Stroke-like Lesions Research Articles

Choriocarcinoma with cerebral metastasis presenting as a stroke-like lesion

Choriocarcinoma is a very aggressive malignant variant of gestational trophoblastic disease characterized by malignant proliferation of trophoblastic tissues and absence of chorionic villi. We present a rare case of metastatic choriocarcinoma presenting with a stroke-like lesion. A 40-year old multiparous woman that presented with bleeding per vaginam, right-sided facial nerve palsy and hemiparesis following eight weeks of amenorrhea. Serum β-hCG was elevated and urine pregnancy test was positive in neat and in serial dilution. She was managed as a case of metastatic choriocarcinoma and had five courses of the EMA-CO drug regimen. She made rapid neurological recovery and was discharged in good condition. We conclude that metastatic choriocarcinoma may present in bizarre forms. It should be suspected in any woman presenting with abnormal vaginal bleeding, unusual systemic physical features and raised serum β-hCG. We conclude that combination chemotherapy is usually effective even in metastatic choriocarcinoma.

Melas, Stroke-Like Episodes and Ketogenic Diet

Investigators at University of Toronto and McMaster University, Canada, report a 22-year-old woman with multiple episodes of status epilepticus and migratory cortical stroke-like lesions.

MR OEF imaging in MELAS.

Oxygen extraction fraction (OEF) is defined as the ratio of blood oxygen that a tissue takes from the blood flow to maintain function and morphological integrity. OEF reflects the efficiency of oxygen utilization by the tissue and, therefore, is a hemodynamic measure in brain ischemia. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a common mitochondrial disorder. It is characterized by neurological remissions and relapses and associated with progressive neurocognitive deficits. Because of abnormalities of mitochondrial function in MELAS, defects in the oxidative metabolic pathways of energy production decrease the cerebral oxygen utilization and lead to the reduction of OEF. Quantification of OEF can reflect the functional status of cerebral mitochondria and provide insight into the pathophysiological changes in the brain in MELAS. In light of recent advances in MRI, the discovery of the blood-oxygen level-dependent signal has allowed development of MRI methods targeted toward quantitative OEF imaging. A new MR sequence, termed the gradient-echo sampling of spin echo, was successfully developed to enable quantitative assessment of the OEF in the brain tissue. MR OEF imaging in patients with MELAS detects extensive OEF reduction in the stroke-like lesions, as well as in the normal-appearing brain regions. More severe dysfunction of the mitochondria in the stroke-like lesions was implied at the onset of the stroke-like episode. Determination of OEF throughout the episode demonstrated a chronological change in mitochondrial function in individual cases. Such neuroimaging findings might provide some clues in the investigation of the underlying mechanisms of stroke-like episodes.

PROTON MR SPECTROSCOPY IN THE DIAGNOSTIC EVALUATION OF SUSPECTED MITOCHONDRIAL DISEASE IN IRAN

Mitochondrial diseases are a group of inherited disorders Caused by a derangement of mitochondrial respiration. The clinical manifestations are heterogeneous, and the diagnosis is often based on information acquired from multiple levels of inquiry that require a variety of diagnostic tests for proper determination. Neuroimaging may play a significant role in diagnosis. The various modalities of nuclear magnetic resonance imaging (MRI) allow for multiple independent detection procedures that can give important anatomical and metabolic clues for diagnosis when the constellation of symptoms is suggestive of mitochondrial disease, neuroimaging features may be diagnostic and suggestive, can help direct further workup, and can help to further characterize the underlying brain abnormalities. The non-invasive nature of neuroimaging also allows for longitudinal studies. To date, no pathognomonic correlation between specific genetic defect and neuroimaging findings have been described. The definitive diagnosis of a mitochondrial disorder can be difficult to establish. Magnetic resonance imaging changes may be nonspecific; however, certain neuroimaging results can give important clues that a patient may have a mitochondrial disease. Conventional MRI may show Brain atrophy, supratentorial white matter lesions, basal ganglia involvement deep gray structural abnormalities, and delayed myelination are the most frequent anomalies in the definite cases. Also they may represent clearly characteristic of a given disorder such as strokelike lesions that do not respect vascular boundaries in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS). White matter hyper intensities with or without associated gray matter involvement may also be observed or stroke-like lesions that do not respect vascular territories. Chemical techniques such as proton magnetic resonance spectroscopy (MRS) may demonstrate high levels of lactate or succinate. When found, these results are suggestive of a mitochondrial disease. MRI and MRS studies may also show nonspecific findings such as delayed myelination or non-specific leukodystrophies picture. However, in the context of other biochemical, structural, and clinical findings, even non-specific findings may support further diagnostic testing for potential mitochondrial disease. Once a diagnosis has been established, these non-invasive tools can also aid in following disease progression and evaluate the effects of therapeutic interventions.

Quantitative Measurement of Cerebral Oxygen Extraction Fraction Using MRI in Patients with MELAS

ObjectiveTo quantify the cerebral OEF at different phases of stroke-like episodes in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) by using MRI.MethodsWe recruited 32 patients with MELAS confirmed by gene analysis. Conventional MRI scanning, as well as functional MRI including arterial spin labeling and oxygen extraction fraction imaging, was undertaken to obtain the pathological and metabolic information of the brains at different stages of stroke-like episodes in patients. A total of 16 MRI examinations at the acute and subacute phase and 19 examinations at the interictal phase were performed. In addition, 24 healthy volunteers were recruited for control subjects. Six regions of interest were placed in the anterior, middle, and posterior parts of the bilateral hemispheres to measure the OEF of the brain or the lesions.ResultsOEF was reduced significantly in brains of patients at both the acute and subacute phase (0.266 ± 0.026) and at the interictal phase (0.295 ± 0.009), compared with normal controls (0.316 ± 0.025). In the brains at the acute and subacute phase of the episode, 13 ROIs were prescribed on the stroke-like lesions, which showed decreased OEF compared with the contralateral spared brain regions. Increased blood flow was revealed in the stroke-like lesions at the acute and subacute phase, which was confined to the lesions.ConclusionMRI can quantitatively show changes in OEF at different phases of stroke-like episodes. The utilization of oxygen in the brain seems to be reduced more severely after the onset of episodes in MELAS, especially for those brain tissues involved in the episodes.

Transient ischemic attack-like episodes without stroke-like lesions in MELAS

A stroke-like episode is a core symptom in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Proton magnetic resonance spectroscopy (1H-MRS) is useful in the diagnosis of mitochondrial diseases. We report an 8-year-old girl with MELAS, presenting with a seizure and blindness. 1H-MRS showed a strikingly elevated lactate peak in the right occipital region, where no abnormal signals appeared on either T2-W or diffusion-weighted MRI. She recovered completely within a day. We describe this mild clinical condition with abnormal lactate peak in normal-appearing gray matter as a transient ischemic attack-like episode in MELAS.

Neuroimaging characteristics in mitochondrial encephalopathies associated with the m.3243A>G MTTL1 mutation

Stroke-like lesions (SLL) are common radiological findings in patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (SLE; MELAS) harboring the m.3243A>G MTTL1 mutation. Imaging patterns in the m.3243A>G mutation carriers with encephalopathies lacking SLE have not been systematically examined to date. The aim of this study was to analyze brain imaging findings in encephalopathies associated with the m.3243A>G mutation irrespective of the presence or absence of SLE. Brain MRI and cranial CT scans from 11 m.3243A>G mutation carriers with encephalopathies were analyzed by two neuroradiologists in consensus. We evaluated stroke-like lesions (SLL), deep grey matter (DGM) changes on T1- and T2-weighted MR images, calcification on CT, brain atrophy, and white matter (WM) changes. SLL were present in all patients showing the full MELAS phenotype with SLE (4/11). Seven patients did not show SLE. DGM changes with T1 hyperintensity and T2 hypointensity were a distinctive finding in most patients (7/11) and present in the majority of m.3243A>G mutation carriers lacking SLE (5/7). DGM changes were also seen in half of our MELAS patients with SLL (2/4), though less pronounced. Brain atrophy was a prominent finding in general and accentuated in the cerebellum. In contrast, WM changes were rather mild and more prevalent and pronounced in MELAS. Our data stress that the distinction between MELAS with SLE and m.3243A>G mutation carriers lacking SLE is rather artificial. In clinical practice, mitochondrial disorders associated with the m.3243A>G mutation should be taken into consideration in encephalopathies with DGM changes, even when SLE and SLL are lacking.

Acute mitochondrial encephalopathy reflects neuronal energy failure irrespective of which genome the genetic defect affects

Mitochondrial dysfunction and disease may arise as a result of mutations in either the mitochondrial genome itself or nuclear encoded genes involved in mitochondrial homeostasis and function. Irrespective of which genome is affected, mitochondrial encephalopathies share clinical and biochemical features suggesting common pathophysiological pathways. Two common paradigms of mitochondrial encephalopathy are mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes caused by maternally transmitted mutations of mitochondrial DNA and mitochondrial spinocerebellar ataxia and epilepsy caused by recessively inherited mutations of the nuclear-encoded DNA polymerase gamma, which replicates and repairs the mitochondrial genome. We studied and compared the disease mechanisms involved in these two syndromes. Despite having different genetic origins, their pathophysiological pathways converge on one critical event, damage to the respiratory chain leading to insufficient energy to maintain cellular homeostasis. In the central nervous system, this appears to cause selective neuronal damage leading to the development of lesions that mimic ischaemic damage, but which lack evidence of decreased tissue perfusion. Although these stroke-like lesions may expand or regress dynamically, the critical factor that dictates prognosis is the presence of epilepsy. Epileptic seizures increase the energy requirements of the metabolically already compromised neurons establishing a vicious cycle resulting in worsening energy failure and neuronal death. We believe that it is this cycle of events that determines outcome and which provides us with a mechanistic structure to understand the pathophysiology of acute mitochondrial encephalopathies and plan future treatments.

MR evaluation of cerebral oxygen metabolism and blood flow in stroke-like episodes of MELAS

Metabolic information is essential in the investigation of the pathophysiology of stroke-like episodes in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Here, we used magnetic resonance imaging to evaluate the dynamic metabolic changes before and after a stroke-like episode in two patients with MELAS caused by the mitochondrial DNA mutation A3243G. We performed functional magnetic resonance imaging, including arterial spin labeling and oxygen extraction fraction imaging, and generated cerebral blood flow and oxygen extraction fraction maps. We recruited eight healthy volunteers to define the normal range of the oxygen extraction fraction. We detected a heterogeneous reduction in the oxygen extraction fraction in the brain in the interictal period as well as at the onset of a stroke-like attack. However, the oxygen extraction fraction in the stroke-like lesions normalized in the acute stage. The stroke-like lesions showed consistent hyperperfusion in the acute phase but hypoperfusion in the chronic phase. We have demonstrated the utility of using new magnetic resonance imaging techniques in the evaluation of the pathophysiology of stroke-like lesions. The increased utilization of oxygen in an acute lesion is a novel finding in our study, which might play a role in the oxidative stress.

Globus pallidus and substantia nigra hypointensities on T2*-weighted imaging in MELAS

We present a 48-year-old mother [with history of seizures, migraine, diabetes mellitus, neurosensory hearing loss, short stature, cognitive deficit, and ataxia, and onset of stroke-like episodes 3 years after initial magnetic resonance imaging (MRI)] and her 20-year-old son (with history of one strokelike episode at the moment of the initial MRI, and another stroke-like episode 3 months later, in absence of other signs) with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS, m.3243A [G tRNALeu[UUR] mutation), both showing on computed tomography (CT) bipallidal microcalcifications and on initial 3-T T2*-weighted MRI (TE = 13 ms, TR = 475 ms) large bilateral hypointensities in the pallidum and the substantia nigra (Fig. 1). Basal ganglia showed normal intensities on T1-weighted and fluid-attenuated inversion recovery (FLAIR) imaging, and very slight hypointense (i.e., nearnormal) signal on T2-weighted imaging (Fig. 1). One strokelike lesion (accompanying stroke-like symptoms) was seen on initial MRI in the son, and another stroke-like lesion occurred 3 months later, and the mother presented strokelike lesions 3 years after the initial MRI (Fig. 2). Both patients also showed cerebral and cerebellar atrophy, and slight bilateral posterior leukoencephalopathy on MRI (Fig. 2). MRI follow-up (3 years in the mother, and 3 months in the son) did not show evolution of the T2*-weighted hypointensities in the pallidum and the substantia nigra. Radiological abnormalities (sometimes absent or discrete, especially in the early stage of the disease) encountered in MELAS include cerebral and cerebellar atrophy, basal ganglia signal changes, stroke-like lesions, and leukodystrophy. Extensive calcifications are the most frequently encountered basal ganglia abnormalities in MELAS, most frequently described on CT and only rarely on MRI in the literature [1]. Basal ganglia calcifications in our two patients were discrete on CT. The extent of the MRI abnormalities, when compared with CT, may be explained by the magnetic susceptibility effect of T2*weighted imaging (potentially exaggerated by the highfield 3-T MRI used in our patients) and/or the presence of microscopic calcium and iron deposition [2, 3]. Both calcium and iron deposition in the globus pallidus have been demonstrated earlier on autopsy in MELAS [2]. T2and diffusion-weighted MRI changes and necrotizing lesions on autopsy have been reported in the substantia nigra in another mitochondrial syndrome, i.e., Leigh syndrome [4, 5]. In a general population, incidence of basal ganglia calcifications on CT scan varies between 0.6 and 0.8 % [6, 7]. Incidence increases with increasing age [7, 8]. In the elderly, basal ganglia calcifications are encountered in 38.7 % of patients on CT scan, with the globus pallidus as the most frequently involved structure [9]. The precise agematched incidence, the MRI-based incidence of age-related basal ganglia calcifications, and the pathophysiology explaining the predominant involvement of certain substructures (e.g., the pallidum in our MELAS patients and in the elderly) are unknown. When MELAS is suspected clinically, T2*-weighted MRI imaging (and thus not only CT scan) may be an interesting additional radiological tool to detect discrete calcium and/or iron deposition, especially in young patients (in whom age-related basal ganglia calcifications are less D. Renard (&) C. Campello A. Le Floch G. Castelnovo G. Taieb Department of Neurology, CHU Nimes, Hopital Caremeau, Place du Pr Debre, 30029 Nimes Cedex 4, France e-mail: dimitrirenard@hotmail.com

Perfusion status of the stroke-like lesion at the hyperacute stage in MELAS

Hypoperfusion on single-photon emission computed tomography (SPECT) of the stroke-like lesion (SLL) at the hyperacute stage of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) is considered to be a supportive evidence of the mitochondrial angiopathy theory. Our objectives were to examine whether other neuroimages, especially transcranial color-coded sonography (TCCS), done at the hyperacute stage of stroke-like episode (SLE) is consistent with hypoperfusion of the SLL. We reviewed the magnetic resonance imaging (MRI), SPECT, cerebral angiography, and TCCS of a patient with MELAS syndrome, all of which were performed at the hyperacute stage of one SLE. MRI on the 1st day post SLE showed right temporoparietal lesion with vasogenic edema. SPECT on the 2nd day showed focal decreased uptake of technetium-99m hexamethylpropyleneamine oxime (99mTc-HMPAO) in the same region, but cerebral angiography and TCCS on the 3rd day showed increased regional cerebral blood flow (rCBF) and distal arteriole dilation in the same region. TCCS can delineate increased rCBF of the SLL at the hyperacute stage of SLE. We propose that the discrepancy between the decreased 99mTc-HMPAO uptake and increased rCBF might be caused by mitochondrial dysfunction. The phenomenon of “hypoperfusion” on SPECT might be caused by cell dysfunction but not decreased rCBF. We suggest that SPECT can be complemented by angiography and TCCS in future studies to delineate the perfusion status of SLLs.

Anti-NMDA receptor antibodies in a case of MELAS syndrome

A 42-year-old man presented with new-onset headache, global aphasia, anteroand retrograde memory deficits, stereotypic behavior, agitation and an inappropriate foolish affect in July 2007. Immediate MRI revealed a T2w lesion in the left temporal lobe with cortical and subcortical involvement, compatible with encephalitis (Fig. 1). CSF analysis showed normal cell count and negative herpes simplex virus type I PCR while protein and lactate levels were elevated (protein: 1.36 g/l; normal: 0.15–0.45 g/l; lactate: 5.6 mmol/l; normal: 0.55–2.2 mmol/l). Repeated history taking revealed progressive bilateral hearing loss for 8 years. Additional MRI investigations showed a hyperintense appearance of the observed lesion in diffusion weighted images (DWI), mixed increased and decreased diffusion on apparent diffusion coefficient (ADC) maps, and a strong lactate peak in MR spectroscopy (Fig. 1). Further work-up revealed myopathic changes in several muscles on electromyography, elevated serum lactate during lactate stress test, hypertrophic cardiomyopathy, and signs of mitochondrial disease in muscle biopsy specimens (increased fuchsinophilia and COX-negative fibers). Family history was negative for mitochondrial disorders, but genetic analysis from leucocytes revealed a heteroplasmic m.3243A[G point mutation in mitochondrial DNA (heteroplasmy rate, 30%), compatible with a diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). No other family members were tested. During the next few years, the patient developed focal epilepsy and progressive cognitive deficits. In 2010, he sustained a stroke-like episode of the left occipital cortex causing right homonymous hemianopia (Fig. 1). At this time, the initial clinical presentation was reconsidered and archived CSF/serum samples obtained 6 days after symptom onset in 2007 were analyzed for autoimmune antibodies. Antibodies were determined by means of a recombinant immunofluorescence assay employing NMDAR transfected HEK cells as described previously [1]. IgG-antibodies against NMDAR were detected in the patient’s serum at a titer of 1:32 (score 2 according to Irani et al. [4]). No antinuclear antibodies (ANA) or antibodies against further neuronal surface antigens (i.e., AMPA receptor, GABAb-receptor) or VGKC-complex were detected in the patient’s serum. On follow-up in 2010, NMDAR antibodies were negative both in serum and CSF. A body-CT revealed no malignancies. Taken together, our patient presented with symptoms compatible with a first manifestation of MELAS syndrome in 2007 [2]. The patient’s lesion in the left temporal lobe likely accounts for his aphasia, memory disturbances, and behavioral changes. Imaging characteristics suggest a stroke-like lesion associated with MELAS syndrome [3]. At the same time, however, the patient tested positive for anti-NMDAR antibodies that are considered highly specific C. Finke (&) H. Pruss F. Ostendorf L. Harms C. J. Ploner Department of Neurology, Charite-Universitatsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany e-mail: carsten.finke@charite.de

66 Ethnic differences in carotid intimal medial thickness and carotid-femoral pulse wave velocity are present in UK children

<h3>Background</h3> Human coenzyme Q4 (COQ4) is essential for coenzyme Q₁₀ (CoQ₁₀) biosynthesis. Pathogenic variants in <i>COQ4</i> cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency. <h3>Methods</h3> Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed. <h3>Results</h3> We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in <i>COQ4</i>. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of <i>COQ4</i> variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ₁₀ and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. <h3>Conclusion</h3> Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of <i>COQ4</i> variants. Due to the insufficient clinical response to oral CoQ₁₀ supplementation, alternative treatment strategies are warranted.

Regression of stroke‐like lesions in MELAS‐syndrome after seizure control

There are some indications that seizure activity promotes the development of stroke-like episodes, or vice versa, in patients with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome or other syndromic mitochondrial disorders. A41-year-old Caucasian female with MELAS syndrome, presenting with short stature, microcytic anaemia, increased blood-sedimentation rate, myopathy, hyper-gammaglobulinaemia, an iron-metabolism defect, migraine-like headaches, and stroke-like episodes, developed complex partial and generalised seizures at age 32years. Valproic acid was ineffective but after switching to lamotrigine and lorazepam, she became seizure-free for five years and stroke-like episodes did not recur. Cerebral MRI initially showed enhanced gyral thickening and a non-enhanced T2-hyperintensity over the left parieto-temporo-occipital white matter and cortex and enhanced caudate heads. After two years without seizures, the non-enhanced hyperintense parieto-temporo-occipital lesion had disappeared, being attributed to consequent seizure control. The caudate heads, however, remained hyperintense throughout the observational period. This case indicates that adequate seizure control in a patient with MELAS syndrome may prevent the recurrence of stroke-like episodes and may result in the disappearance of stroke-like lesions on MRI.

A common pattern of brain MRI imaging in mitochondrial diseases with complex I deficiency

ObjectiveTo identify a consistent pattern of brain MRI imaging in primary complex I deficiency. Complex I deficiency, a major cause of respiratory chain dysfunction, accounts for various clinical presentations, including...

The use of neuroimaging in the diagnosis of mitochondrial disease

Mutations in nuclear and mitochondrial DNA impacting mitochondrial function result in disease manifestations ranging from early death to abnormalities in all major organ systems and to symptoms that can be largely confined to muscle fatigue. The definitive diagnosis of a mitochondrial disorder can be difficult to establish. When the constellation of symptoms is suggestive of mitochondrial disease, neuroimaging features may be diagnostic and suggestive, can help direct further workup, and can help to further characterize the underlying brain abnormalities. Magnetic resonance imaging changes may be nonspecific, such as atrophy (both general and involving specific structures, such as cerebellum), more suggestive of particular disorders such as focal and often bilateral lesions confined to deep brain nuclei, or clearly characteristic of a given disorder such as stroke-like lesions that do not respect vascular boundaries in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS). White matter hyperintensities with or without associated gray matter involvement may also be observed. Across patients and discrete disease subtypes (e.g., MELAS, Leigh syndrome, etc.), patterns of these features are helpful for diagnosis. However, it is also true that marked variability in expression occurs in all mitochondrial disease subtypes, illustrative of the complexity of the disease process. The present review summarizes the role of neuroimaging in the diagnosis and characterization of patients with suspected mitochondrial disease.

Localized cerebral energy failure in DNA polymerase gamma-associated encephalopathy syndromes

Mutations in the catalytic subunit of the mitochondrial DNA-polymerase gamma cause a wide spectrum of clinical disease ranging from infantile hepato-encephalopathy to juvenile/adult-onset spinocerebellar ataxia and late onset progressive external ophthalmoplegia. Several of these syndromes are associated with an encephalopathy that characteristically shows episodes of rapid neurological deterioration and the development of acute cerebral lesions. The purpose of this study was to investigate the nature, distribution and natural evolution of central nervous system lesions in polymerase gamma associated encephalopathy focusing particularly on lesions identified by magnetic resonance imaging. We compared radiological, electrophysiological and pathological findings where available to study potential mechanisms underlying the episodes of exacerbation and acute cerebral lesions. We studied a total of 112 magnetic resonance tomographies and 11 computed tomographies in 32 patients with polymerase gamma-encephalopathy, including multiple serial examinations performed during both the chronic and acute phases of the disease and, in several cases, magnetic resonance spectroscopy and serial diffusion weighted studies. Data from imaging, electroencephalography and post-mortem examination were compared in order to study the underlying disease process. Our findings show that magnetic resonance imaging in polymerase gamma-related encephalopathies has high sensitivity and can identify patterns that are specific for individual syndromes. One form of chronic polymerase gamma-encephalopathy, that is associated with the c.1399G > A and c.2243G > C mutations, is characterized by progressive cerebral and cerebellar atrophy and focal lesions of the thalamus, deep cerebellar structures and medulla oblongata. Acute encephalopathies, both infantile and later onset, show similar pictures with cortical stroke-like lesions occurring during episodes of exacerbation. These lesions can occur both with and without electroencephalographic evidence of concurrent epileptic activity, and have diffusion, spectroscopic and histological profiles strongly suggestive of neuronal energy failure. We suggest therefore that both infantile and later onset polymerase gamma related encephalopathies are part of a continuum.

The “good” limb makes the “bad” limb worse: Experience-dependent interhemispheric disruption of functional outcome after cortical infarcts in rats.

Following stroke-like lesions to the sensorimotor cortex in rats, experience with the ipsi-to-lesion (ipsilesional), "nonparetic", forelimb worsens deficits in the contralesional, "paretic", forelimb. We tested whether the maladaptive effects of experience with the nonparetic limb are mediated through callosal connections and the contralesional sensorimotor cortex. Adult male rats with proficiency in skilled reaching with their dominant (for reaching) forelimb received ischemic bilateral sensorimotor cortex lesions, or unilateral lesions, with or without callosal transections. After assessing dominant forelimb function (the paretic forelimb in rats with unilateral lesions), animals were trained with their nonparetic/nondominant forelimb or underwent control procedures for 15 days. Animals were then tested with their paretic/dominant forelimb. In animals with unilateral lesions only, nonparetic forelimb training worsened subsequent performance with the paretic forelimb, as found previously. This effect was not found in animals with both callosal transections and unilateral lesions. After bilateral lesions, training the nondominant limb did not worsen function of the dominant limb compared with controls. Thus, the maladaptive effects of training the nonparetic limb on paretic forelimb function depend upon the contralesional cortex and transcallosal projections. This suggests that this experience-dependent disruption of functional recovery is mediated through interhemispheric connections of the sensorimotor cortex.

Bevacizumab-induced diffusion-restricted lesions in malignant glioma patients

Bevacizumab is an anti-vascular endothelial growth factor (VEGF) antibody with activity against recurrent malignant glioma inducing high rates of objective responses as assessed by magnetic resonance imaging (MRI). However, the mechanisms of the anti-tumor action of bevacizumab are controversial. In particular, it is unclear whether and when bevacizumab induces hypoxia in gliomas. Vascular normalization with hyperperfusion and enhanced oxygen delivery to the tumor has been suggested as an alternative mechanism. We analyzed diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps in 18 consecutive patients with recurrent malignant glioma before and after exposure to bevacizumab. Stroke-like lesions with diffusion restriction on DWI and corresponding ADC decrease were induced by bevacizumab within the previously enhancing tumor area in 13 of 18 patients. These lesions were detectable as early as 4 weeks after initiation of therapy and were maintained for up to 80 weeks. In one patient, an ADC-decreased lesion was biopsied, and histology showed atypical necrosis and nuclear hypoxia-inducible factor 1alpha upregulation but no tumor recurrence. Normalized regional cerebral blood flow (rCBF) and regional cerebral blood volume (rCBV) were analyzed in selected patients. Both parameters were decreased in responders with diffusion-restricted lesions. Within the tumor bed, bevacizumab induces diffusion-restricted lesions in the presence of reduced rCBF and rCBV. The cause of these alterations is unclear but may involve atypical necrosis and chronic hypoxia.

CT und MRT des Zerebrums bei mitochondrialen Erkrankungen

The central nervous system (CNS) is the second most frequently affected organ in mitochondrial disorders (MD). In the majority of the cases, clinical CNS manifestations correlate with the CNS lesions on imaging and vice versa. The most important method to demonstrate CNS abnormalities in MD is the MRI. This imaging technique can demonstrate structural lesions, such as strokelike lesions, focal or diffuse atrophy, cysts or lacunas, focal or diffuse white matter lesions, grey matter lesions of the cortex or deep grey matter, and increased iron deposition. Functional abnormalities such as increased lactate in the white and grey matter or increased cholin in the white matter can be demonstrated by proton spectroscopy. Abnormlities of the intracerebral vessels can also be documented by MRI. Calcification and bleeding, however, are still more easily accessible by CT. Differentiation between disseminated, focal MD lesions of the white matter from nonactive MS plaques requires inclusion of the individual and family history and all instrumental investigations which are usually necessary to establish the diagnosis of a MD.