Displaying 1-10 letters out of 478 published
How useful and how safe is a Datscan?
In 2009 GE Healthcare revealed that 219,000 people had undergone the Datscan test ; by now it must be many more. The review article  by one employee of the company and two GE Healthcare sponsored clinicians considers the utility of the test. They begin by disparaging experienced clinical assessment. It is unarguable that expertise at a specialised centre doesn't extend to general practice (they cite a study from North Wales in 1999 that found that 47% of patients diagnosed did not fulfil Parkinson's Disease Brain Bank Criteria (PDBBC)} but this is a comment on education and service delivery, not the accuracy of experienced clinical diagnosis. They cite a study in which a full clinical assessment, with history and examination, was replaced by a videotape of patients with tremor. They go on to damn clinical assessment with faint praise, and I quote, "in practice clinical diagnosis is sufficient for many patients with advanced and typical manifestations of PD", thus ignoring the many years of clinical experience that tell us that in practice clinical diagnosis at symptom onset is usually correct  and when it isn't, then time or a second opinion often help. Patients may be happy to wait, and to allow the clinical picture to become clearer, before they decide to take medication.
The authors then consider why between 4 and 15% of PD patients fulfilling PDBBC have a normal Datscan. I repeatedly explained to the manufacturers (then Amersham International) and many of their sponsored clinicians many years ago that, based on experience with 18Fdopa PET scanning, I was concerned that the technique showed insufficient separation between the range of values in the healthy population and that in the de-novo PD population; one could however establish the rate of false negatives in a de-novo PD population by comparing mean and standard deviation in this group with mean and standard deviation of an age-matched healthy population, the larger the sample sizes the better. They didn't listen and that study has never been carried out. In fairness to them, regulations wisely prevent the exposure of too many healthy people to radio-pharmaceuticals. My estimate in 2005, based on the limited data then available, was that the majority of the so-called SWEDD's would be false negatives . The quoted long-term follow-up of SWEDD's in the ELLDOPA study (that has appeared in abstract only) was for a maximum of six years. The heterogeneity of progression in Parkinsonism (in Hoehn and Yahr's study  the average duration of life after diagnosis varied between one and thirty three years) means that short term follow-up has little value. Until every SWEDD has been followed up for many years, ideally to post-mortem, then the authors shouldn't imply that SWEDD's are likely to represent misdiagnoses. But the de-novo population is one in which around 90% will, by clinical assessment, have PD. In a population in which only 50% have parkinsonism as, for example, when separating PD from ET then, using the same data sources as above, Bayes theorem tells that the chance of an erroneous diagnosis may be as high as 50%.
There are other issues to consider. The quoted national Datscan audit showed that one in twenty five Datscans were misreported in the 50% of centres that took part in the audit; we don't know the rate of misreporting in the other centres. A further problem for what is essentially an in-vivo biochemical measurement is that few human studies have been carried out with commonly used medications (for example anti- psychotics, anti-hypertensives or anti-depressants) that could affect scan results. With regard to quantitation the authors state that "the routine clinical use of quantitation...... cannot be recommended for clinical practice without a visual read". The picture we see is a colour scale interpretation of the numbers generated by the scan's detectors and computer; if quantitation can't be recommended, how can the authors recommend assessing the resulting images by eye?
Eventually, after undermining clinical assessment and hinting loudly that the visually normal scans in patients presenting as clinical PD are explained by clinicians' diagnostic errors, the authors acknowledge that the true accuracy of the test is unknown.
For a test to have clinical utility in helping us confidently tell a patient whether they have PD or not, we need to know the false negative and false positive rate in de-novo patients, the rate of error in image reporting in all centres, and the effect of all medications that a patient might be taking. That it has been used so extensively without this information represents a triumph of persuasive marketing over clinicians' common sense. That so many people have been exposed to radiation (one quoted author  has put the risk of cancer at 1 in 5000) for a test with such limitations is a worry. Instead of the 100% reliable, very safe and inexpensive test that we and our patients might want, we have false negatives (number unknown), misreading of scan images (4% in 50% of centres), possible confounding effects of medication (unknown), expense (around 800 UK pounds or 1500 US dollars per scan) and a significant risk of cancer.
When given these facts and figures, patients will surely prefer to trust a clinician who is aware of their own limitations than a scan that has more limitations than is publicly acknowledged.
References: 1. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM186404.pdf (accessed February 2014) 2. Bajaj N, Hauser RA and Grachev ID. Clinical utility of dopamine transporter single photon emission CT (DaT-SPECT) with (123I) ioflupane in diagnosis of parkinsonian syndromes. J Neurol Neurosurg Psychiatry 2013; 84:1288-1295 3. De la Fuente-Feernandez R. Role of DaTSCAN and clinical diagnosis in Parkinson's disease. Neurology 2012; 78:696-701 4. Morrish PK. Controversies in Neuroimaging. 2008 Chapter 28 in Parkinson's disease; Diagnosis and Clinical Management. Demos Publishing (New York). Eds Factor and Weiner 5. Hoehn MM, Yahr MD. Parkinsonism: onset, progression, and mortality. Neurology 1967;17:427-42.
Conflict of Interest:
In 2001 I was interviewed for a job with what was then Amersham international. I used the interview to tell the company of my concerns about the test (based on my experience with 18Fdopa PET scanning). Not surprisingly I decided that I didn't want the job and they decided that they didn't want to employ me.
Misdiagnosed case of right paraspinal abscess.
We read the article by Mackenzie et al.  with great interest. We would like to share our experience of an Asian patient in 20s with paraspinal abscess. The patient is a nonsmoker, nondrinker but had been active IV heroine abuser on weekends for past 5 years. He was referred to emergency services for sudden onset of right flank pain, fever (103? Fahrenheit), chills. The pain was progressive, radiated from right flank to right upper quadrant and epigastrium, 8/10 in intensity, squeezing. He denied chest pain, palpitation, weight loss or loss of appetite. Immediate physical examination showed soft abdomen but was negative for any discoloration, distention, mass, costovertebral angle tenderness, psoas sign, rovsing's sign, or obturator sign. Blood results were remarkable for WBC count 13000 cells/?L (mainly neutrophils). Initial reports of ultrasonography and CT abdomen were negative. The patient was transferred to internal medicine ward. There, I asked the patient to walk and found that he had progressive weakness 3/5 in right leg and could not walk since last 2 days ago. Reflexes at right knee and ankle were exaggerated. We ordered a repeat CT and were able to find a swelling at right paraspinal region at T-12. CT guided biopsy of the abscess was sent to pathology and was positive for staphylococcus . He was treated with vancomycin IV for 6 weeks and recovered well. This case points out to the missed diagnosis of paraspinal abscess on CT scan in surgery ward. Surgeons while suspecting abdominal pathologies should keep such a presentation in mind and look for spinal areas on imaging studies. It is also important to emphasize that physical exam is important and that is what led us here to repeat imaging.
1 Mackenzie et al. Spinal epidural abscess: the importance of early diagnosis and treatment J. Neurol. Neurosurg. Psychiatry 1998 65:209-212.
Conflict of Interest:
Disconnection Vs standard anterior temporal lobectomy-which one is better?
I read with interest the research paper by Massager et al. and the accompanying editorial by Schramm on the long term outcome of surgical disconnection of the epileptic zone in patients with medically refractory nonlesional mesial temporal lobe epilepsy (MTL) 1, 2. High functioning patients with MTL in whom WADA testing reveals bihemispheric dominance for memory frequently experience a decline in either verbal or non-verbal memory after standard anterior temporal lobectomy (ATL) with amygdalohippocampectomy (AH). Do the authors have any data to share whether their surgical disconnection technique leads to less memory dysfunction than seen after standard ATL.?
1. Massager N, Tugendhaft P, Depondt C, Coppens T, Drogba L, Benmebarek N, De Witte O, Van Bogaert P, Legros B. Long-term outcome of surgical disconnection of the epileptic zone as an alternative to resection for nonlesional mesial temporal epilepsy. J Neurol Neurosurg Psychiatry 2013; 84:1378-83.
2. Schramm J. Disconnecting epileptogenic zone is as effective as resection. J Neurol Neurosurg Psychiatry 2013; 84:1300-1.
Conflict of Interest:
Re:Setting the Gold Standard
More evidence needed before retiring the Wada test
We thank Dr. Baxendale and colleagues for her useful comments regarding our meta-analysis and the opportunity to clarify a few points.
The study of Janacek and colleagues provides important information on the question of validity of the Wada test and fMRI. Although at the time of submission we were not aware of this publication, we do address this issue in the beginning of the discussion , and cite studies that have shown Wada to be incorrect. We also discuss the potential caveats in fMRI that could lead to incorrect classification, such as parameter settings. Brain areas that are involved in, but are not critical for, language function are detected by fMRI but not by the Wada test. We agree that these non-critical areas may indeed have supportive function for recovery, but we believe more evidence needs to be provided before this can be stated with any certainty
Rather than advocating the use of the Wada test as a standard, we suggest to use fMRI as standard screen, thereby reducing the number of invasive procedures. Given the potential severity of inadvertent surgery- induced deficits we believe a conservative diagnostic approach is at this point still warranted. Hence, If fMRI results are unclear, inconclusive or if they suggest atypical lateralization (which may also be caused by scan artifacts, poor task performance or poor fMRI contrast-to-noise), we recommend an additional test to evaluate laterality, such as the Wada test if that is a local standard procedure, or cortical stimulation during surgery. Novel techniques such as TMS may eventually be of use but they also require rigorous validation tests.
We know that in some parts of the world, notably in the UK, the Wada test has already been largely replaced by fMRI. In the Netherlands, and other countries, clinical decision making still heavily relies on the Wada test, although fMRI is increasingly used as a complementary technique. fMRI may some day replace the Wada test for most cases, but we believe that complete replacement requires more evidence, indeed based on outcome research. The aim of our analysis is to encourage further steps towards routine use of non- invasive techniques.
Conflict of Interest:
C9ORF72 in dementia with Lewy bodies
INTRODUCTION Recent studies have shown that a large hexanucleotide expansion in C9ORF72 is the most common cause of inherited Frontotemporal Lobar Degeneration (FTLD) and Motor Neurone Disease (MND).1 In pathological terms, expansion carriers show a distinctive molecular signature within the dentate gyrus granule cells and CA4 pyramidal cells of the hippocampus and granule cells of the cerebellum characterised by TDP-43-negative, but p62-positive, neuronal cytoplasmic inclusions (NCI).2 In clinical terms, psychosis is one of the major clinical traits in patients with FTLD and/or MND who carry expansions in C9ORF72.3 Given that psychosis is also common in Dementia with Lewy bodies (DLB), we previously genetically screened 102 patients with clinically diagnosed DLB, and detected an expansion in C9ORF72 in 2 patients.4 Consequently, we immunostained tissue sections of hippocampus and cerebellum for p62 protein from a series of 53 pathologically confirmed cases of DLB in order to ascertain to what extent expansions in C9ORF72 might be present in this disorder. METHODS Brain tissues were available from a series of 53 patients with pathologically confirmed DLB within the Manchester Brain Bank. All had been obtained with full ethical permission following consent by the next of kin. Paraffin sections were cut (at a thickness of 6?m) from formalin fixed blocks of temporal cortex (with hippocampus) and cerebellar cortex and immunostained for p62 proteins (rabbit polyclonal antibody to p62-lck ligand, B D Biosciences, Oxford, UK, 1:100 dilution), involving pressure cooking the sections for antigen retrieval and employing a standard ABC Elite kit (Vector, Burlingame, CA, USA) with DAB as chromagen. Immunostained sections were assessed for presence of p62-immunoreactive NCI within the dentate gyrus and CA2/3/4 regions of the hippocampus, and within the granule cells of the cerebellum. RESULTS No p62-immunoreactive NCI were seen within the hippocampus or cerebellum in any of the 53 cases. DISCUSSION Previously, when screening a series of 102 patients fulfilling criteria for probable DLB we detected an expansion in C9ORF72 in two patients.4 Similar to expansion carriers with FTLD,3 both patients displayed psychotic features, though in neither was a previous family history of dementia recorded, nor was there pathological confirmation of DLB or other underlying neurodegenerative disease. Therefore it was possible that these 2 individuals were misdiagnosed. Indeed, a frontotemporal dementia phenotype that mimics DLB has been reported.5 We therefore investigated 53 pathologically confirmed cases of DLB for an expansion in C9ORF72, using the presence of p62-immunoreactive NCI in hippocampus and cerebellum as a surrogate marker, but did not detect any cases where relevant tissue changes were present. Although only a few of the cases had undergone formal genetic analysis for expansions in C9ORF72, and shown to be negative, evidence indicates that the presence of p62-positive NCI in these brain regions can nevertheless act robustly as a marker of the expansion in the absence of genetic analysis. From this study, we therefore conclude that expansions in C9ORF72 in confirmed cases of DLB are unlikely, and in those patients bearing expansions in clinically assessed cohorts an atypical presentation of an underlying process of frontotemporal lobar degeneration is likely to be present.
Andrew Robinson, Yvonne Davidson, Julie S Snowden, David M A Mann
Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.
Correspondence to Professor David Mann, Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK; firstname.lastname@example.org Contributors DMAM conceived the study, performed microscopic analyses and prepared the manuscript. AR and YD prepared tissue sections and performed immunohistochemical staining. JS assisted with clinical characterization of the cohort. Funding The work of the Manchester Brain Bank is supported by Alzheimers Research UK and Alzheimer's Society under the Brains for Dementia Research (BDR) initiative. The study was supported in part by MRC and Wellcome Trust Neuroscience Initiative MRC G0701441).
Competing Interests None
Ethics Approval Ethics approval was provided by Newcastle and North Tyneside 1 Local Research Ethics Committee under Generic Tissue Bank Ethical Agreement.? References
1. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked amyotrophic lateral sclerosis-frontotemporal dementia. Neuron 2011;72:257-68. 2. Mann DMA, Rollinson S, Robinson A, et al. Dipeptide repeat proteins are present in the p62 positive inclusions in patients with Frontotemporal Lobar Degeneration and Motor Neurone Disease associated with expansions in C9ORF72. Acta Neuropathol Comm 2013;1:68. DOI: 10.1186/2051-5960-1-68. 3. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical characteristics in patients with frontotemporal dementia and C9ORF72 mutations: a study of demographics, neurology, behaviour, cognition, and histopathology. Brain 2012;135:693-708. 4. Snowden JS, Rollinson S, Lafon C, et al. Psychosis, C9ORF72 and Dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 2012;83:1031-2. 5. Claasen DO, Parisi JE, Giannini C, et al. Frontotemporal dementia mimicking dementia with Lewy bodies. Cogn Behav Neurol 2008; 21:157-63.
Conflict of Interest:
Does clinical evidence for lower motor neuron dysfunction support prion-like spreading in ALS?
In a recent, impressive article, Teruhiko Sekiguchi et al. (1) hypothesize that misfolded proteins accumulating in some neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), can cause aggregation of their native counterparts through a mechanism similar to the infectious prion protein's induction of a pathogenic conformation onto its normal cellular isoform. Recent in vitro studies have indicated that newly formed aggregates of TAR DNA-binding protein 43 as well as superoxide dismutase 1 (SOD1) can act as templates for the subsequent misfolding of the respective native proteins, and that the misfolded proteins can be intercellularly transferred in cultured cells (2).
Neurodegeneration in ALS typically begins focally and then spreads spatiotemporally until neurons of the respiratory system are lost. Some researchers, therefore, suggest that ALS pathology is similarly initiated at a single site and spreads via cell-to-cell transmission of prion-like pathogenic conformers in a 'single seed and simple propagation' model of ALS (2). Assuming that ALS progresses according to the proposed model, ALS lesions will spread contiguously along the spinal segments. Using needle electromyography (EMG), Sekiguchi et al. analyzed abnormal spontaneous activity of pairs of muscles innervated from different spinal segments in patients with early-stage sporadic ALS. They found that abnormal lower motor neuron activity showed a noncontiguous pattern in many ALS patients, suggesting that this skipping pattern of rostrocaudal spread does not support the 'single seed' hypothesis. Instead, they proposed a 'multifocal hits and local propagation' hypothesis. In their article, however, they do not present the data to support their hypothesis of local disease spread in a prion-like manner on the grounds that such data are not required from a methodological point of view.
A motor pool refers to all of the individual motor neurons that innervate a single muscle. Because of motor pools in the spinal cord are clustered in distinct columns of motor neurons extending over multiple spinal cord segments, a longitudinal study for estimating the number of motor units from individual muscles in ALS patients may provide a mechanistic insight into local disease spread.
Over the years a number of techniques have been developed to estimate the number of motor units in humans by defining a motor unit as the spinal motor neuron and its axon together with the muscle fibers it innervates. Motor unit number estimation (MUNE) is a technique that uses EMG to estimate the number of motor units in a muscle. Ridall PG et al.(3) developed a Bayesian statistical methodology to analyze electrophysiological data to provide an estimate of motor unit numbers. This method uses mathematical equations that express the basic elements of motor unit activation after electrical stimulation, allows for sources of variability and uncertainty, and has the capacity to estimate a larger number of motor units.
The exponential decimation of remaining lower motor neurons over time and different rates of progression have recently been demonstrated using the Bayesian MUNE (one of the most reliable methods for estimation of the total number of motor units) in both ALS patients and SOD1-linked familial ALS patients in all of the muscles examined (4). Furthermore, using SOD1 transgenic mice, MUNE values obtained with the Bayesian method showed a solid correlation with the histologically determined number of remaining lower motor neurons in the spinal cord. The exponential kinetics of neuronal cell loss are consistent with the 'one-hit' model of neurodegeneration described by Clarke et al. in which the death of a neuron is initiated randomly in time by a single, rare, catastrophic event independently of any neighboring neuron (5). Thus, the endogenous, stochastic occurrence of the one-hit events in a homogenous population of lower motor neurons may play a pivotal role in local disease spread. These features are clearly distinct from those of the prion-like propagation model of disease spread.
These findings, together with the study by Sekiguchi et al., suggest that lower motor neuron dysfunction defined by the electrophysiological evidence in ALS supports neither the 'simple propagation' nor the 'single seed' hypothesis.
1. Sekiguchi T et al. Spreading of amyotrophic lateral sclerosis lesions--multifocal hits and local propagation? J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2013-305617
2. Polymenidou M, Cleveland DW. The seeds of neurodegeneration: prion-like spreading in ALS. Cell 2011; 147:498-508.
3. Ridall PG, Pettitt AN, Henderson RD, McCombe PA. Motor unit number estimation-a Bayesian approach. Biometrics. 2006; 62:1235-1250.
4. Baumann F et al. Quantitative studies of lower motor neuron degeneration in amyotrophic lateral sclerosis: evidence for exponential decay of motor unit numbers and greatest rate of loss at the site of onset. Clin Neurophysiol. 2012; 123:2092-8.
5. Clarke G, Lumsden CJ. Scale-free neurodegeneration: cellular heterogeneity and the stretched exponential kinetics of cell death. J Theor Biol. 2005; 233:515-525.
Conflict of Interest:
Setting the Gold Standard
We read the above study with interest and appreciated the thorough analysis. Whilst the authors acknowledge in their discussion that the Wada test is a 'silver standard', they nevertheless conclude that the Wada test is warranted when fMRI fails to show clear left lateralisation. We would make the following points:
1. The true "gold standard" for language dominance tests is prediction of outcome. The authors acknowledge this in their discussion.
2. Recent studies suggest that high-quality fMRI is somewhat more accurate than the Wada test in predicting postoperative language outcomes. Sabsevitz et al showed better prediction of naming outcome by fMRI than by Wada in an unselected sample of left anterior temporal lobectomy patients. Janecek et al demonstrated that in patients with discordant fMRI and Wada, fMRI is generally more accurate at predicting language outcomes than the Wada test. Thus it is erroneous to consider fMRI results as inaccurate simply because the technique picks up more activation in the right hemisphere. It turns out that this "non-essential activation" probably helps patients recover.
3. For these reasons, it makes little sense to use fMRI as a screening tool and Wada as the standard in patients with atypical language representation.
4. The conclusion that the Wada test is warranted cannot be justified using this methodology employing a suboptimal clinical standard.
Sabsevitz DS, Swanson SJ, Hammeke TA, Spanaki MV, Possing ET, Morris GL, Mueller WM, Binder JR. Use of preoperative functional neuroimaging to predict language deficits from epilepsy surgery. Neurology, 2003; 60: 1788 -1792.
Janecek JK, Swanson SJ, Sabsevitz DS, Hammeke TA, Raghavan M, Mueller W, Binder JR. Naming outcome prediction in patients with discordant Wada and fMRI language lateralization. Epilepsy & Behavior, 2013; 27: 399- 403.
Conflict of Interest:
We celebrate the excitement shown by Unterberger and Bauer to our contribution on trigeminalepsy, since they give us the chance to include some technical data which were considered of limited interest for clinicians. Figure 1 in our original paper shows a 4.20 seconds frame from a conventional 32-channel video-EEG register filtered within 0.5-70 Hz. 
We chose figure 1 because it unequivocally shows interictal epileptic activity, with non-rhythmic spikes of an amplitude >50 microvolts (up to 120 microvolts) after a tactile stimulation with no subsequent pain attack. Interictal spike activity was asymmetric, predominantly registered in the right central and right parietal leads. Such a pattern of interictal spikes is widely accepted as a finding that points towards epilepsy. A following simple EEG showed spike-and-wave discharges during an episode of facial pain. Contrarily to what Unterberger and Bauer state, our patient was awake before and after the arrow in figure 1.
Any exhausting mention of the current controversies on epilepsy, as unintelligibly quoted by Unterberger and Bauer, is far beyond the scope of our neurological picture. Our humble contribution claims for attention to antidepressant selection in patients with rebel epilepsy, and invites to further explore epilepsy as a potential differential diagnosis of trigeminal neuralgia as Haan remarks. Age of onset was critical to consider other diagnoses than trigeminal neuralgia in our patient. As reported in detail, a systematic approach led us to the diagnosis of epilepsy.
1. Miró C, Ortiz T. Neurological pictures. Trigeminalepsy. J Neurol Neurosurg Psychiatry 2013;84:857-8.
2. de Curtis M, Avanzini G. Interictal spikes in focal epileptogenesis. Prog Neurobiol 2001;63:541-67.
3. Haan J. F1000Prime Recommendation of [Miro C and Ortiz T, J Neurol Neurosurg Psychiatr 2013, 84(8):857-8]. In F1000Prime,11 Sept 2013;doi:10.3410/f.718097750.793483143. F1000Prime.com/718097750#eval793483143.
Conflict of Interest:
Sirs, We read with interest and some kind of excitement the contribution of Mir? and Ortiz about "Trigeminalepsy" (1). We would like to concentrate our comments on "Figure 1 Video-EEG trace revealing spike discharges ..." No technical details like montage, filters and time frame are indicated. Therefore, a post hoc interpretation includes uncertainities. However, a change of dominant activities after the arrow ("touch of the cheek") is evident. The first part of the EEG shows a state of drowsiness or light sleep, after the touch rhythmical activities are predominant. The change of vigilance starts with a type of arousal response the authors called spike discharge. The pattern certainly cannot be interpreted as a seizure pattern. Furthermore, the spiky component is not followed by a slow wave as with interictal spikes. In summary, the published figure shows an arousal from light sleep due to touch of the cheek. The trace is no proving for an epileptic event and definitely not for a seizure onset zone. The contribution opens several other questions like the controversy about migraine and epilepsy (2), the localizing significance of painful auras (3), the diagnostic value of fMRI for epilepsies without corresponding ictal EEG signs, the role of AEDs in the treatment of neuralgias and the proof of medical refractoriness as a prerequisite for the indication of epilepsy surgery. The exciting interpretation of trigeminal neuralgia as focal reflex epilepsy would have justified a more complete clinical description.
Conflict of Interest:
A CASE OF RECURRENT BICKERSTAFF BRAINSTEM ENCEPHALITIS
We read with great interest the review by Dr Shahrizaila and Prof Yuki on Bickerstaff brainstem encephalitis (BBE) and Fisher syndrome (FS) (1) and would like to refer in particular to the section about recurrent illnesses. As stated, FS and BBE are typically monophasic and recurrent episodes are rare. Although recurrent episodes have been described in the literature, after a thorough literature search, only one clear documented case of recurrent BBE was found. (2) In this respect, we would like to present our case of recurrent Bickerstaff Brainstem Encephalitis. A 35 year old male patient presented with a one day history of progressively worsening double vision, numbness and paraesthesia of the hands and feet and unsteady gait. A week prior to the onset of these symptoms, he admitted to having had a diarrhoeal illness which had resolved completely. The patient insisted that these symptoms were identical to those preceding a "viral encephalitis" he had suffered ten years before. On examination at the time he was fully conscious. However he had complex ophthalmoplegia and a wide-based, ataxic gait. Tone and power were normal in all four limbs and he was areflexic. Interestingly, both plantar responses were extensor. Sensory examination was normal. Initial blood investigations, CT scan and MRI of the brain, and cerebrospinal fluid (CSF) analysis were all normal. A clinical diagnosis of FS was made and he was immediately started on treatment with intravenous immunoglobulins (IvIg). Several hours later, on the same day of admission, the patient developed rapid deterioration in his level of consciousness. He became drowsy and non-communicative, vomited incessantly, and developed fever. He adopted a decorticate posture with markedly increased tone in all four limbs, the upper limbs in flexion and the lower limb in extension. He was urgently transferred to the Intensive Therapy Unit (ITU), intubated and ventilated. At this point a clinical diagnosis of BBE was made. The presence of progressive symmetrical ophthalmoplegia and ataxia, decreased level of consciousness, pyramidal signs and normal peripheral power met the criteria (3) for this condition. Intravenous Methylprednisolone was added to the treatment regime. A repeat MRI of the brain was normal. EEG showed theta activity consistent with a non-specific encephalopathy. Nerve conduction studies showed an axonal sensori-motor peripheral neuropathy. A serum sample for anti GQ1b antibodies taken prior to commencing treatment with IvIg eventually confirmed the diagnosis with a strongly positive titre (224; normal range up to 30). C. jejuni antibodies were also positive (1:80; normal range <1:10). During the patient's stay in ITU, he showed no neurological improvement despite treatment. In addition he had persistent pyrexia and evidence of dysautonomia with sinus tachycardia and labile hypertension. An elective tracheostomy was performed and a decision to empirically perform plasma exchange was taken after two weeks. During the fourth week in intensive care, the patient gradually started to regain consciousness and continued to improve. He was eventually transferred to the neurology ward where he underwent intensive rehabilitation and recovered fully after a period of about six weeks. He was seen at the neurology out-patients clinic 3 months following discharge from hospital where he was found to have no neurological deficit. Discussion with the patient's family revealed that at 25 years of age, the patient had suffered an identical illness and was treated in a hospital in his home country. Review of the case notes showed that the patient had developed abdominal pain and diarrhoea for 48 hours. Days after this resolved he had developed speech disturbances, numbness over the trunk and upper limbs and ataxia. There was then deterioration in level of consciousness with decorticate posturing and respiratory insufficiency necessitating transfer to intensive care. An MRI of the brain had shown a possible hypointense area in the medial temporal lobe. CSF had revealed normal protein 0.33 g/l and normal cell count. EEG had shown a slow background with occasional high voltage signals. Apart from receiving Ceftriaxone and Acyclovir, the patient had also received IvIg and intravenous steroids. At the time the presumed diagnosis was that of a viral encephalitis. In retrospect this event was more probably the patient's first episode of BBE following a diarrhoeal illness. There have been cases of FS or Guillaine-Barre syndrome (GBS) followed by a second episode which involved clouding of consciousness. (4,5) However we consider our case to be remarkable because it was recurrent BBE. To our knowledge, there is only one other reported case of recurrent BBE. (2) This same case showed MRI changes, namely hyperintensity on T2 weighted images in the brainstem, with no contrast enhancement. Furthermore we would like to highlight two other issues. The first is that in our patient there was clear progression from a clinical diagnosis of FS to BBE within 24 hours, giving support to the proposed "anti-GQ 1b antibody syndrome" with the two conditions being at the ends of a clinical spectrum. Moreover, although the outcome of BBE is more often than not benign, the duration of unconsciousness in an immobile decorticate posture with severe dysautonomia can lead to potentially life-threatening complications of sepsis and thromboembolism. Therefore we feel the need to emphasise the importance of having evidenced based and well defined therapeutic options aimed at shortening as far as possible this period of unconsciousness and would appreciate any contributions from your readership relevant to this.
1. Shahrizaila N, Yuki N. Bickerstaff brainstem encephalitis and Fischer syndrome: anti-GQ1b antibody syndrome. J Neurol Neurosurg Psychiatry 2013; 84:576-583 2. Mond?jar RR, Santos JM, Villalba EF. MRI findings in a remitting- relapsing case of Bickerstaff encephalitis. Neuroradiology 2002; 44(5): 411-4. 3. Odaka M, Yuki N, Hirata K. Anti-GQ1b IgG antibody syndrome: clinical and immunological range. J Neurol Neurosurg Psychiatry 2001; 70(1): 50-5.
4. Sharma V, Chan Y C, Ong, Teoh H L, Wilder- Smith E P. Bickerstaff's brainstem encephalitis: can it recur? Journal of Clinical Neuroscience 2006; 13(2): 277-9.
5. DONG Hui-qing, LIU Zheng, TANG Yi, LU Yan, WANG Qi and JIA Jian- ping. Recurrent Fisher- Bickerstaff syndrome: report of a Chinese case. Chinese Medical Journal 2011; 124(17): 2786-2788.
Conflict of Interest:
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