PostScript
Ethics approval This study was conducted with the approval of the local institutional review board (Lyon, London and Nijmegen). Provenance and peer review Not commissioned; externally peer reviewed. Received 2 October 2009 Revised 9 November 2009 Accepted 27 November 2009 Published Online First 28 July 2010 J Neurol Neurosurg Psychiatry 2011;82:467e469. doi:10.1136/jnnp.2009.196550
REFERENCES 1.
2.
3.
4.
5.
Misu T, Takano R, Fujihara K, et al. Marked increase in cerebrospinal fluid glial fibrillar acidic protein in neuromyelitis optica: an astrocytic damage marker. J Neurol Neurosurg Psychiatry 2009;80:575e7. Petzold A, Eikelenboom MJ, Gveric D, et al. Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations. Brain 2002;125:1462e73. Petzold A, Keir G, Green AJ, et al. An ELISA for glial fibrillary acidic protein. J Immunol Methods 2004;287:169e77. Petzold A, Keir G, Green AJ, et al. A specific ELISA for measuring neurofilament heavy chain phosphoforms. J Immunol Methods 2003;278:179e90. Petzold A, Keir G, Lim D, et al. CSF and serum S100B: release and wash-out pattern. Brain Res Bull 2003;61:281e5.
In vivo amyloid imaging in cortical superficial siderosis INTRODUCTION In superficial siderosis (SS), haemosiderin is deposited in the subpial layers of the central nervous system. SS can be diagnosed by the presence of a hypointense rim over the brain surface on gradient recalled echo (GRE) T2 weighted MRI, typically surrounding the brainstem and filling the cerebellar sulci. The classical triad consists of slowly progressive hearing loss, cerebellar ataxia and corticospinal tract signs. SS has classically been attributed to chronic or repeated subarachnoid haemorrhage, which may be otherwise clinically silent. In up to 65% of patients a bleeding source can be detected; the other cases have been labelled idiopathic.1 Recently, Feldman et al presented two patients with SS and histopathology of neuritic plaques and cerebral amyloid angiopathy (CAA).2 A few more patients have been published with both sporadic CAA and SS, without evidence of intraparenchymal amyloid.1 3 In a population based study Vernooij et al found SS in 0.7% of nondemented individuals, all of whom also had intracerebral microbleeds.4 11 C-Pittsburgh compound B (PIB) positron emission tomography (PET) marks both vascular and parenchymal b amyloid plaques in vivo. We report 11C-PIB PET findings in two cases with SS. Our findings suggest that SS in the context of b amyloidosis may have a distinct clinical and MRI signature. J Neurol Neurosurg Psychiatry April 2011 Vol 82 No 4
CASE NO 1 A 76-year-old woman with a history of hypercholesterolaemia who was taking acetylsalicylate presented with two episodes of hypoesthesia migrating from the right gluteal region to the right arm, associated with non-fluent speech, which lasted for a total of 15 min. Clinical neurological examination on admission was normal. Brain CT scan showed a hyperdense signal in the left central sulcus (figure 1A). CT angiography of the intracranial and extracranial vessels was negative. CSF analysis did not demonstrate blood, bilirubin or (oxy) haemoglobin. GRE T2 weighted MRI showed a hypointense signal delineating the cerebral sulci along the supratentorial brain surface, together with a single punctiform microhaemorrhage in the medial occipital cortex (figure 1B). An MRI full spine and two EEGs were normal. A tentative diagnosis of simple partial epileptic seizures was made. Simvastatine and valproic acid were initiated. Two months later the patient spontaneously reported memory problems as well as depressive symptoms. Sertraline was prescribed. The Mini-Mental State Examination score 5 months after the first symptoms was 26/30. Neuropsychological evaluation demonstrated an episodic memory deficit along with executive dysfunction. Using a Biograph PET-CT scanner, 11C-PIB images were acquired from 0 to 90 min following injection of 268 MBq. The pattern of 11C-PIB uptake (figure 1E,I) was closely similar to what is typically seen in clinically probable Alzheimer ’s disease (figure 1G,I).
CASE NO 2 A 72-year-old man with a history of arterial hypertension, hypercholesterolaemia and a myocardial infarction 25 years ago consulted the general neurology outpatient clinic with recurrent attacks of mild frontal and occipital headache over the past 2 months with slight photophobia and sonophobia, lasting 10 min. Subsequently these headache attacks became associated with, and later replaced by, short episodes of leftsided numbness and weakness of the mouth and tongue, migrating to the fingers of the left hand. He was treated with altizide, spironolactone, atenolol, atorvastatin, acetylsalicylate and dipyridamol. Clinical examination, brain CT, routine blood examination, carotid sonography, three EEGs, 24 h EEG, 24 h cardiac monitoring and transoesophageal echocardiography were negative. A GRE T2 weighted MRI revealed distributed hypointensities within the sulci of the cerebral convexity, sparing the posterior fossa. Several intraparenchymatous macro- and microhaemorrhages were present (figure 1D), as well as periventricular white matter fluid attenuated inversion recovery hyperintensities and several old lacunes. A tentative diagnosis of simple partial epileptic seizures was made. Valproic acid was initiated. Symptoms recurred, but now
in the right hemicorpus, 5 and 15 months later. On the latter occasion a brain CT scan revealed a subarachnoid haemorrhage within the left precentral sulcus (figure 1C). Dipyridamol was discontinued. MR intracranial angiography and MRI full spine were negative. Apolipoprotein E genotype was 33/33. Nineteen months after the initial symptoms the patient presented to the memory clinic with cognitive complaints and a limited impact on Instrumental Activities of Daily Living (IADL). The Mini-Mental State Examination score was 29/30. Neuropsychological examination revealed an episodic memory deficit, mild anomia, mild constructional disturbances and executive dysfunction. A 11C-PIB PET scan following the same procedure as in case No 1 demonstrated increased 11C-PIB uptake in neocortical association zones (figure 1F,I), according to a pattern that was closely similar to what is typically seen in clinically probable Alzheimer’s disease (figure 1G,I). Across the two cases, within the left and right lateral frontal, temporal, parietal and posterior cingulate volumes of interest, 11 C-PIB DVR values were significantly higher in the immediate vicinity of the haemosiderin deposits (mean distribution volume ratio (DVR) 1.89, SD 0.38) than at a distance (mean DVR 1.78, SD 0.33) (two tailed paired Student’s t test p¼0.0071).
DISCUSSION These cases differ from classical SS: haemosiderin deposition was most prominent along the supratentorial cortical surface while in classical SS haemosiderin deposition is localised to the posterior fossa. Patients presented with recurrent focal sensorimotor symptoms and cognitive decline while typical SS causes a slowly progressive hearing loss, cerebellar ataxia and corticospinal tract signs.1 Thirdly, SS in our cases was associated with raised b amyloid load while classical SS has been mainly attributed to tumours, trauma, (pseudo)meningocoele, root pathology or arteriovenous malformations or aneurysms.1 The two cases also differ from clinically probable Alzheimer’s disease: cognitive decline was preceded by transient sensorimotor symptoms suggestive of partial epileptic seizures. A CT scan following one of these episodes demonstrated intrasulcal blood in each case. The impact on Instrumental Activities of Daily Living was limited. The vascular abnormalities on MRI were too pronounced to permit a diagnosis of clinically probable Alzheimer’s disease in these patients. The first case also differed from CAA because the GRE hypointense signal was almost exclusively localised to the cortical outer surface. The second case met the Boston criteria for probable CAA. We propose the term ‘cortical superficial siderosis’ for this combination of radiological 469
PostScript
Figure 1 (A, C) CT scan demonstrating a small intrasulcal haemorrhage in case Nos 1 and 2, respectively. (B, D) Gradient recalled echo (GRE) T2 weighted MRI in case Nos 1 and 2, respectively, showing intraparenchymal (arrowheads) and intrasulcal (arrows) hypointensities. (EeH) Distribution volume ratio (DVR) images with the cerebellar cortex as the reference (image acquisition 0e90 min post-injection). (E) Case No 1. (F) Case No 2 (G) Average of 13 11C-PIB positive patients with clinically probable AD.5 (H) Average of 13 11C-PIB negative age matched cognitively intact controls.5 (I) DVR values in the frontal, parietal, lateral temporal and posterior cingulate volumes of interest (automatised anatomical labelling template) in 13 probable Alzheimer’s disease patients (red triangle),5 13 cognitively intact age matched controls (green circle) 5 and in case Nos 1 (red square) and 2 (red square). lat. temp, lateral temporal volume of interest; p. cingul, posterior cingulate volume of interest; R, the right side of the patient.
470
J Neurol Neurosurg Psychiatry April 2011 Vol 82 No 4
PostScript and clinical findings. Cortical superficial siderosis falls within the spectrum of CAA and Alzheimer’s disease and constitutes an occasional complication of cerebral amyloidosis. Isabel Dhollander,1 Natalie Nelissen,2 Koen Van Laere,3 Dirk Peeters,4 Philippe Demaerel,5 Wim Van Paesschen,1 Vincent Thijs,1,6 Rik Vandenberghe1,2 1
Department of Neurology, University Hospitals Leuven, Belgium; 2Laboratory for Cognitive Neurology, KU Leuven, Belgium; 3Department of Nuclear Medicine, University Hospitals Leuven, Belgium; 4Department of Neurology, AZ Groeninge, Kortrijk, Belgium; 5Department of Radiology, University Hospitals Leuven, Belgium; 6 Vesalius Research Center, VIB, Leuven, Belgium Correspondence to Dr R Vandenberghe, UZ Leuven, Herestraat 49, 3000 Leuven, Belgium; rik.
[email protected] Funding Research Foundation Flanders and Bijzonder Onderzoeksfonds KU Leuven. Competing interests RV has been the principal investigator and KVL co-investigator of a GE HC sponsored phase I trial. RV, KVL and VT are senior clinical investigators and NN is a PhD Fellow of the Flemish Research Foundation Flanders (FWO). Patient consent Obtained. Ethics approval This study was conducted with the approval of the ethics committee of the University Hospitals Leuven. Provenance and peer review Not commissioned; externally peer reviewed. Received 9 September 2009 Revised 8 December 2009 Accepted 9 December 2009 Published Online First 28 July 2010 J Neurol Neurosurg Psychiatry 2011;82:469e471. doi:10.1136/jnnp.2009.194480
REFERENCES 1. 2.
3.
4.
5.
Kumar N, Cohen-Gadol AA, Wright RA, et al. Superficial siderosis. Neurology 2006;66:1144e52. Feldman HH, Maia LF, Mackenzie IRA, et al. Superficial siderosis, a potential marker of cerebral amyloid angiopathy in Alzheimer disease. Stroke 2008;39:2894e7. Linn J, Herms J, Dichgans M, et al. Subarachnoid haemosiderinosis and superficial cortical haemosiderinosis in cerebral amyloid angiopathy. AJNR 2008;29:184e6. Vernooij MW, Ikram MA, Hofman A, et al. Superficial siderosis in the general population. Neurology 2009;73:202e5. Nelissen N, Vandenbulcke M, Fannes K, et al. Abeta amyloid deposition in the language system and how the brain responds. Brain 2007;130:2055e69.
Cervical cord and brain grey matter atrophy independently associate with long-term MS disability In MRI studies of multiple sclerosis (MS), brain grey matter (GM) and spinal cord atrophy correlate with disability.1 2 However, J Neurol Neurosurg Psychiatry April 2011 Vol 82 No 4
it is uncertain whether they independently associate with long-term disability. We measured upper cervical cord cross-sectional area (UCCA) in a cohort of patients w20 years after presenting with a clinically isolated syndrome (CIS) suggestive of MS. Associations of brain GM atrophy and white matter (WM) lesion load with disability had been previously observed in the cohort.1 We now report UCCA measurements and independent associations of the cord and brain measures with disability. Seventy patients presenting with CIS had analysable brain and MRI scans acquired on a 1.5 T scanner after a median of 20 years (range 18e27). Clinically definite MS (CDMS) was diagnosed clinically.3 Disability was assessed with the expanded disability status scale (EDSS)4 and MS functional composite score (MSFC) plus its three components, paced serial auditory attention test (PASAT; 3 s interval), nine-hole peg test (9HPT) and 25-foot timed walk (T25FW). CDMS subgroups were defined as relapsingeremitting (RR) or secondary progressive (SP) MS; those with an EDSS #3 were classified as benign.5 At the 20-year follow-up, 27 remained CIS, 32 had RRMS (21 benign MS, 11 nonbenign RRMS (EDSS>3)), and 11 had SPMS. UCCA and brain MR parameters were measured as previously described.1 2 UCCA was also measured in 17 healthy volunteers. Statistical analysis was performed using the SPSS Version 11.0 (SPSS, Chicago, Illinois) and Stata 9.2 (Stata Corporation, College Station, Texas). Subgroup comparisons of UCCA were performed using linear regression with total intracranial volume (TICV), age and gender as covariates. The Spearman rank-correlation (rs) evaluated the correlation of UCCA with EDSS, MSFC, WMF, GMF and lesion load. The association of UCCA, GMF, WMF and lesion load with long-term disability was assessed using ordinal logistic regression (for EDSS) and linear regression (for MSFC). EDSS (as an ordinal scale) and MFSC (as a continuous variable) were modelled as response variables, with UCCA, GMF, WMF, lesion load (from T2-weighted MRI scans), TICV, age and gender as potential associations. No significant effects of CIS type were found, so this was not included. Lesion load was log-transformed to improve normality before including it in the model (lesion load¼zero was assigned a nominal log volume value of 0.01).
The R2 obtained from linear regression analysis was used to compare the proportion of variability in MSFC scores explained by each MRI measure alone (from regressions with the single MRI measure) and by the composite of MRI measures (in the multiple regressions). The median age of patients was 51 years (range 39e68) and controls 41 years (31e59). Forty-eight/70 patients and 10/17 controls were female. The median EDSS was 2.5 (0e8) for all patients and 3.5 (1e8) for CDMS. The mean UCCA was 83.17 mm2 in controls (SD 8.32), 79.22 mm2 (10.19) in those who remained CIS, 75.07 mm2 (8.32) in RRMS (78.52 mm2 (5.63) in benign and 68.08 mm2 (7.20) in non-benign RRMS) and 66.76 mm2 (5.99) in SPMS. UCCA did not differ significantly between controls and CIS or benign MS but did between controls and SPMS (15.88, 26.24 to 12.80, p
