Short latency afferent inhibition differs among the subtypes of mild cognitive impairment.

Mild cognitive impairment (MCI) is considered a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer disease (AD). The role of the cholinergic system in MCI is not clearly defined and needs to be further investigated. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. We aimed to evaluate in the present study the relationship of SAI to the specific clinical subtypes of MCI. SAI was examined in 20 patients with amnestic MCI (10 SD, 10 MD), twenty patients with nonamnestic MCI (10 SD, 10 MD) and ten control subjects. Motor threshold, central motor conduction time, intracortical inhibition and facilitation to paired-TMS were also evaluated. Mean SAI was significantly reduced in amnestic MCI-MD patients when compared with the controls, while it was not significantly different in amnestic MCI-SD patients and in nonamnestic patients. SAI was increased after administration of a single dose of donepezil in a subgroup of four amnestic MCI-MD patients. The other TMS parameters did not differ significantly between the four MCI groups and the control group. We demonstrated that this putative marker of central cholinergic activity differs among MCI subtypes. The amnestic-MD type of MCI might be a phenotype of incipient AD. However, this hypothesis would be better addressed in a longitudinal study of individual patients. TMS studies may be useful in identifying MCI individuals in whom cholinergic degeneration is occurred and therefore at increased risk of conversion to AD.

Cognitive function and cholinergic transmission in patients with subcortical vascular dementia and microbleeds: a TMS study.

There has been little investigation on the association between cognitive impairment and the microbleeds (MBs) frequently seen in subcortical vascular dementia (SVaD). One possible mechanism of cognitive decline in individuals with SVaD could be disruption of cholinergic fibers by vascular lesions. Central cholinergic circuits in human brain can be tested non-invasively by means of a transcranial magnetic stimulation (TMS) protocol named short latency afferent inhibition (SAI) of motor cortex. In the present study, we used this test in SvaD patients with and without MBs. SAI was evaluated in 13 SVaD patients with MBs (MB-positive group) and the data were compared with those from a group of 15 SVaD patients without MBs (MB-negative group) and with those from 20 healthy subjects. Moreover, we studied covariation of individual SAI values with the Mini-Mental State Examination (MMSE) total score and subscores. SAI was significantly reduced in the MB-positive group when compared with the MB-negative group and the control subjects. Total MMSE score, "attention and calculation" and "orientation" subscores were significantly lower in the MB-positive group than in the MB-negative group; SAI showed a positive correlation with total MMSE score. Adjustment for age, gender, education, presence of lacunae, severe white matter hyperintensities or severe periventricular hyperintensities did not affect these findings. This study provides novel physiological evidence that MBs have an impact on central cholinergic function that is independent of the extent of associated white matter changes and ischaemic stroke. This finding shows that TMS have potential diagnostic and therapeutic implications. TMS studies may help in evaluating the causes of cognitive impairment in cerebrovascular diseases.

A review of transcranial magnetic stimulation in the in vivo functional evaluation of central cholinergic circuits in dementia.

Central cholinergic circuits of human brain can be tested non-invasively by coupling electrical peripheral stimulation with transcranial magnetic stimulation (TMS) of the motor cortex. The short-latency afferent inhibition (SAI) is reduced in cholinergic forms of dementia, such as Alzheimer disease (AD) and dementia with Lewy bodies, while it is normal in non-cholinergic forms of dementia, such as frontotemporal dementia. This finding suggests that this method can be used as a non-invasive additional tool for discriminating between cholinergic and non-cholinergic forms of dementia. Interestingly, SAI was also found to be significantly smaller in early AD patients. Identification of SAI abnormalities that occur early in the course of AD will allow earlier diagnosis and treatment with cholinergic drugs. In patients with vascular dementia, SAI responses varied widely; the number of patients with abnormal SAI conceivably reflects the percentage of subjects with a significant cholinergic dysfunction. It has recently been demonstrated that brain microbleeds have an impact on SAI that is independent of the extent of associated white matter changes and ischemic stroke. Since SAI can be increased by acetylcholinesterase inhibitors, TMS may help in identifying the patients who would be suitable for long-term treatment with cholinergic agents.

Posterior circulation ischemia in patients with fetal-type circle of Willis and hypoplastic vertebrobasilar system.

Little attention has been given to the fetal-type posterior circle of Willis (FTP) in the literature; also symptomatic basilar artery (BA) hypoplasia has been rarely reported. We aimed to illustrate that the association of a hypoplastic vertebrobasilar system (VBS) with the FTP may lead to posterior circulation ischemia. Magnetic resonance imaging and three-dimensional time-of-flight magnetic resonance angiography were performed in 88 consecutive patients with ischemic stroke or TIA in the VBS. Thirteen patients were identified with either stroke or TIA in the context of a hypoplastic VBS and a fetal origin of the posterior cerebral arteries. All patients had unilateral or bilateral FTP, hypoplastic BA and at least one hypoplastic vertebral artery. Transcranial color-coded duplex revealed decreased flow velocity and increased pulsatility index along the BA. A hypoplastic VBS may be accompanied by the FTP and its simultaneous occurrence can predispose to ischemic events in the posterior circulation.

A dual-route perspective on brain activation in response to visual words: evidence for a length by lexicality interaction in the visual word form area (VWFA).

Based on our previous work, we expected the Visual Word Form Area (VWFA) in the left ventral visual pathway to be engaged by both whole-word recognition and by serial sublexical coding of letter strings. To examine this double function, a phonological lexical decision task (i.e., "Does xxx sound like an existing word?") presented short and long letter strings of words, pseudohomophones, and pseudowords (e.g., Taxi, Taksi and Tazi). Main findings were that the length effect for words was limited to occipital regions and absent in the VWFA. In contrast, a marked length effect for pseudowords was found throughout the ventral visual pathway including the VWFA, as well as in regions presumably engaged by visual attention and silent-articulatory processes. The length by lexicality interaction on brain activation corresponds to well-established behavioral findings of a length by lexicality interaction on naming latencies and speaks for the engagement of the VWFA by both lexical and sublexical processes.

Cytokine and growth factor concentration in cerebrospinal fluid from patients with hydrocephalus following endovascular embolization of unruptured aneurysms in comparison with other types of hydrocephalus.

To better understand the development of hydrocephalus of different origins, we evaluated cytokine and growth factor concentration in cerebrospinal fluid from patients with hydrocephalus. CSF was collected from patients developing hydrocephalus following hemorrhage (n = 15), patients with normal pressure hydrocephalus (n = 10), and following the embolization of unruptured intracranial aneurysms (n = 9). Myelography patients (n = 15) served as controls. Quantification of 11 molecules relating angiogenesis, inflammation, and wound healing in the CSF was performed using ELISA. All three hydrocephalus groups had decreased concentration of TIMP-4 compared to the normal group. The hemorrhage group showed increased concentration of IL-6, IL-8, MCP-1, MMP-9, and TIMP-1 compared to the control group. The unruptured aneurysm group had increased concentration of IL-6 and decreased concentration of TIMP-2 compared to the control group. Compared to the normal patients, increased concentrations of wound healing molecules were evident in all three groups. Increased inflammation was evident in the hemorrhage and unruptured aneurysm groups.

Cholinergic dysfunction and amnesia in patients with Wernicke-Korsakoff syndrome: a transcranial magnetic stimulation study.

The specific neurochemical substrate underlying the amnesia in patients with Wernicke-Korsakoff syndrome (WKS) is still poorly defined. Memory impairment has been linked to dysfunction of neurons in the cholinergic system. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. In the present study, we measured SAI in eight alcoholics with WKS and compared the data with those from a group of age-matched healthy individuals; furthermore, we correlated the individual SAI values of the WKS patients with memory and other cognitive functions. Mean SAI was significantly reduced in WKS patients when compared with the controls. SAI was increased after administration of a single dose of donezepil in a subgroup of four patients. The low score obtained in the Rey Complex Figure delayed recall test, the Digit Span subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the Corsi's Block Span subtest of the WAIS-R documented a severe impairment in the anterograde memory and short-term memory. None of the correlations between SAI values and these neuropsychological tests reached significance. We provide physiological evidence of cholinergic involvement in WKS. However, this putative marker of central cholinergic activity did not significantly correlate with the memory deficit in our patients. These findings suggest that the cholinergic dysfunction does not account for the memory disorder and that damage to the cholinergic system is not sufficient to cause a persisting amnesic syndrome in WKS.

Altered motor cortex excitability to magnetic stimulation in alcohol withdrawal syndrome.

BACKGROUND: Alcohol addiction is a complex brain disease caused by alterations in crucial neurotransmitter systems, including gamma-aminobutyric acid (GABA) and glutamate. These disturbances could be revealed by changes in cortical excitability parameters, as assessed by transcranial magnetic stimulation (TMS). This study was aimed to further investigate the complex pathophysiology of alcohol withdrawal syndrome (AWS). METHODS: Motor cortex excitability was examined in 13 subjects with AWS in a mild predelirial state, in 12 chronic alcoholics and in 15 age-matched control subjects, using a range of TMS protocols. Central motor conduction time, resting and active motor threshold, duration of the cortical silent period, short latency intracortical inhibition (SICI), and intracortical facilitation (ICF) to paired TMS were examined. RESULTS: Intracortical facilitation was significantly increased in the AWS patients when compared with the chronic alcoholics and the control subjects. The other TMS parameters did not differ significantly from the controls. Administration of a single oral dose of the glutamatergic antagonist riluzole in a subgroup of 8 patients significantly reduced ICF; motor threshold and SICI were not affected by riluzole. CONCLUSION: Transcranial magnetic stimulation shows a selective increase in intracortical facilitation after ethanol withdrawal. Our findings support the theory that altered glutamatergic receptor function plays an important role in the pathogenesis of human alcohol withdrawal. This study provides further physiological evidence that antiglutamatergic approaches represent an efficacious alternative for treating alcohol withdrawal symptoms.

Functional involvement of the cerebral cortex following paramedian bithalamic infarction.

To investigate further the functional mechanisms underlying the so-called 'loss of psychic self-activation' following paramedian bithalamic lesions, we used transcranial magnetic stimulation (TMS) in a patient who presented with this clinical picture after paramedian bithalamic infarction due to arterial occlusion. The patient showed higher motor thresholds than the controls; the cortical silent period and intracortical inhibition to paired-pulse stimulation, two different forms of inhibition that are believed to reflect GABAergic mechanisms, were significantly increased; short latency afferent inhibition (SAI), a technique that may give direct information about the function of some cholinergic circuits in the human brain, was significantly reduced. This study first demonstrates that there are changes in the intracortical excitatory and inhibitory circuits in this neurobehavioral syndrome, that lead to cortical hypoexcitability. The modulation in GABAergic activity may result in excitability changes in those cholinergic cortical networks that are involved in SAI. TMS may provide important information on connections between the thalamus and cortex and may help in better understanding the role of the thalamo-cortical relationship in behavioural changes associated with thalamic stroke.

Subdural hematoma in a patient with spontaneous intracranial hypotension and cerebral venous thrombosis.

We report a patient with clinical and neuroimaging findings of spontaneous intracranial hypotension (SIH) who developed cerebral venous thrombosis (CVT). An association between SIH and CVT has rarely been observed. Anticoagulation therapy was administered. The clinical course was subsequently complicated by a large subdural hematoma that required neurosurgical evacuation. The present report indicates that SIH should not be always considered a benign condition, especially when associated with CVT and subdural fluid collections. Furthermore, clinicians should be aware of the potential risks of anticoagulant therapy in patients with SIH and CVT.

Magnetic resonance imaging and motor-evoked potentials in spinal cord infarction: report of two cases.

Because in the early phases of spinal cord ischemia magnetic resonance imaging (MRI) can be normal, its clinical diagnosis is often difficult. We aimed to explore if motor-evoked potentials (MEPs) recordings may contribute to earlier diagnosis of spinal cord stroke. The clinical, MRI, and MEP findings in one case each of cervical and lumbar spinal cord infarction were reported. Spinal MRI at admission was unremarkable in both patients. At this time, MEPs were abnormal in both patients, to the upper and lower limbs in the first patient, exclusively to the lower limbs in the second. Follow-up MRI examinations documented an infarction in the territory of the anterior spinal artery and of the Adamkiewicz artery, respectively. MEP study can be useful in demonstrating spinal cord involvement also when radiological evidence for spinal cord damage is absent or equivocal. Early diagnosis may allow earlier intervention and contribute to improved patient management.

Spontaneous subdural spinal haematoma presenting as occipital headache: a case report.

Spinal subdural hematoma (SSDH) with no underlying pathology is a very rare condition and has been rarely reported. Our patient presented with severe occipital headache as isolated symptom during the first 4 days. SSDH slowly enlarges with time, and first determines tension of the pain-sensitive dural membrane, resulting in cervicogenic-like headache. Therefore, spontaneous SSDH should be considered in the differential diagnosis of recent occipital headache.

Influence of interferon-beta therapy switching on neutralizing antibody titres: results from the Austrian Switch Study.

Neutralizing antibodies against interferon-beta are associated with a reduction of the efficacy of this drug. Continuing treatment leads to a decline or even loss of neutralizing antibodies over years. No strategies are currently available to shorten the period of neutralizing antibody positivity. The objective of this study was to investigate the effect of switching between high and low immunogenic interferon-beta products on neutralising antibody titres. Twenty-four patients treated with the subcutaneously administered interferon-beta 1b or 1a and high titres of neutralizing antibodies were included. At baseline interferon-beta therapy was interrupted for 3 months and two pulses of high dose methylprednisolone were applied. Patients were then randomized to receive either the previous interferon-beta preparation or the low immunogenic intramuscular interferon-beta 1a. The primary end-point was the change of neutralizing antibody titres 12 months after randomization. Twelve patients were switched to interferon-beta 1a intramuscularly and 12 patients remained on previous treatment. Median neutralizing antibody titres were 846 NU at baseline and 196 NU at the end of the study. The median change of neutralizing antibody titres did not differ significantly between therapy switchers and non-switchers. Baseline and final neutralizing antibody titres correlated significantly. In conclusion, neither switching nor continuous therapy with any subcutaneous interferon-beta preparation significantly changed neutralizing antibody titres.

Delayed oxaliplatin-induced sensorimotor polyneuropathy.

BACKGROUND: To date, only a few cases have been reported that indicate that a delayed polyneuropathy may occur after chemotherapy with oxaliplatin. The clinical and electrophysiological manifestations of this delayed neurotoxicity have never been well documented. CASE REPORTS: Nerve conduction studies were performed in 4 patients who developed acute peripheral neuropathy several months after completion of oxaliplatin-containing chemotherapy. Sensory nerve conduction was abnormal in all patients. In 2 patients, the electrodiagnostic studies showed a mixed axonal and demyelinating sensorimotor polyneuropathy. CONCLUSIONS: Delayed polyneuropathy occurring after oxaliplatin-based chemotherapy can be confirmed by electrophysiological studies.

Clinical decision rules for the use of liquor diagnostics in hospitalized neurology patients reduced costs without affecting clinical outcomes.

OBJECTIVES: Excessive use of laboratory diagnostics has been common. This study aimed to evaluate whether clinical decision rules for the use of liquor diagnostics would enable cost containment without affecting medical care. METHODS: This was a single-center, retrospective, cost-minimization study based on the records of all 16,319 patients hospitalized and discharged at a Neurology Clinic in Austria between 2004 and 2006. Cost of liquor diagnostics, discharge diagnosis, duration of hospital stay, and mortality were compared along the line before, during, and after implementation of decision rules in mid-2005. RESULTS: There were no significant changes in patient characteristics over time, not in the diagnoses at discharge, nor in the percentage of patients undergoing liquor diagnostics. The average number of tests per patient significantly decreased. Standard tests largely replaced serological tests for infections, regardless of diagnosis. Annual costs for liquor diagnostics decreased by 32.9 percent. Overall, the duration of hospital stay and mortality significantly decreased as well; however, differences were not significant for any single diagnosis-related group. CONCLUSIONS: Diagnostic algorithms may allow cost containment without affecting medical care.

Comparison of experimental aneurysms embolized with second-generation embolic devices and platinum coils.

PURPOSE: The purpose of the study was to compare the performance of second-generation embolic devices with that of platinum coils in experimental aneurysms. METHODS: Microsurgically constructed bifurcation aneurysms in rabbits were embolized with platinum coils (n = 7), HydroCoils 10 (n = 10), HydroSoft (n = 14) or Cerecyte (n = 6) devices. After 1 month, angiographic occlusion was scored and the aneurysms were histologically evaluated by light microscopy. Continuous and ordinal results were compared using ANOVA/Tukey-Kramer HSD and chi(2) tests respectively. RESULTS: Angiographic occlusion at follow-up was increased in the HydroCoil and HydroSoft groups and decreased in the platinum coil and Cerecyte groups. Fibrovascular tissue was observed in the sac of the Cerecyte group, while mixtures of fibrovascular tissue and fibrinous thrombus were observed in the other three groups. The inflammatory response and endothelialization of the neck were similar in all groups. CONCLUSIONS: Expansile hydrogel devices have led to increased progressive occlusion, while degradable polymer devices led to an increased rate of thrombus organization compared with platinum coils.

[Contribute of functional magnetic resonance imaging to the understanding of psychiatric disorders]. / Beitrag der funktionellen Magnetresonanztomographie zum Verständnis psychiatrischer Störungen.

Functional magnetic resonance imaging (fMRI) has been shown to be a very useful tool to do research on psychiatric disorders, validating psychotherapeutical interventions, medication as well as disorder-specific deficits. The field of fMRI-research is examining the potential of identifying differences of activity between brains of clinical, subclinical and healthy subjects. The design of such research is drawn to evaluate the average activation to different conditions. We remark that there are still some methodological problems to face, i.e. choosing the sample with special considerations on comorbidity and medication, accounting individual differences in brain activation, complex statistical calculations etc. When evaluating therapeutical interventions it is necessary to take the placebo-effect into account. However, fMRI is a highly promising research method. For future application of fMRI in clinical practice it would be worth building standard paradigms. Then, valid diagnostics of impaired functionality may be possible. Furthermore, fMRI should be combined with other neurodiagnostical technologies and with genetics. The cooperation of different fields in brain research with fMRI may provide further knowledge about psychiatric disorders.

Modern multiple sclerosis treatment - what is approved, what is on the horizon.

In the mid-1990s, the implementation of the immunomodulatory drugs interferon-beta and glatiramer acetate offered the first evidence-based treatment option for multiple sclerosis (MS). These new drugs were beneficial in a huge number of MS patients worldwide, leading to a delay in disease-related disability. Moreover, MS was suddenly the focus not only of patients and their physicians but also of pharmaceutical companies, with a tremendous increase in interest by scientists. As a result of these efforts the first monoclonal antibody treatment has recently been implemented in MS. It will presumably be followed by several other more specific, more effective and more comfortable therapies within the next few years. Here, we will show the current MS treatment options as well as recent progress in the field, and we will introduce the potential new treatment options for future MS therapy.

Motor cortex excitability changes following a lesion in the posterior columns of the cervical spinal cord.

We used transcranial magnetic stimulation (TMS) to explore if an impairment of central sensory function produced by an isolated lesion in the cervical posterior white columns would change motor cortex excitability. Cortical silent period duration was prolonged when compared with the control subjects, while central motor conduction and motor thresholds were in the normal limits. We first demonstrate that the involvement of the ascending proprioceptive sensory pathways in spinal cord diseases may have direct consequences on the activity of intracortical inhibitory interneuronal circuits. These findings further elucidate the role of afferent inputs in motor cortex reorganisation.

Cortical silent period following TMS in a patient with supplementary sensorimotor area seizures.

The cortical silent period (CSP) following transcranial magnetic stimulation (TMS) was evaluated in a patient with a dysembrioplastic neuroepithelial tumor (DNET) in the lateral portion of the right superior frontal gyrus (SFG) who suffered from supplementary sensorimotor area (SSMA) seizures. CSP duration was shortened on the affected side. Ipsilateral alterations of motor cortex excitability with TMS in epileptogenic DNET located outside the PMA argue in favour of cortico-cortical connections to primary motor cortex from SSMA. This functional connectivity should be taken into consideration to better understand the pathophysiology of ictal motor manifestations.