Management approach including pembrolizumab for fingolimod-associated progressive multifocal leukoencephalopathy in a patient with relapsing-remitting multiple sclerosis.

A 62-year-old man with relapsing-remitting multiple sclerosis developed progressive multifocal leukencephalopathy (PML) after 6 years on fingolimod. The fingolimod was immediately discontinued and preexisting mirtazepine increased. Three weeks later, with brain magnetic resonance imaging (MRI) appearances worsening and cerebrospinal fluid (CSF) JC virus (JCV) titres increasing, maraviroc was introduced. At 6 weeks, subtle punctate contrast enhancement raised the possibility of immune reconstitution inflammatory syndrome (IRIS), followed by a single focal-to-generalised tonic clonic seizure and a further deterioration in clinical disability. Mefloquine was commenced alongside three doses of pembrolizumab administered a month apart. Serial CSF examinations and several imaging modalities including spectroscopy and fused FDG-PET-MRI (18F-fluoro-deoxy-glucose-positron emission tomography-magnetic resonance imaging) were used to help distinguish between PML, PML-IRIS and rebound MS activity and guide optimal management at each stage. A handful of small, enhancing ovoid lesions developed between the first two doses of pembrolizumab, probably representative of a mild rebound phenomenon. A sustained improvement became obvious thereafter with CSF JCV-DNA undetectable 16 weeks following fingolimod withdrawal. To our knowledge, this is the first case of combined therapy and use of pembrolizumab in a fingolimod-associated PML.

Factors Influencing Driving following DBS Surgery in Parkinson's Disease: A Single UK Centre Experience and Review of the Literature.

Parkinson's disease (PD) is a complex neurodegenerative disorder, leading to impairment of various neurological faculties, including motor, planning, cognitivity, and executive functions. Motor- and non-motor symptoms of the disease may intensify a patient's restrictions to performing usual tasks of daily living, including driving. Deep Brain Stimulation (DBS) associated with optimized clinical treatment has been shown to improve quality of life, motor, and non-motor symptoms in PD. In most countries, there are no specific guidelines concerning minimum safety requirements and the timing of return to driving following DBS, leaving to the medical staff of individual DBS centres the responsibility to draw recommendations individually regarding patients' ability to drive after surgery. The aim of this study was to evaluate factors that might influence the ability to drive following DBS in the management of PD. A total of 125 patients were included. Clinical, epidemiological, neuropsychological, and surgical factors were evaluated. The mean follow-up time was 129.9 months. DBS improved motor and non-motor symptoms of PD. However, in general, patients were 2.8-fold less likely to drive in the postoperative period than prior to surgery. Among the PD characteristics, patients with the akinetic subtype presented a higher risk to lose their driving licence postoperatively. Furthermore, the presence of an abnormal postoperative neuropsychological evaluation was also associated with driving restriction following surgery. Our data indicate that restriction to drive following surgery seems to be multifactorial rather than a direct consequence of DBS itself. Our study sheds light on the urgent need for a standardised multidisciplinary postoperative evaluation to assess patients' ability to drive following DBS.

Colour-centred Release Hallucinations in a Patient with Early Parkinson's Disease and Unrecognised Autosomal Dominant Optic Atrophy.

Visual hallucinations in Parkinson's disease (PD) are usually attributed to medications and dysfunction in higher order sensory processing as the disease progresses. However deficits in visual processing, including colour discrimination, have been reported in early, untreated PD and it is unclear how these, along with co-morbid conditions affecting vision, could contribute to hallucinations. This case describes a 66-year-old otherwise fully independent woman with early, mild PD who presented with discrete episodes of unusual vivid hallucinations centred on colour. She was later found to have a subclinical colour deficiency in excess of her PD and, after reporting a lifelong history of poor vision in her father, tested positive for autosomal dominant optic atrophy. This case illustrates how a lifelong extrinsic deficiency in colour vision can interact with the effects of visual changes in early stage PD and medication to provoke colour hallucinations. It therefore emphasises the importance of full ophthalmological work up in similar cases where hallucinations are atypical and unexpected for the severity and stage of PD.

123I-Ioflupane dopamine transporter imaging (DaTSCAN) appearances in relation to emotional responsiveness, impulsivity and olfaction in suspected Parkinsonian syndrome.

OBJECTIVE: The aim of our study was to ascertain relationships between DaTSCAN, olfactory loss, behavioural and subjective measurements of impulsivity and emotional responsiveness in patients with clinically suspected Parkinsonian syndrome (PS). METHODS: A prospective study of 20 drug-naive patients with parkinsonism, underwent the University of Pennsylvania Smell Identification Test, impulsivity measurements and mood-state-questionnaires before visual and semi-quantitative DaTQUANT analyses. There were two subgroups: nine patients with scans without evidence of dopaminergic deficit (SWEDD - controls) and 11 patients with PS. RESULTS: The PS group reported lower non-planning impulsivity than the SWEDD group (P = 0.039). A positive correlation was found between the non-planning impulsivity ratings and right anterior putamen/background (bck) ratio in PS group (r = 0.598, P = 0.068). Higher ratings of anger (r = 0.575, P = 0.016), fatigue (r = 0.746, P = 0.001), confusion (r = 0.561, P = 0.019) and depression were positively correlated with putamen/caudate ratios (R > L) on DaTSCAN. Higher self-reported arousal was associated with lower right putamen/caudate ratio (P = -0.581, P = 0.014). Only fatigue was positively correlated with putamen/bck (r = 0.564, P = 0.018). The degree of smell deficit correlated negatively with performance on reflection impulsivity tasks (r = -0.470, P = 0.049). CONCLUSION: DaTSCAN appearances correlated with emotional dysfunction and self-reported impulsivity in patients with PS. Olfactory impairment was associated with increased reflection impulsivity and the age of patients. Higher DaTSCAN putamen/caudate ratios were associated with higher emotional responsiveness and higher non-planning impulsivity in PS patients. These preliminary findings may be relevant in clinical practice in differentiating PS from SWEDD and identifying susceptibility to impulse control disorder although larger studies are warranted.

Balancing immunosuppression and infection: recurrent enterovirus encephalitis in SLE.

A young woman with systemic lupus erythematosus (SLE) developed recurrent enterovirus meningoencephalitis while taking prednisolone, azathioprine and rituximab. After reducing the immunosuppression, she developed a central nervous system (CNS) flare of SLE, with enterovirus still present in the cerebrospinal fluid (CSF). There are no evidence-based specific treatments for enterovirus encephalitis, but she responded well to intravenous immunoglobulin alongside pulsed methylprednisolone and rituximab. This case highlights the difficulties in managing people with co-existing infective and autoimmune conditions, especially if each affects the CNS. A viral infection and SLE flare can resemble one another clinically, although here the radiological differentiation of CNS lupus versus enterovirus encephalitis helped to guide the diagnosis.

Symptom dimensions in people affected by long-term neurological conditions: a factor analysis of a patient-centred palliative care outcome symptom scale.

Long-term neurological conditions (LTNCs) often cause debilitating symptoms. Better understanding of symptom dimensions in LTNCs is needed to support health professionals and improve care. This can be achieved by exploring the factor structure of a standardised measure of symptoms in LTNC patients. The symptom subscale of the Integrated Palliative Outcome Scale for LTNCs (IPOS Neuro-S24) comprises 24 items measuring symptom severity. Descriptive statistics and psychometric properties of the scale were assessed, followed by differential item functioning (DIF), exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Data from N = 238 patients were analysed. The mean IPOS Neuro S-24 score was 27.0 (possible range 0-96) and floor effects were found for 21 items. The scale had good internal consistency (Cronbach's alpha = 0.77). Weak evidence of DIF was found for nine items. All but one item (falls) loaded onto four factors with loadings > 0.3. The factors represented four clinically meaningful symptom dimensions: fatigue, motor symptoms, oral problems and non-motor symptoms. We identified a reliable four-factor structure of symptom experience in LTNC patients. The results suggest that symptom dimensions are common across LTNCs. The IPOS Neuro S-24 is an appropriate tool to measure symptoms in LTNC patients, which may improve care.

Evaluating the causality of novel sequence variants in the prion protein gene by example.

The estimation of pathogenicity and penetrance of novel prion protein gene (PRNP) variants presents significant challenges, particularly in the absence of family history, which precludes the application of Mendelian segregation. Moreover, the ambiguities of prion disease pathophysiology renders conventional in silico predictions inconclusive. Here, we describe 2 patients with rapid cognitive decline progressing to akinetic mutism and death within 10 weeks of symptom onset, both of whom possessed the novel T201S variant in PRNP. Clinically, both satisfied diagnostic criteria for probable sporadic Creutzfeldt-Jakob disease and in one, the diagnosis was confirmed by neuropathology. While computational analyses predicted that T201S was possibly deleterious, molecular strain typing, prion protein structural considerations, and calculations leveraging large-scale population data (gnomAD) indicate that T201S is at best either of low penetrance or nonpathogenic. Thus, we illustrate the utility of harnessing multiple lines of prion disease-specific evidence in the evaluation of the T201S variant, which may be similarly applied to assess other novel variants in PRNP.

Predictors of survival in progressive supranuclear palsy and multiple system atrophy: a systematic review and meta-analysis.

OBJECTIVE: To undertake a systematic review and meta-analysis of studies that investigated prognostic factors and survival in patients with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). METHODS: Publications of at least 10 patients with a likely or confirmed diagnosis of PSP or MSA were eligible for inclusion. Methodological quality was rated using a modified version of the Quality in Prognostic Studies tool. For frequently examined prognostic factors, HRs derived by univariate and multivariate analysis were pooled in separate subgroups; other results were synthesised narratively and HRs could not be reported here. RESULTS: Thirty-seven studies presenting findings on 6193 patients (1911 PSP, 4282 MSA) fulfilled the inclusion criteria. We identified the following variables as unfavourable predictors of survival. In PSP, PSP-Richardson's phenotype (univariate HR 2.53; 95% CI 1.69 to 3.78), early dysphagia and early cognitive symptoms. In MSA, severe dysautonomia and early development of combined autonomic and motor features but not MSA phenotype (multivariate HR 1.22; 95% CI 0.83 to 1.80).In PSP and MSA, survival was predicted by early falls (multivariate HR 2.32; 95% CI 1.94 to 2.77), the Neuroprotection and Natural History in Parkinson Plus Syndromes Parkinson Plus Score and the Clinical Global Impression Disease Severity Score but not sex (multivariate HR 0.93; 95% CI 0.67 to 1.28). There was conflicting evidence regarding the prognostic effect of age at onset and stridor. CONCLUSION: Several clinical variables were strongly associated with shorter survival in PSP and MSA. Results on most prognostic factors were consistent across methodologically diverse studies; however, the lack of commonality of prognostic factors investigated is a significant limitation.

Exploring Issues Around Wearing-off and Quality of Life: The OFF-PARK Survey of People with Parkinson's Disease and their Care Partners.

BACKGROUND: The negative impact of wearing-off on the quality of life (QoL) of people with Parkinson's (PWPs) is well established. However, most studies have been performed from the clinician's perspective, and the needs of PwPs and care partners have been considered separately. OBJECTIVE: This survey aimed to better understand the impact of wearing-off on both patient and care partner lives and to assess how often they are asked about their QoL in their specialist consultations. METHODS: PwPs and care partners registered with The Cure Parkinson's Trust database were invited to participate in an online survey consisting of 21 questions about wearing-off and QoL. Data was collected for matched pairs (PwP and their care partner). RESULTS: 47 matched pairs completed the survey. The five symptoms most commonly reported as troublesome were: tiredness, slowness, reduced dexterity, slowness of movement and slowness in the early morning. Overall, 47% of PwPs indicated that they discuss their QoL at all/most appointments. Whereas most PwPs and their care partners (87% and 74% , respectively) said that they understood what 'wearing-off' means, only 30% of PwPs and 17% of care partners gave a correct answer on further questioning. There was no evidence to support the idea that care partners notice the signs of wearing-off before the PwP. CONCLUSIONS: This matched survey underscores the broad impact that Parkinson's has on daily life on both PwPs and their care partners, and indicates the need for improved communication between PwPs, care partners and their physicians.

Patent foramen ovale closure following cryptogenic stroke or transient ischaemic attack: Long-term follow-up of 301 cases.

Patent foramen ovale has been identified as a conduit for paradoxical embolism resulting in cryptogenic stroke or transient ischemic attack (TIA). We aimed to establish rates of death, recurrent stroke or TIA among patients undergoing PFO closure for stroke or TIA at our unit. A retrospective analysis of all PFO closure patients was performed between May 2004 and January 2013. Follow up was performed by mortality tracing using the Medical Research Information Service of the Office of National Statistics. With regard to stroke or TIA recurrence, written consent forms and questionnaires were mailed with follow up telephone calls. Medical notes and imaging records were consulted where adverse events were noted. 301 patients aged 48.6 ± 11.0 years, 54.4% male, with ≥1 thromboembolic neurovascular event had percutaneous PFO closure with one of eight devices, with successful implantation in 99% of cases. Follow-up duration was 40.2 ± 26.2 months (range 1.3-105.3); complete in 301 patients for mortality (100%) and 283 patients (94.0%) for neurovascular events. Two patients died during follow-up (respiratory failure n = 1; road traffic accident n = 1). Recurrent stroke (MRI or CT confirmed) was observed in five patients (0.5%; 0.55 per 100 person-years) and TIA in 9 (1.1%; 0.98 per 100 person-years). Atrial fibrillation requiring treatment was documented in 14 patients (1.7%). Percutaneous PFO closure in patients with cryptogenic stroke or TIA is a safe treatment with a low incidence of procedural complications and recurrent neurovascular events. Registry data like these may help to demonstrate the utility of PFO closure in stroke.

A case of persistent hemifacial weakness.

Hemifacial weakness, or palsy, results from disruption of communication between cortical motor centres and the facial musculature along the course of the facial nerve. Bell's palsy has a typical presentation of sudden onset, mild otalgia, altered facial sensation and/or taste, with no obvious prodrome. It represents over half of hemifacial weakness cases in primary care. However, as a diagnosis of exclusion, there are a number of key clinical features of more sinister diagnoses that must be considered. Acute hemifacial weakness secondary to isolated facial nerve palsy must be differentiated from acute cerebrovascular accident. The latter results in sparing of the brow musculature due to the bilateral innervation of the frontalis. Altered facial sensation and mild otalgia are common in Bell's palsy, however severe pain is suggestive of Ramsay Hunt syndrome. Recent facial or head trauma and surgery should also be excluded in causation. Patients with the following conditions should be referred: lagophthalmos if the weakness persists beyond a few days or ocular damage is suspected; Ramsay Hunt syndrome (immunocompromised patients, those with significant pain, and where intraoral vesicles prohibit oral intake); and palsy secondary to trauma or surgery. A parotid mass with facial palsy implies malignant change and must be referred within the two-week wait pathway. A history of progressive hearing loss and tinnitus with palsy also requires urgent referral to neuro-otology for assessment of cerebellopontine angle tumours. All cases of facial palsy associated with infective otological symptoms should be discussed with ENT.

Late onset dopa-responsive dystonia with tremor, gait freezing and behavioural disturbance and a normal dopamine transporter scan.

A 79-year-old woman presented with dystonic posturing of the right leg while walking and an action tremor of her hands, both of which were levodopa responsive. She subsequently developed gait freezing. However, there was neither generalised bradykinesia nor rigidity. Structural imaging showed no significant changes, and a dopamine transporter scan was normal. She subsequently required rapidly escalating doses of levodopa in order to achieve symptom control, raising concerns over the possible development of a dopamine dysregulation syndrome. Issues raised included the difficulties of managing patients with a rare diagnosis and the role of dopaminergic medication with the potential for abuse.