Axel Rohr

Febrile infection–related epilepsy syndrome (FIRES): A nonencephalitic encephalopathy in childhood

Encephalitis is generally presumed, even when seizures follow banal febrile infection, and pathogen detection in cerebrospinal fluid fails. This retrospective multicenter case series reports on 22 previously healthy children aged 3–15 years (median 6.5 years) with prolonged or recurrent seizures occurring 2–14 days (median 5 days) after fever onset (19 children with respiratory or nonspecific infections). Cerebrospinal fluid studies revealed 2–42 cells/μl (median 5 cells/μl) and no pathogens. Electroencephalography showed diffuse slowing or multifocal discharges. Neuroimaging demonstrated normal findings in 10 children. Brain biopsies were performed in seven children showing gliosis but no inflammation. Anesthetic barbiturates were used in 14 children with refractory status epilepticus, and immunotherapy in 9. Two children died, eight remained in a state of impaired consciousness, eight developed therapy‐refractory epilepsies, two had behavioral disturbances, and two recovered. The lack of evidence for encephalitis suggests another infection‐related pathogenesis of this disastrous epileptic encephalopathy. Therefore, we propose the term “febrile infection–related epilepsy syndrome” (FIRES).

Assessment of thrombus in acute middle cerebral artery occlusion using thin-slice nonenhanced Computed Tomography reconstructions.

Background and Purpose— We sought to evaluate how accurately length and volume of thrombotic clots occluding cerebral arteries of patients with acute ischemic stroke can be assessed from nonenhanced CT (NECT) scans reconstructed with different slice widths. Methods— NECT image data of 58 patients with acute ischemic stroke with vascular occlusion proven by CT angiography were reconstructed with slice widths of 1.25 mm, 2.5 mm, 3.75 mm, and 5 mm. Thrombus lengths and volumes were quantified based on these NECT images by detecting and segmenting intra-arterial hyperdensities. The results were compared with reference values of thrombus length and volume obtained from CT angiography images using Bland-Altman analysis and predefined levels or tolerance to find NECT slice thicknesses that allow for sufficiently accurate thrombus quantification. Results— Thrombus length can be measured with high accuracy using the hyperdense middle cerebral artery sign detected in NECT images with slice thicknesses of 1.25 mm and 2.5 mm. We found mean deviations from the reference values and limits of agreement of −0.1 mm±0.6 mm with slice widths of 1.25 mm and 0.1 mm±0.7 mm for slice widths of 2.5 mm. Thrombus length measurements in NECT images with higher slice width and all evaluated thrombus volume measurements exhibited severe dependence on the level and did not match the accuracy criteria. Conclusion— The length of the hyperdense middle cerebral artery sign as detected on thin-slice NECT reconstructions in patients with acute ischemic stroke can be used to quantify thrombotic burden accurately. Thus, it might qualify as a new diagnostic parameter in acute stroke management that indicates and quantifies the extent of vascular obliteration.

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.

Camptocormia in idiopathic Parkinson's disease: A focal myopathy of the paravertebral muscles†

The objective of our study was to describe the clinical features of camptocormia, an involuntary, marked flexion of the thoracolumbar spine in idiopathic Parkinsons disease (PD) and to understand its etiology. In a prospective, cross‐sectional study, we examined 15 patients with PD and camptocormia using laboratory parameters, EMG, muscle magnetic resonance imaging, and biopsy of the paravertebral muscles. The clinical data were compared with a matched control group of PD patients without camptocormia, and the biopsies were compared with muscles from age‐matched autopsies. Almost all the patients (median age, 68.0 years; 7 women) with camptocormia suffered from advanced PD. Camptocormia occurred at a median of 9.0 years after the PD diagnosis. Compared with our clinical control group, back pain was more frequent and less dopa‐sensitive in the patients with camptocormia who suffered more often from additional diseases of the back. On EMG, we found mainly a myopathic pattern. The MRI of the paravertebral muscles showed localized changes ranging from edema with contrast enhancement, which are considered to be early signs, to atrophy and/or fatty degeneration, interpreted as late degenerative changes. Early signs were seen mainly during the first year and degenerative changes after 1.5 years. Biopsies revealed consistently myopathic changes and in some cases fatty degeneration. Clinical or electromyographic features favoring dystonia were absent. Camptocormia is a major disabling, non‐fluctuating and levodopa‐resistant complication of advanced PD. The cause of camptocormia in idiopathic PD is a focal myopathy. Our findings suggest that the myopathy has a progressive course, which finally leads to degeneration of the paravertebral muscles.

Evaluation of epileptogenic networks in children with tuberous sclerosis complex using EEG-fMRI.

Purpose: Ninety percent of patients with tuberous sclerosis complex (TSC) have epilepsy. Identification of epileptogenic areas can be difficult and studies are needed to characterize the epileptogenic network in more detail.

Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.

Febrile infection-related epilepsy syndrome (FIRES) is a severe postinfectious epileptic encephalopathy in previously healthy children and has three phases: the initial phase with a simple febrile infection, a few days later the acute phase characterized by a peracute onset of highly recurrent seizures or refractory status epilepticus often with no more fever and generally without additional neurological features (the classical pure seizure phenotype), and last, the chronic phase with a drug-resistant epilepsy and neuropsychological impairments. FIRES seems to be sporadic and very rare: we estimated the annual incidence in children and adolescents by a prospective hospital-based German-wide surveillance as 1 in 1,000,000. Because of the preceding infection and lacking evidence of infectious encephalitis, an immune-mediated pathomechanism and, therefore, a response to immunotherapies may be involved. To test the hypothesis that antibodies against neuronal structures cause FIRES, we analyzed sera of 12 patients aged 2 to 12 years (median 6 years) and cerebral spinal fluids (CSFs) of 3 of these 12 patients with acute or chronic FIRES. We studied six patients (two including CSF) 1 to 14 weeks (median 3 weeks) and six patients 1 to 6 years (median 3.5 years) after seizure onset. All samples were analyzed for antibodies against glutamate receptors of type N-methyl-D-aspartate (NMDA) and type α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), gamma-aminobutyric acid (GABA)B-receptors, voltage-gated potassium channel (VGKC)-associated proteins leucin-rich glioma inactivated 1 (LGI1) and contactin-associated protein like 2 (CASPR2), and glutamic acid decarboxylase (GAD) by a multiparametric recombinant immunofluorescence assay employing human embryonic kidney (HEK) cells transfected with cDNAs for the antigens. In addition, indirect immunohistochemistry using rat whole-brain sections was done in three patients. Finally, sera of 10 patients were tested for VGKC complex antibodies by radioimmunoprecipitation assay (RIA). None of the antibody tests were positive in any of the patients. Moreover, steroids, immunoglobulins, and plasmapheresis had no clear effect in the seven patients receiving immunotherapy. The failure of antibody-detection against the known neuronal antigens as well as the ineffectiveness of immunotherapy questions a role for autoantibodies in the epileptogenesis of classical FIRES. As we discuss, other underlying causes need to be considered including the possibility of a mitochondrial encephalopathy.

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.

Progressive hemiparesis 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

MR Imaging Findings in Patients with Secondary Intracranial Hypertension

BACKGROUND AND PURPOSE: IH can alter the configuration of anatomic structures of the central nervous system. We determined the sensitivity and specificity of MR imaging to detect these changes in patients with secondary IH. MATERIALS AND METHODS: Patients (n = 36) with IH were prospectively investigated with MR imaging and were matched to 36 controls. MR images were evaluated for elongation and edema of the optic nerves, protrusion of the optic disc, flattening of the posterior sclera, height of the pituitary gland, and width of the optic nerve sheath. On MRV, we recorded venous sinus abnormalities and measured the luminal width of the superior ophthalmic veins. A grading score was introduced to define cranial venous outflow obstruction. RESULTS: Cranial venous outflow obstruction and ONS hydrops were the most valid signs indicating IH with a sensitivity of 94% and 92% and a specificity of 100% and 89%, respectively. Sensitivities and specificities were 56% and 97% for reduced pituitary height, 64% and 78% for flattening of the posterior sclera, 31% and 97% for widening of the superior ophthalmic veins, 33% and 100% for optic disc protrusion, 14% and 100% for optic nerve edema, and 6% and 100% for elongation of the optic nerve. At least 2 MR imaging findings could be demonstrated in each patient but in none of the controls. The number of positive MR imaging findings correlated with CSF pressure (r = 0.62, P = .01). CONCLUSIONS: The combination of cranial and orbital MR imaging and MRV can be highly sensitive and specific in the diagnosis of patients with IH.