesophageal echocardiography (TOE) and to test the reliability of additional MRI in stroke of undetermined aetiology.
74 acute stroke patients were examined by both TOE and MRI at 3 Tesla with special regard to aortic high risk plaques (ie, >=4 mm, superimposed thrombi). ECG synchronised pre- and post-contrast T1 weighted 3D imaging (spatial resolution ~1 mm
Differences in maximum aortic wall thickness for TOE and MRI were not statistically significant for all aortic segments. The overall number of high risk plaques detected by MRI (n = 74) was substantially higher compared with TOE (n = 47). Most noticeably, MRI identified aortic high risk pathologies in 8/26 (30.8%) patients with cryptogenic stroke after standard diagnostics, including TOE (n = 2: dissection or thrombus; n = 6: plaques >=4 mm).
Our results demonstrate the feasibility of this 3D MRI protocol for the reliable detection of aortic high risk plaques in acute stroke patients. Because of improved visualisation of the aortic arch and the detection of additional embolic sources not seen by standard diagnostics, this novel technique may become a valuable tool for future patients with cryptogenic stroke.
Ulegyria refers to cerebral cortex scarring, which results from a perinatal ischaemic brain injury. It presents with a characteristic gyral pattern: small circumvolutions with atrophy at sulci bottom and spared apex. Ulegyria is frequently associated with epilepsy, cerebral palsy and mental disability. We analysed electroclinical and MRI features in patients with ulegyria and epilepsy.
We reviewed 25 patients (14 males/11 females) with ulegyria and epilepsy from the database (about 5000 patients with epilepsy) of our unit. Patients were examined clinically, underwent high resolution MRI, EEG recordings, positron emission tomography, single photon emission computed tomography and neuropsychological testing. Two patients with refractory seizures underwent epilepsy surgery.
Mean age of patients was 34 years (5–66) at the reassessment time. The majority (16/25, 64%) had a history of perinatal asphyxia. 15 patients had delayed developmental milestones; 20 had learning disabilities and five patients were severely disabled. Mean age at seizure onset was 4.2 years (1–18). 17 patients (68%) had medically intractable epilepsy. 11 patients (44%) had occipital lobe seizures. The majority (n = 24, 96%) had parieto-occipital lesions on MRI. In 13 patients (52%), ulegyria was bilateral. 12 patients (48%) had hippocampal sclerosis. Two patients underwent epilepsy surgery with an excellent postoperative outcome (Engel class IA and IC).
Patients with ulegyria often have a history of perinatal asphyxia and present with pharmacoresistant seizures. Their presurgical assessment is complicated because of frequent dual pathology (hippocampal sclerosis) and bilateral lesions.
To determine the efficacy of epidural blood patch (EDBP) for the treatment of post dural puncture headache (PDPH).
We randomised 42 patients who presented with PDPH, lasting 24 h to 1 week, to receive EDBP (n = 19) or conservative treatment (n = 23). The primary end point was any headache at 24 h after the start of treatment. Secondary end points were presence and severity of headache after 1 week. Stratified Mantel–Haenzel analysis was used to adjust for confounders.
Two patients refused to participate directly after randomisation and allocation to conservative treatment. They were excluded from the study. At 24 h after the start of treatment, headache was present in 11 (58%) patients allocated to EDBP and in 19 (90%) patients allocated to conservative treatment (RR 0.64, 95% CI 0.43 to 0.96). At day 7, headache was present in three (16%) patients allocated to EDBP and in 18 (86%) allocated to conservative treatment (RR 0.18, 95% CI 0.06 to 0.53). Headache was mild in all three EDBP patients, but in 10 of 18 conservatively treated patients who had not recovered by day 7 it was classified as moderate or severe. Adjustments for confounders did not affect these results.
EDBP is an effective treatment for PDPH. It offers complete resolution of symptoms in a large proportion of patients. In the remaining patients, it reduces headache severity and allows them to return to their everyday activities.
Patients with superior canal dehiscence (SCD) have large sound-evoked vestibular reflexes with pathologically low threshold. We wished to determine whether a recently discovered measure of the vestibulo-ocular reflex—the ocular vestibular evoked myogenic potential (OVEMP)—produced similar high-amplitude, low-threshold responses in SCD, and could differentiate patients with SCD from normal control patients.
Nine patients with CT-confirmed SCD and 10 normal controls were stimulated with 500 Hz, 2 ms tone bursts and 0.1 ms clicks at intensities up to 142 dB peak SPL. Conventional VEMPs were recorded from the ipsilateral sternocleidomastoid muscle to determine threshold, and OVEMPs were recorded from electrode pairs placed superior and inferior to the eyes. Three-dimensional eye movements were measured with scleral dual-search coils.
In patients with SCD, OVEMP amplitudes were significantly larger than normal (p<0.001) and thresholds were pathologically low. The n10 OVEMP in the contralateral inferior electrode became particularly large with increasing stimulus intensity (up to 25 µV) and with up-gaze (up to 40 µV). Sound-evoked (slow-phase) eye movements were present in all patients with SCD (vertical: upward; torsional: upper pole away from the affected side; and horizontal: towards or away from the affected side), but began only as the OVEMP response became maximal, which is consistent with the surface potentials being produced by activation of the extraocular muscles that generated the eye movements.
OVEMP amplitude and threshold (particularly the contralateral inferior n10 response) differentiated patients with SCD from normal controls. Our findings suggest that both the OVEMPs and induced eye movements in SCD are a result of intense saccular activation in addition to superior canal stimulation.
Subjects with moderate head injury are a particular challenge for the emergency physician. They represent a heterogeneous population of subjects with large variability in injury severity, clinical course and outcome. We aimed to determine the early predictors of outcome of subjects with moderate head injury admitted to an Emergency Department (ED) of a general hospital linked via telemedicine to the Regional Neurosurgical Centre.
We reviewed, prospectively, 12 675 subjects attending the ED of a General Hospital between 1999 and 2005 for head injury. A total of 309 cases (2.4%) with an admission Glasgow Coma Scale (GCS) 9–13 were identified as having moderate head injury. The main outcome measure was an unfavourable outcome at 6 months after injury. The predictive value of a model based on main entry variables was evaluated by logistic regression analysis.
64.7% of subjects had a computed tomographic scan that was positive for intracranial injury, 16.5% needed a neurosurgical intervention, 14.6% had an unfavourable outcome at 6 months (death, permanent vegetative state, permanent severe disability). Six variables (basal skull fracture, subarachnoid haemorrhage, coagulopathy, subdural haematoma, modified Marshall category and GCS) predicted an unfavourable outcome at 6 months. This combination of variables predicts the 6-month outcome with high sensitivity (95.6%) and specificity (86.0%).
A group of selected variables proves highly accurate in the prediction of unfavourable outcome at 6 months, when applied to subjects admitted to an ED of a General Hospital with moderate head injury.
To evaluate patient outcome and investigate the prognostic factors of high-grade meningiomas by adopting the 2000 World Health Organization (WHO) classification system.
Between 1986 and 2004, 74 patients were diagnosed with high-grade meningioma: 33 with atypical and 41 with anaplastic meningioma. The mean follow-up was 58.5 months. We reclassified all surgical specimens, according to the 2000 WHO classification system, using two expert neuropathologists.
Forty of 74 meningiomas were reclassified as atypical meningioma and 24 as anaplastic meningioma. Overall and recurrence-free survivals were significantly longer in patients with atypical than in those with anaplastic meningioma: 142.5 versus 39.8 months and 138.5 versus 32.2 months, respectively (p<0.001). In patients with atypical meningiomas, brain invasion and adjuvant radiotherapy were not associated with survival; however, in the brain invasion subgroup, adjuvant radiotherapy improved patients’ survival. In patients with anaplastic meningioma, the prognostic factors were brain invasion, adjuvant radiotherapy, malignant progression, p53 overexpression and extent of resection. The p53 overexpression was the only factor associated with malignant progression (p = 0.009).
The 2000 WHO classification has identified the truly aggressive meningiomas better than did the previous criteria. A precise meningioma grading system may help to avoid over-treatment of patients with an atypical meningioma as, once the tumour has "declared itself" by recurrence and histological features, it becomes a tumour that is poorly amenable to current therapies.
To study the effect of botulinum toxin A in the subscapular muscle on shoulder pain and humerus external rotation.
22 stroke patients with spastic hemiplegia, substantial shoulder pain and reduced external rotation of the humerus participated in a randomised, double blind, placebo controlled effect study. Injections of either botulinum toxin A (Botox, 2x50 units) or placebo were applied to the subscapular muscle at two locations. Pain was scored on a 100 mm vertical Visual Analogue Scale; external rotation was recorded by means of electronic goniometry. Assessments were carried out at 0 (baseline), 6 and 12 weeks.
21 patients completed the study. We observed no significant changes in pain or external rotation as a result of administration of botulinum toxin A. External rotation improved significantly (p = 0.001) for both the treatment group (20.4° (16.6) to 32.1° (14.0)) and the control group (10.3° (19.5) to 23.7° (20.7)) as a function of time.
Application of botulinum toxin A into the subscapular muscle for reduction of shoulder pain and improvement of humeral external rotation in spastic hemiplegia does not appear to be clinically efficacious.
SPG10 is an autosomal dominant form of hereditary spastic paraplegia (HSP), which is caused by mutations in the neural kinesin heavy chain KIF5A gene, the neuronal motor of fast anterograde axonal transport. Only four mutations have been identified to date.
To determine the frequency of SPG10 in European families with HSP and to specify the SPG10 phenotype.
80 index patients from families with autosomal dominant HSP were investigated for SPG10 mutations by direct sequencing of the KIF5A motor domain. Additionally, the whole gene was sequenced in 20 of these families.
Three novel KIF5A mutations were detected in German families, including one missense mutation (c.759G>T, p.K253N), one in frame deletion (c.768_770delCAA, p.N256del) and one splice site mutation (c.217G>A). Onset of gait disturbance varied from infancy to 30 years of age. All patients presented clinically with pure HSP, but a subclinical sensory–motor neuropathy was detected by neurophysiology studies.
SPG10 accounts for approximately 3% of European autosomal dominant HSP families. All mutations affect the motor domain of kinesin and thus most likely impair axonal transport. Clinically, SPG10 is characterised by spastic paraplegia with mostly subclinical peripheral neuropathy.
To evaluate prospectively the relationship between appetite, food composition, nutritional habits and weight loss following administration of topiramate (TPM) and to identify predictors for TPM induced weight loss.
22 patients with epilepsy who were started on TPM were prospectively followed for 6 months and contacted again after a mean follow-up time of 37.1 months.
Body mass index (BMI) loss occurred in 59% of patients, with a mean weight loss of 9.5 kg after 6 months while receiving TPM without further weight loss at the long term follow-up. Weight loss was associated with reduction in appetite without affecting food composition. Predictors for BMI loss after 6 months were high initial BMI and body fat. After 3 weeks of treatment with TPM, the recorded parameters did not predict BMI loss but at 3 months, weight loss, reduction of appetite and amount of food intake were predictive for the amount of BMI loss after 6 months.
The Call–Fleming syndrome (CFS) comprises acute severe recurrent (thunderclap) headaches, occasional transient or fluctuating neurological abnormalities and reversible segmental cerebral vasoconstriction. It is a benign condition with an excellent prognosis, yet because it is often clinically and radiologically similar to a number of commonly encountered conditions, diagnostic difficulties may arise, leading to inappropriate, and even potentially harmful, investigative and therapeutic approaches.
Three personal cases are presented to highlight the occurrence of subarachnoid haemorrhage (SAH) as part of CFS. In two patients with a positive CT head, SAH involved the sulci in the upper cerebral convexity, an unusual location in aneurysmal SAH.
SAH is not an uncommon feature of CFS, occurring in approximately 25% of reported cases, and may pose a diagnostic challenge. CFS has a relatively characteristic spectrum of features, allowing a confident diagnosis in most cases, even when atypical features such as SAH are present.
Recognising the spectrum of abnormalities seen in CFS, including particularly SAH, allows a sound approach to a safe diagnosis.