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Journal Reviews

Posted in Journal Reviews on 28th May 2013

Muddied waters (on the brain)

Diagnosis in the dementias remains challenging.The prospect of disease modifying treatments for neurodegenerative pathologies demands an improvement in the prediction of underlying pathology during lifetime. There is an argument that diagnostic accuracy is better in PSP than other diseases. The NNIPPS study found those with a clinical diagnosis of PSP were likely to have tau-based PSP pathology in 95% of cases (Bensimon et al). However, uncertainty remains around patients with PSP pathology at post-mortem who may have a lifetime diagnosis of other conditions such as Parkinson’s disease,or no diagnosis at all.The waters are further muddied by a study from the Queen Square group (Magdalinou et al) who identified three patients with a lifetime diagnosis of idio- pathic Normal Pressure Hydrocephalus (iNPH),but tau-associ- ated PSP pathology at post-mortem, and an additional patient with clinical iNPH and alpha-synuclein Parkinson’s disease pathology.All four patients had an initial positive response to lumbar puncture, classically considered to be central to a diagnosis of iNPH alongside the triad of urinary incontinence, impaired balance and cognitive decline. One may wish to quibble that some red flags were present during life, such as the presence of swallowing problems in 3/4 patients, classic MRI findings of mid-brain atrophy in one patient, and suffi- cient concern about a co-existing diagnosis in two patients not to proceed with shunting. However, eye movements were not noticed to be abnormal until late in the disease course in all three subjects and the fact remains that the primary clinical label during life was iNPH in all four patients. The authors accept their sample may be biased by the high number of patients with movement disorders in their brain bank.Previous reports have raised more issues concerning vascular disease or Alzheimer’s pathology in the context of clinical iNPH.However, a single subject with PSP was identified in a series from the Mayo Clinic (Klassen et al). We are not told when the diagnoses were made,and recent attempts to strengthen diagnostic guide- lines for both iNPH and PSP may assist the clinician. Despite this, predicting neurodegenerative pathology during life remains challenging and a diagnosis of iNPH should be made with caution and an open mind, even if there is an initial response to lumbar puncture. – TR

Magdalinou NK, Ling H, Smith JDS, et al. Normal pressure hydrocephalus or progressive supranuclear palsy? A clinicopathological case series.Journal Of Neurology 2013;260:1009–13.

Bensimon G, Ludolph A, Agid Y, et al. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study. Brain 2009;132:156–71.

Klassen BT, Ahlskog JE. Normal pressure hydrocephalus: how often does the diagnosis hold water? Neurology 2011;77:1119–25.

Brain pathology goes 3D

While Drosophila biologists have long been able to produce beautiful, technicolour images of whole mount preparations, mammalian neuroscience has been left behind in the 2D world. Wouldn’t it be amazing if we could do human brain pathology in 3D? Researchers from Stanford University pushed the boundaries of tissue fixation and appear to have devel- oped a method, termed CLARITY, which makes brain tissues ‘optically and chemically accessible’. The Deisseroth lab at Stanford first fixed and stabilised cellular proteins, nucleic acids and other molecules (but, importantly, not lipids) using conventional fixatives, together with hydrogels such as acry- lamide.They then used a detergent to wash away the unfixed lipids, accelerating this process using electrophoresis. The result is ‘clarified’ tissue, free of the optical dispersion caused by lipid membranes, and more permeable to antibodies for immunoprofiling. Their images are simply stunning. The ‘invisible brain’ is truly astounding!

Their pictures and 3D fly-through videos clearly indicate the power of this tool. The ability to resolve subcellular architecture in 3D, repeatedly antibody stain and not have to section are attractive, and although it may takes weeks to process a whole mouse brain, this may be a small price to pay for the sheer quality and quantity of data one could obtain. Aside from pretty mouse brains, CLARITY is also applicable to other vertebrates, most importantly humans. Archived brain speci- mens can be clarified.

The group provide detailed directions for setting up the apparatus needed to ‘clarify’ tissue. One just hopes that other research labs and brain banks will be able to easily use their methods to replicate and even improve upon their results. – JS

Chung K, Wallace J, Kim SY, et al. Structural and molecular interrogation of intact biological systems. Nature. 2013 Apr 10. doi: 10.1038/nature12107

NMDAR encephalitis– hit hard and fast?

Most clinicians will remember their first patient with Anti-NMDAR encephalitis. First described in 2005, as a paraneoplastic, neuropsychiatric disorder associated with ovarian teratoma, Dalmau and colleagues first identified the specific antibody associated with this syndrome in 2007. Patients with anti-NMDAR encephalitis typically develop a multistage illness that encompasses psychosis, seizures, abnormal movements, reduced levels of consciousness and autonomic instability.

In the largest observational study of patients with anti-NMDAR encephalitis published to date, Titulaer and colleagues recently described in the Lancet Neurology the presentation, treatment and outcome factors of 577 patients with the disease (median age 21 years, range 8 months to 85 years). Of this cohort, most (501) had at least four months follow-up, with a median follow-up time of two years. Whilst seizures or movement disorders were the most frequent presenting symptoms in children, adults more commonly presented with behav- ioural disturbance. In total,38% of patients had an underlying malignancy,which were nearly all ovarian teratomas. Non-teratoma neoplasms accounted for only 4% of tumours.As awareness of this disorder among clinicians has increased, people with atypical presentations are increasingly being tested for antibodies. Interestingly, only 1% of patients in this cohort remained monosymptomatic at four weeks suggesting that antibody testing in such patients is unlikely to yield positive results.

In early studies, response to tumour removal and first-line immunotherapies (steroids, intra- venous immunoglobulins and plasmapheresis) was sub-optimal in many patients but there has been controversy surrounding the benefits of escalating to second-line immunotherapies (rituximab and/or cyclophosphamide). Of the 472 patients in this cohort treated with tumour removal and/or first-line therapies, 53% had improved symptomatically within four weeks.Of the remaining 47% of“non-responders”,just over half were prescribed second-line treatments. Results supported the theory that those patients receiving additional treatment with rituximab and/or cyclophosphamide had better outcomes than patients who only received first-line therapies, with 78% of treated patients attaining a modified Rankin Scale score of 0-2 by 24 months compared with only 55% those who did not receive second-line immunothera-pies.Furthermore,those initial “non-responders” treated with second-line immunotherapies had a comparatively reduced number of relapses and minimal adverse events were reported.

Overall this study has provided important information about the presentation, treatment and prognosis of this serious but treatable autoimmune disease. It provides evidence that early intervention results in better outcomes and should encourage clinicians to intervene with cyclophosphamide and/or rituximab if first line therapies fail to lead to a significant improvement after four weeks of treatment. Although limited by not being randomised, this study sets the stage for future trials to establish the efficacy of each individual treatment as well as recommended duration of therapies.– GC

Titulaer MJ et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013 Feb;12(2):157-65

Caspr2 and limbic encephalitis

The classical phenotype of anti-voltage gated potassium channel (VGKC) antibody limbic encephalitis (LE), in which patients present with psychiatric deterioration, encephalopathy and seizures, is now well recognised. However, recent work has identified that the antibody target in autoimmune LE is not the VGKC itself but rather VGKC associated proteins that co- precipitate in the radioimmunological assay (RIA). The contactin-associated protein-2 (Caspr2), which forms part of the molecular scaffold responsible for maintaining VGKC appears to be one such antibody target. Balint and colleagues from Heidelberg have published a case of Caspr2 antibody positive but VGKC antibody negative LE.They detected the antibody (IgM; titre 1:100) with a cell- based assay using full length human Caspr2 (Euroimmun) after standard RIA using brain tissue extract was negative. Their case is noteworthy as, in addition to the usual features of the disease, the patient manifested cerebellar ataxia, myoclonus and dyskinesia suggesting that Caspr2 antibody positive LE may have a broad and severe clinical phenotype. The authors argue that more targeted assays should be employed for detecting antibodies in LE. Over the coming years, distinguishing the different clinical subtypes of autoimmune LE will be increasingly relevant in helping to guide prognosis and therapy. – TH

Balint B, Regula JU, Jarius S, Wildemann B. Caspr2 antibodies in limbic encephalitis with cerebellar ataxia, dyskinesias and myoclonus. J Neurol Sci. 2013 Apr 15;327(1-2):73-4. doi: 10.1016/j.jns.2013.01.040. Epub 2013 Mar 5.

Seeing music

In some recent pieces on the neurology of music, Oliver Sacks summarises 8 case histories of subjects, including 2 with Parkinson’s disease, with visual hallucinations consisting of the staves and notes of musical notation, which on closer inspection tend to reveal nonsensical ‘pseudomusic’, a feature those with text hallucinations also experience. He contrasts this to musical alexia without print alexia, as described in a personal account by Ian McDonald. Zamm and colleagues apply diffusion tractography to colour-music synes- thetes and controls and provide some evidence for the role of the white matter bundle of the inferior fronto-occipital fasciculus (IFOF) as substrate for this form of synesthesia (having previously highlighted the left superior temporal gyrus in subjects with perfect pitch).Basaglia-Pappas and colleagues design a musical battery of old French songs (the POP 10), revealing a strong reminiscence stimulating effect of the test which could be harnessed in occupational and cognitive therapy. – MZ

Sacks O. Hallucinations of musical notation. Brain. 2013 Mar 25 [advanced access]

McDonald I. Musical alexia with recovery: a personal account. Brain 2006;129:2554-61.

Zamm A, Schlaug G, Eagleman DM, Loui P. Pathways to seeing music: Enhanced structural connectivity in colored-music synesthesia. Neuroimage. 2013 Jul 1;74:359-66.

Loui P, Zamm A, Schlaug G. Enhanced functional networks in absolute pitch. Neuroimage. 2012 Nov 1;63(2):632-40.

Basaglia-Pappas S, et al. Exploration of verbal and non-verbal semantic knowledge and autobiographical memories starting from popular songs in Alzheimer’s disease. Int Psychogeriatr. 2013 May;25(5):785-95.

Panel of reviewers

Tim Rittman, Herchel Smith building, Cambridge University

Jemeen Sreedharan, Dept of Neurobiology/Neurology, University of Massachusetts Medical School, Worcester, US.

Gemma Cummins, Van Geest Centre for Brain Repair, Cambridge University.

Todd Hardy, Concord Hospital, Sydney, Australia.

Mike Zandi, Addenbrooke’s Hospital, Cambridge.