Thorsten Bartsch

Transient global amnesia: functional anatomy and clinical implications

More than 50 years after its initial description, transient global amnesia (TGA) remains one of the most enigmatic syndromes in clinical neurology. Recent MRI data suggest that a transient perturbation of hippocampal function is the functional correlate of TGA because focal diffusion lesions can be selectively detected in the CA1 field of the hippocampal cornu ammonis. Although various factors, such as migraine, focal ischaemia, venous flow abnormalities, and epileptic phenomena, have been suggested to be involved in the pathophysiology of TGA, the factors triggering the emergence of these lesions are still elusive. Recent data suggest that the vulnerability of CA1 neurons to metabolic stress plays a pivotal part in the pathophysiological cascade, leading to an impairment of hippocampal function during TGA. In this Review, we discuss clinical aspects, new imaging findings, and recent clinical-epidemiological data with regard to the phenotype, functional anatomy, and putative cellular mechanisms of TGA.

Activation of 5-HT1B/1D receptor in the periaqueductal gray inhibits nociception

It is considered that the site of action of the abortive antimigraine compounds acting at serotonin, 5‐HT1B/1D, receptors (triptans) is the trigeminovascular system. We tested whether there is a non‐trigeminal site of action. The 5‐HT1B/1D agonist, naratriptan, was microinjected into the ventrolateral periaqueductal gray (vlPAG), and activity in the trigeminal nucleus caudalis (TNC) was monitored. Recordings were made from 20 nociceptive neurons in the dorsal horn of the TNC that received convergent input from the dura mater and face. Responses of neurons to dural, facial cutaneous and corneal stimulation were studied before and after injection of naratriptan. Naratriptan decreased the excitability to electrical stimulation of the dura mater as the A‐fiber response decreased by 24 ± 4.1% (p < 0.001) and the C‐fiber response decreased by 42 ± 8.2% (p < 0.001). Spontaneous activity was decreased by 38 ± 7.5% (p < 0.001). After injection, the mechanical thresholds of the dura mater increased from (n = 14, p < 0.01). Responses to stimulation of the face and cornea were not altered by injection of naratriptan. These results suggest that 5‐HT1B/1D receptor activation in the vlPAG activates descending pain‐modulating pathways that inhibit dural, but not facial and corneal nociceptive input. These findings have implications for the understanding of the action of triptans in migraine and cluster headache, suggesting that brain loci other than the trigeminal nucleus may play a role in the clinical action of triptans. Ann Neurol 2004

Animal models of migraine: looking at the component parts of a complex disorder.

Animal models of human disease have been extremely helpful both in advancing the understanding of brain disorders and in developing new therapeutic approaches. Models for studying headache mechanisms, particularly those directed at migraine, have been developed and exploited efficiently in the last decade, leading to better understanding of the potential mechanisms of the disorder and of the action for antimigraine treatments. Model systems employed have focused on the pain‐producing cranial structures, the large vessels and dura mater, in order to provide reproducible physiological measures that could be subject to pharmacological exploration. A wide range of methods using both in vivo and in vitro approaches are now employed; these range from manipulation of the mouse genome in order to produce animals with human disease‐producing mutations, through sensitive immunohistochemical methods to vascular, neurovascular and electrophysiological studies. No one model system in experimental animals can explain all the features of migraine; however, the systems available have begun to offer ways to dissect migraines component parts to allow a better understanding of the problem and the development of new treatment strategies.

CA1 neurons in the human hippocampus are critical for autobiographical memory, mental time travel, and autonoetic consciousness.

Autobiographical memories in our lives are critically dependent on temporal lobe structures. However, the contribution of CA1 neurons in the human hippocampus to the retrieval of episodic autobiographical memory remains elusive. In patients with a rare acute transient global amnesia, highly focal lesions confined to the CA1 field of the hippocampus can be detected on MRI. We studied the effect of these lesions on autobiographical memory using a detailed autobiographical interview including the remember/know procedure. In 14 of 16 patients, focal lesions in the CA1 sector of the hippocampal cornu ammonis were detected. Autobiographical memory was significantly affected over all time periods, including memory for remote periods. Impairment of episodic memory and autonoetic consciousness exhibited a strong temporal gradient extending 30 to 40 y into the past. These results highlight the distinct and critical role of human hippocampal CA1 neurons in autobiographical memory retrieval and for re-experiencing detailed episodic memories.

Neurostimulation approaches to primary headache disorders

Purpose of reviewConventional management options in medically intractable chronic-headache syndromes, such as chronic migraine, chronic cluster headache and hemicrania continua, are often limited. This review summarizes the current concepts, approaches and outcome data of invasive device-based neurostimulation approaches using occipital-nerve stimulation and deep-brain stimulation. Recent findingsRecently, there has been considerable progress in neurostimulation approaches to medically intractable chronic-headache syndromes. Previous studies have analysed the safety and efficacy of suboccipital neurostimulation in drug-resistant chronic-headache syndromes such as in chronic migraine, chronic cluster headache and hemicrania continua. The studies suggest suboccipital neurostimulation can have an effect even decades after onset of headaches, thus representing a possible therapeutic option in patients that do not respond to any medication. Similarly, to date over 50 patients with cluster headaches underwent hypothalamic deep-brain stimulation. From these, an average of 50–70% did show a significant positive response. SummaryThese findings will help to further elucidate the clinical potential of neurostimulation in chronic headache.

Occipital Nerve Stimulation for Headache: Mechanisms and Efficacy

Headache disorders are common problems in medicine and it is this commonness that often provides an air of the simple or obvious. Patients expect doctors understand headache; indeed doctors expect they may understand headache, and in turn since simple treatments exist and can be purchased from a supermarket, the very concept of the difficult headache problem has a pejorative connotation. A decade ago none of the authors were using device‐based therapies to any substantial extent, and now hardly a week goes by when we will not see a patient who has considerable potential to benefit from such approaches. Here we cover the most promising of the device‐based approaches, neurostimulation therapy using occipital nerve stimulation. Far from proven and with much work to be done, this is an exciting potential development for patients and doctors. Other device‐based therapies, such as deep brain stimulation for cluster headache and patent foramen ovale closure, are covered elsewhere.

Evolution of hippocampal CA‐1 diffusion lesions in transient global amnesia

Selective focal MR‐Signal (diffusion‐) changes in the CA‐1 sector of the hippocampus have been described in transient global amnesia (TGA), but the pathophysiological substrate of these lesions is largely unknown. As several imaging and epidemiological findings point to a vascular origin an analysis of the temporal evolution of the hippocampal apparent diffusion coefficient (ADC) changes may offer new understanding of the pathomechanisms of TGA.

Trigeminal antinociception induced by bicuculline in the periaqueductal gray (PAG) is not affected by PAG P/Q-type calcium channel blockade in rat.

We have recently shown that injection of the P/Q-type (Ca(v)2.1/alpha(1A)) calcium channel blocker, omega-agatoxin IVA, into the periaqueductal gray (PAG) facilitates meningeal dural stimulation-evoked trigeminal nociceptive processing. We injected the GABA(A) antagonist bicuculline into the PAG in addition to the agatoxin and observed bicucullines effect on neurons responding to dural stimulation recorded in the trigeminal nucleus caudalis of rats in order to determine if P/Q channel-mediated changes acted through GABAergic mechanisms. The inhibition of trigeminal nociceptive neurons characteristic of bicuculline administered into the PAG was maintained in the presence of blocked PAG P/Q-type calcium channels. This suggests the PAG descending pain modulatory pathway is not affected by P/Q-type calcium channel blockade at the postsynaptic GABAergic inhibitory interneuron and the facilitation produced by agatoxin is mediated by another mechanism. These findings have implications for disorders involving the PAG or P/Q-type channels, such as migraine, in particular for the development of preventative treatments, suggesting GABAergic and voltage-gated calcium channels could be separately modulated.

Progressive neurologic dysfunction in a psoriasis patient treated with dimethyl fumarate

Progressive multifocal leukoencephalopathy (PML) has recently been described in psoriasis or multiple sclerosis patients treated with fumaric acid esters (fumarates), who had developed severe and long‐standing lymphocytopenia (<500/mm3). We report a psoriasis patient who presented with progressive neurologic dysfunction and seizures after 2.5 years of fumarate therapy. Despite absolute lymphocyte counts remaining between 500‐1000/mm3, his CD4+ and CD8+ T‐cell counts were markedly low. MRI showed right hemispheric and brainstem lesions and JC virus DNA was undetectable in his cerebrospinal fluid. Brain biopsy revealed typical features of PML as well as JC virus‐infected neurons. Clinicians should consider PML in the differential diagnosis of fumarate‐treated patients presenting with brain lesions or seizures even in the absence of severe lymphocytopenia. ANN NEUROL 2015;78:501–514

The entire dural sinus tree is compressed in patients with idiopathic intracranial hypertension: a longitudinal, volumetric magnetic resonance imaging study

IntroductionThe objective of this study was to explore the volumetric alterations of dural sinuses in patients with idiopathic intracranial hypertension (IIH).MethodsStandardized cranial magnetic resonance imaging (MRI) was used in 17 patients prior to and following treatment of IIH and in seven controls. Magnetic resonance venographies (MRV) were employed for (a) judgement of circumscript dural sinus stenoses and (b) computation of sinus volumes. Cross-sectional areas (CSA) of the superior sagittal sinuses (SSS) were measured on T2-weighted images. Results of the initial MRIs were compared to those on follow-up MRIs and to results of controls.ResultsStenoses of the transverse sinuses (TS) resulting in cranial venous outflow obstruction (CVOO) were present in 15/17 (88%) patients, normalizing in 7/15 cases (47%) after treatment of IIH. CVOO was not detected in the control group. Segmentation of MRV revealed decreased dural sinus volumes in patients with IIH as compared to controls (P = 0.018). Sinus volumes increased significantly with normalization of intracranial pressure independent from disappearing of TS stenoses (P = 0.007). The CSA of the SSS were normal on the initial MRIs of patients with IIH and increased on follow-up after treatment (P < 0.001). However, volumetries displayed overlap in patients and controls.ConclusionsPatients with IIH not only exhibit bilateral stenoses of the TS as has been reported, but volume changes of their entire dural sinus system also occur. The potential etiopathological and diagnostic roles of these changes are discussed.