In vivo exploration of retinal nerve fiber layer morphology in Parkinson's disease patients.

Thinning of the retinal nerve fiber layer (RNFL) is a recently discovered feature of Parkinson's disease (PD). Its exact pathological mechanism is yet unknown. We aimed to determine whether morphological changes of the RNFL are limited to RNFL thinning or also comprise an altered internal structure of this layer. Therefore, we investigated RNFL thickness and applied the RNFL attenuation coefficient (RNFL-AC), a novel method derived from optical coherence tomography, in PD patients and healthy controls (HCs). In this pilot study, we included 20 PD patients and 20 HCs matched for age, sex, and ethnicity. An ophthalmologist investigated all participants thoroughly, and we acquired retinal images from both eyes of each participant with a Spectralis optical coherence tomography system. We obtained both the RNFL-AC and RNFL thickness from peripapillary RNFL scans for the entire RNFL, as well as for each quadrant separately. We found no significant differences in the average RNFL-AC or the RNFL-AC of the separate retinal quadrants between PD patients and the HC group. However, compared to the HC group, PD patients had a significantly thinner RNFL in the temporal retinal quadrant. RNFL thinning was found in the temporal quadrant in PD patients without a corresponding change in the RNFL-AC. These findings suggest a reduction in the number of RNFL axons (atrophy) without other major changes in the structural integrity of the remaining RNFL.

A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia.

The progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEs have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. A locus for PME was mapped in a consanguineous family with a single affected individual to chromosome 17q21. An identical-by-descent, homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene, was identified in this patient and in four apparently unrelated individuals. A comparison of the phenotypes in these patients defined a clinically distinct PME syndrome characterized by early-onset ataxia, action myoclonus by age 6, scoliosis, and mildly elevated serum creatine kinase. This p.Gly144Trp mutation is equivalent to a loss of function and results in failure of GOSR2 protein to localize to the cis-Golgi.

'North Sea' progressive myoclonus epilepsy: phenotype of subjects with GOSR2 mutation.

We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline; patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.

Need for prolonged immunosupressive therapy in CLIPPERS--a case report.

BACKGROUND: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) was first described in 2010 by Pittock and colleagues. All reported patients presented with diplopia and gait ataxia and had similar typical MRI findings with punctuate gadolinium enhancement of the pons. Alternative diagnoses were excluded by means of laboratory, radiological and histological tests. All patients were successfully treated with steroids. We present a case in which the steroid therapy was switched to long term immunosuppressive therapy, leading to several severe side-effects, but sustained clinical improvement. CASE PRESENTATION: A 63-year-old male presented with sub-acute diplopia and progressive gait ataxia. During admission his neurological condition worsened and he developed multiple cranial nerve deficits, paraparesis and urine retention. MRI-findings were remarkable with punctuate enhancement with gadolinium of the pons. Cerebrospinal fluid only showed elevated protein levels and all other additional investigations were normal. The probable diagnosis of CLIPPERS was made and intravenous corticosteroids were administered. This led to rapid clinical recovery and decreased enhancement on the MRI-scan. Long-term oral immunosuppressive therapy was started. One-and-a-half year later our patient has no recurrence of neurological symptoms, however due to the side effects of the immunosuppressive therapy he was readmitted several times. CONCLUSION: CLIPPERS presents with distinctive clinical and MRI-findings and may be diagnosed after excluding other differential diagnoses. Patients are treated with corticosteroids with good clinical results. Since short term glucocorticoid treatment results into relapse of the disease, longer term immunosuppressive therapy appears to be mandatory for sustained improvement, although accompanied by severe side effects.

Seeing ophthalmologic problems in Parkinson disease: Results of a visual impairment questionnaire.

OBJECTIVE: To determine the prevalence and clinical effect of ophthalmologic symptoms in patients with Parkinson disease (PD), compared with controls, using a standardized questionnaire. METHODS: In this observational, cross-sectional, multicenter study, 848 patients with PD and 250 healthy controls completed the Visual Impairment in Parkinson's Disease Questionnaire (VIPD-Q). The VIPD-Q addressed 4 domains according to structures: (1) ocular surface; (2) intraocular; (3) oculomotor; and (4) optic nerve. The questionnaire also assessed the effect of ophthalmologic symptoms on daily activities. RESULTS: One or more ophthalmologic symptoms were reported by 82% (95% confidence interval [CI], 80-85) of patients, compared with 48% (95% CI, 42-54) of controls (p < 0.001). Patients with PD experienced more ophthalmologic symptoms across all domains than controls (p < 0.001), as reflected by a higher VIPD-Q total score among patients (median 10 [interquartile range (IQR) 13]) than controls (median 2 [IQR 5]; p < 0.001). Ophthalmologic symptoms interfered with daily activities in 68% (95% CI, 65-71) of patients, compared with 35% (95% CI, 29-41) of controls (p < 0.001). CONCLUSION: Patients with PD have a higher prevalence of ophthalmologic symptoms than controls. Moreover, these frequently interfere with daily activities. A screening questionnaire such as the VIPD-Q may help with identifying ophthalmologic symptoms in PD, thereby enabling more timely treatment.

Diplopia in Parkinson's disease: visual illusion or oculomotor impairment?

INTRODUCTION: Approximately 20% of patients with Parkinson's disease (PD) experience diplopia; however, the cause of the diplopia is unclear. We aimed to explore the association of diplopia, and its subtypes, with oculomotor abnormalities, impaired vision, and visual hallucinations, in patients with PD. METHODS: This exploratory study included 41 PD patients, recruited from two general hospitals, of whom 25 had diplopia and 16 did not have diplopia, as well as 23 healthy controls (HCs). We defined subtypes of diplopia as selective diplopia, i.e., diplopia of single objects, and complete diplopia, i.e., diplopia of the entire visual field. All participants underwent a full orthoptic and ophthalmologic examination. RESULTS: PD patients with diplopia had a high prevalence of oculomotor abnormalities (84%), impaired vision (44%), and visual hallucinations (44%), compared to PD patients without diplopia (33%, 6%, and none, respectively, p < 0.01), and compared to HCs (23%, 9%, and none, respectively, p < 0.01). Oculomotor abnormalities were equally prevalent in both subtypes of diplopia (selective and complete), whereas impaired vision was predominantly found in patients with selective diplopia. Moreover, only patients with selective diplopia had visual hallucinations. CONCLUSIONS: In PD patients, diplopia may be indicative of oculomotor or visual impairments. Hence, it is worthwhile to refer PD patients with diplopia to an orthoptist and an ophthalmologist for evaluation and, possibly, treatment of diplopia. Furthermore, in the case of selective diplopia, the neurologist should consider the presence of visual hallucinations, which may require the adjustment of the patient's medication.

The predictive value of transcranial duplex sonography for the clinical diagnosis in undiagnosed parkinsonian syndromes: comparison with SPECT scans.

BACKGROUND: Transcranial duplex sonography (TCD) of the substantia nigra has emerged as a promising, non-invasive tool to diagnose idiopathic Parkinson's disease (IPD). However, its diagnostic accuracy in patients with undefined parkinsonism remains to be determined. In this study we determined the predictive value of TCD for the clinical diagnosis in undiagnosed parkinsonian syndromes. Additionally we compared the predictive value of TCD with that of presynaptic and postsynaptic single photon emission computer tomography (SPECT) scans. METHODS: We studied 82 patients with an unclassified parkinsonian syndrome. All 82 patients were subjected to a TCD, 59 of them underwent a presynaptic SPECT scans and 32 underwent a postsynaptic SPECT scan. We determined the diagnostic accuracy of TCD and SPECT scans in differentiating: 1) IPD patients from patients without nigrostriatal degeneration and 2) IPD patients from patients with atypical parkinsonian syndromes (APS). To compare the diagnostic accuracy of TCD and SPECT scans, we used the clinical diagnosis after follow-up according to generally accepted clinical criteria as the gold standard. This clinical diagnosis was determined by a movement disorder specialist. 3) Finally, we ascertained the predictive value of the TCD for the SPECT result. RESULTS: The clinical diagnoses after follow-up resulted in 51 cases of IPD, 7 patients with APS and 17 patients without nigrostriatal degeneration. In total 7 patients remained undiagnosed. 1) The accuracy of TCD, assessed by sensitivity and specificity, to differentiate IPD patients from patients without nigrostriatal degeneration was 50% and 82% respectively. For the presynaptic SPECT scans sensitivity was 97% and specificity 100%. 2) In differentiating IPD patients from APS patients, the sensitivity and specificity of TCD was 50% and 43% respectively. For presynaptic SPECT scans this was 97% and 0%. For the postsynaptic SPECT scans the sensitivity was 75% and the specificity 81%. 3) The positive predictive value (PPV) of an abnormal TCD for an abnormal presynaptic SPECT scan was 88%. CONCLUSION: Presynaptic SPECT scanning has a higher predictive value for the clinical diagnosis than TCD. However, since the PPV of an abnormal TCD for parkinsonism with nigrostriatal degeneration is high, TCD might be used as screening tool, before ordering a presynaptic SPECT.

Diagnostic value of 123I-ioflupane and 123I-iodobenzamide SPECT scans in 248 patients with parkinsonian syndromes.

BACKGROUND: SPECT is one of the most employed techniques in the diagnostic workup of idiopathic Parkinson's disease (IPD). Despite its widespread use, the exact diagnostic accuracy of this technique in parkinsonian syndromes remains controversial. METHODS: In this study, we investigated the diagnostic accuracy of an initial (123)I-ioflupane (FP-CIT) and/or (123)I-iodobenzamide (IBZM) SPECT to differentiate between IPD and other parkinsonian disorders. 248 patients underwent a SPECT scan because of an as yet unclassified parkinsonian syndrome in our clinic between 2001 and 2006. Gold standard was the clinical diagnosis derived from the latest available clinical record, or, when this was not possible, a new complete physical and neurological examination by a blinded movement disorder specialist neurologist. Mean follow-up between SPECT and the latest clinical information was 18 months (range 3 months to 5 years). RESULTS: 223 of the 248 patients were clinically definitely diagnosed after follow-up: IPD 127, atypical parkinsonian syndromes (APS) 27, essential tremor (ET) 22, vascular parkinsonism (VP) 16, drug-induced parkinsonism (DIP) 5, doubt between PD and APS 2, other diseases without dopaminergic involvement 24. The mean odds ratio (95% CI) for FP-CIT SPECT's ability to distinguish between IPD and ET was 82 (11-674); between IPD and VP 61 (8-490); between IPD and DIP 36 (2-697) and between IPD and APS was 1 (0-4). The odds ratio for the IBZM SPECT tracer to differentiate between IPD and APS was 7 (2-17). CONCLUSIONS: FP-CIT SPECT is accurate to differentiate patients with IPD from those with ET, and IPD from VP and DIP. The accuracy of both FP-CIT and IBZM SPECT scans to differentiate between IPD and APS is low.

Meta-analysis of the literature on diagnostic accuracy of SPECT in parkinsonian syndromes.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder. One of the most widely used techniques to diagnose PD is a Single Photon Emission Computer Tomography (SPECT) scan to visualise the integrity of the dopaminergic pathways in the brain. Despite this there remains some discussion on the value of SPECT in the differential diagnosis of PD. We did a meta-analysis of all the existing literature on the diagnostic accuracy of both pre- and post-synaptic SPECT imaging in the differential diagnosis of PD. METHODS: Relevant studies were searched in Medline, EMBASE and Cochrane databases with back-searching of their reference lists. We limited our analysis to studies with a clinically relevant methodology: i.e. when they assessed the ability of the SPECT to provide 1. diagnosis of PD in an early phase vs. normalcy; 2 diagnostic differentiation between PD and essential tremor (ET); 3. distinguishing between PD and vascular parkinsonism (VP); 4. delineation of PD from atypical parkinsonian syndromes (APS). Gold standard was, dependent on the study type, clinical examination at initial visit or follow-up, and/or response to dopaminergic agents. RESULTS: The search gave 185 hits, of which we deemed 32 suitable for our analysis. From these we recalculated the diagnostic odds ratio of SPECT for the clinical questions above. The pooled odds ratio (with 95%CI) for presynaptic SPECT scan's ability to distinguish between early PD and normalcy was 60 (13 - 277). For the ability to differentiate between PD and ET this ratio was 210 (79-562). The ratio for presynaptic SPECT's ability to delineate PD from VP was 105 (32 - 348). The mean odds ratio for the presynaptic SPECT scans to differentiate between PD and the two APS was 2 (1 - 4), and for the postsynaptic SPECT imaging this was 19 (9-36). CONCLUSION: SPECT with presynaptic radiotracers is relatively accurate to differentiate patients with PD in an early phase from normalcy, patients with PD from those with ET, and PD from VP. The accuracy of SPECT with both presynaptic and postsynaptic tracers to differentiate between PD and APS is relatively low.

Protocol of a prospective study on the diagnostic value of transcranial duplex scanning of the substantia nigra in patients with parkinsonian symptoms.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder. As there is no definitive diagnostic test, its diagnosis is based on clinical criteria. Recently transcranial duplex scanning (TCD) of the substantia nigra in the brainstem has been proposed as an instrument to diagnose PD. We and others have found that TCD scanning of substantia nigra duplex is a relatively accurate diagnostic instrument in patients with parkinsonian symptoms. However, all studies on TCD so far have involved well-defined, later-stage PD patients, which will obviously lead to an overestimate of the diagnostic accuracy of TCD. We have therefore set out to conduct a prospective study testing the diagnostic accuracy of TCD in patients with a parkinsonism of unclear origin. METHODS/DESIGN: We will enroll 250 consecutive patients, who are referred to neurology outpatient clinics of two teaching hospitals, for analysis of clinically unclear parkinsonism. Patients, whose parkinsonism is clearly diagnosable at the first visit, will be excluded from the study. All patients will undergo a TCD of the substantia nigra. As a surrogate gold standard we will use the consensus clinical diagnosis reached by two independent, blinded, movement disorder specialist neurologists after 2 years follow-up. At the time of TCD, patients will also undergo a SPECT scan of the brain. DISCUSSION: As this prospective trial enroll only patients with an early-stage parkinsonism, it will yield data on the diagnostic accuracy of TCD that is relevant to daily clinical practice: The neurologist needs a diagnostic tool that provides additional information in patients with a clinically indefinable parkinsonian syndrome. The above described observational longitudinal study was designed to explicitly study this aspect in the diagnostic process.

Clinical Pain and Neuropsychological Functioning in Parkinson's Disease: Are They Related?

Introduction. Pain is an important nonmotor symptom of Parkinson's disease (PD). Brain areas such as the hippocampus and the prefrontal cortex play an important role in the processing of pain. Since these brain areas are also involved in cognitive functioning, for example, episodic memory and executive functions, respectively, we examined whether a relationship exists between cognitive functioning and spontaneous pain in PD. Methods. Forty-eight patients with PD and 57 controls participated. Cognitive functioning was measured by a comprehensive battery of neuropsychological tests. Both the sensory-discriminative aspect and the motivational-affective aspect of pain were assessed. Multiple linear regression analyses were performed to assess a relation between cognition and pain. Results. Cognition was related to neither the sensory nor the affective aspect of pain in our sample of PD patients. Variance in pain measures was primarily explained by symptoms of depression and anxiety. Discussion. The difference between the affective and the sensory aspect of pain might be due to the neuropathology of PD, which is mainly present in areas processing the affective aspect of pain. Pain treatment might improve when mood is taken into account. We provide several explanations for the lack of an association between pain and cognition.

Specificity and sensitivity of transcranial sonography of the substantia nigra in the diagnosis of Parkinson's disease: prospective cohort study in 196 patients.

OBJECTIVE: Numerous ultrasound studies have suggested that a typical enlarged area of echogenicity in the substantia nigra (SN+) can help diagnose idiopathic Parkinson's disease (IPD). Almost all these studies were retrospective and involved patients with well-established diagnoses and long-disease duration. In this study the diagnostic accuracy of transcranial sonography (TCS) of the substantia nigra in the patient with an undiagnosed parkinsonian syndrome of recent onset has been evaluated. DESIGN: Prospective cohort study for diagnostic accuracy. SETTING: Neurology outpatient clinics of two teaching hospitals in the Netherlands. PATIENTS: 196 consecutive patients, who were referred to two neurology outpatient clinics for analysis of clinically unclear parkinsonism. Within 2 weeks of inclusion all patients also underwent a TCS and a (123)I-ioflupane Single Photon Emission CT (FP-CIT SPECT) scan of the brain (n=176). OUTCOME MEASURES: After 2 years, patients were re-examined by two movement disorder specialist neurologists for a final clinical diagnosis, that served as a surrogate gold standard for our study. RESULTS: Temporal acoustic windows were insufficient in 45 of 241 patients (18.67%). The final clinical diagnosis was IPD in 102 (52.0%) patients. Twenty-four (12.3%) patients were diagnosed with atypical parkinsonisms (APS) of which 8 (4.0%) multisystem atrophy (MSA), 6 (3.1%) progressive supranuclear palsy (PSP), 6 (3.1%) Lewy body dementia and 4 (2%) corticobasal degeneration. Twenty-one (10.7%) patients had a diagnosis of vascular parkinsonism, 20 (10.2%) essential tremor, 7 (3.6%) drug-induced parkinsonism and 22 (11.2%) patients had no parkinsonism but an alternative diagnosis. The sensitivity of a SN+ for the diagnosis IPD was 0.40 (CI 0.30 to 0.50) and the specificity 0.61 (CI 0.52 to 0.70). Hereby the positive predictive value (PPV) was 0.53 and the negative predictive value (NPV) 0.48. The sensitivity and specificity of FP-CIT SPECT scans for diagnosing IPD was 0.88 (CI 0.1 to 0.95) and 0.68 (CI 0.58 to 0.76) with a PPV of 0.75 and an NPV of 0.84. CONCLUSIONS: The diagnostic accuracy of TCS in early stage Parkinson's disease is not sufficient for routine clinical use. CLINICALTRIALS.GOV IDENTIFIER: NCT0036819.

Transcranial sonography for the discrimination of idiopathic Parkinson's disease from the atypical parkinsonian syndromes.

We reviewed eight studies on transcranial sonography (TCS) as a tool for differentiating idiopathic Parkinson's disease (IPD) from atypical parkinsonian syndromes (APS) and included some first data on TCS findings in the subforms of PSP. Changes of specific structures on TCS like the substantia nigra (SN), lenticular nucleus (LN), and the third ventricle are discussed as well as how they can contribute to differentiate between IPD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Lewy body disease (LBD), and corticobasal degeneration (CBD). We finish with an algorithm that may be used to employ TCS as a diagnostic instrument delineating IPD from the APS and discerning among the APS themselves. As TCS is at present the most promising tool for this particular diagnostic problem, this algorithm might be a suitable hypothesis to study in future research.

Posterior reversible encephalopathy syndrome in paediatric leukaemia.

This report describes four patients with acute lymphoblastic leukaemia, suffering from posterior reversible encephalopathy syndrome during the induction period of treatment. A review of the literature on posterior reversible encephalopathy syndrome in paediatric leukaemia is given. The exact mechanism of posterior reversible encephalopathy syndrome is not clear and seems to be multifactorial. Hypertension is likely to play a major role in the development but could be also secondary. All patients in this case series presented after introduction of the new induction protocol for acute lymphoblastic leukaemia. Treatment of hypertension is likely to have a favourable role and posterior reversible encephalopathy syndrome is most often reversible. It is important to consider this diagnosis during the induction phase of leukaemia treatment in the presence of neurological symptoms. The incidence of PRES in the induction scheme should be investigated, in order to optimize the ALL treatment.

Transcranial duplex in the differential diagnosis of parkinsonian syndromes: a systematic review.

BACKGROUND: Transcranial duplex scanning (TCD) of the substantia nigra (SN) is increasingly used to diagnose Idiopathic Parkinson's Disease (IPD). Up until now 70 diagnostic studies have been published, not only on investigation of the SN, but also of the lenticular nucleus (LN) and the Raphe nuclei (RN). METHOD: We systematically reviewed all diagnostic TCD studies in parkinsonian patients up to June 2008. RESULTS: We found 35 eligible studies. Of the 1534 IPD patients investigated in the 35 studies 200 (13%) had an inconclusive SN-TCD. An increased echo-intensity of the SN was seen in 1167 (87%) of the 1334 IPD patients, 276 (12%) of the 2340 healthy controls and in 41 (30%) of the 138 patients with an atypical parkinsonian syndrome (APS). On the contrary, a pathological LNTCD was found more often in APS patients (79%) than in IPD patients (23%) and healthy controls (6%). A decreased echo-intensity of the RN was found more often in depressed (46%) than in non-depressed IPD patients (16%). CONCLUSIONS: SN-TCD accurately differentiates between patients with IPD and healthy controls, but not between patients with IPD and APS. LN-TCD is only moderate accurate to delineate IPD from APS, but combinations of SN- and LN-TCD may be more promising. RN-TCD has only marginal diagnostic accuracy in diagnosing depression in IPD and non-IPD patients. Before TCD can be implicated, more research is needed to standardize the TCD technique, to investigate the TCD in non-research settings and to determine the additional value of TCD compared with currently used clinical techniques like SPECT imaging.