Our dementia challenge: arise palliative care.

While many of the maladies of the 20th century are steadily coming under control, the march of neurodegenerative disorders continues largely unchecked. Dementias are an exemplar of such disorders; their incidence and prevalence continue to rise, in large part due to a steadily ageing population worldwide. They represent a group of chronic, progressive and, ultimately, fatal neurodegenerative diseases. Dementia has remained therapeutically recalcitrant. It is not a single disease, and because of that, we cannot expect a single panacea. While primary prevention rightly gains prominence, those with established disease currently require a shift in focus from curative intent towards improved quality of life. Enter palliative care. The sheer number and complexity of needs of patients with dementia, from the physical to the psychosocial and spiritual, necessitates the engagement of a wide range of medical disciplines, nursing and allied health professionals. One of those disciplines, as highlighted in the recent Australian Royal Commission into Aged Care Quality and Safety, is palliative care. This paper shall expand upon that role in the overall context of care for those with dementia.

The neuropalliative multidisciplinary team-Members and their roles.

Neurodegenerative conditions are prominent contributors to both morbidity and mortality worldwide. They pose a significant challenge to health professionals, health systems, and the often unpaid, untrained family members and carers. The many and varied challenges encountered are best managed by a multidisciplinary neuropalliative team, as it is impossible for a single clinician to possess and deliver the wide range of skills and services required to optimally care for these patients. This chapter discusses the assembly, maintenance, and care of such a team, as well as potential difficulties and solutions in domains such as funding, training, geographical remoteness, as well as the potential lack of awareness and acceptance by colleagues. A comprehensive description of the role of all possible team members is discussed. The chapter outlines the concept, content, and potential benefits of a multidisciplinary team in neuropalliative care. Its thesis is twofold: that multidisciplinary care is vital and, second, that the sum of the whole of a team can be greater than the individual parts with respect to organization, planning, experience, and creativity of approach. With all these factors considered, and implemented wherever possible, we may all move closer to optimizing the comfort and care of our shared neuropalliative patients.

Motor neuron disease: The last 12 months.

BACKGROUND: For patients with motor neuron disease (MND), the final 12 months of life can be a tumultuous period, with rapid and significant losses in function and independence, regular contact with the health system and carer stress. OBJECTIVE: The aim of this article is to provide an outline of the challenges encountered during the last 12 months of life and the role of the specialised multidisciplinary team in managing the challenges that may arise. DISCUSSION: While MND remains rare overall, it is likely that most general practitioners (GPs) will encounter at least one patient with MND during their career. An understanding of the complexity of this group of diseases, including management in the terminal phase, is important given the GP is a valuable member of the multidisciplinary team.

Parkinsonism and cerebrovascular disease.

The relationship between cerebrovascular disease and parkinsonism is commonly seen in everyday clinical practice but remains ill-defined and under-recognised with little guidance for the practising neurologist. We attempt to define this association and to illustrate key clinical, radiological and pathological features of the syndrome of Vascular Parkinsonism (VaP). VaP is a major cause of morbidity in the elderly associated with falls, hip fractures and cognitive impairment. Although acute parkinsonism is reported in the context of an acute cerebrovascular event, the vast majority of VaP presents as an insidious syndrome usually in the context of vascular risk factors and radiological evidence of small vessel disease. There may be an anatomic impact on basal ganglia neuronal networks, however the effect of small vessel disease (SVD) on these pathways is not clear. There are now established reporting standards for radiological features of SVD on MRI. White matter hyperintensities and lacunes have been thought to be the representative radiological features of SVD but other features such as the perivascular space are gaining more importance, especially in context of the glymphatic system. It is important to consider VaP in the differential diagnosis of Parkinson disease (PD) and in these situations, neuroimaging may offer diagnostic benefit especially in those patients with atypical presentations or refractoriness to levodopa. Proactive management of vascular risk factors, monitoring of bone density and an exercise program may offer easily attainable therapeutic targets in PD and VaP. Levodopa therapy should be considered in patients with VaP, however the dose and effect may be different from use in PD. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.

Severe Hypothyroidism Complicated by Myopathy and Neuropathy with Atypical Demyelinating Features.

Autoimmune hypothyroidism may result in a wide range of neuromuscular disorders. The frequently observed neurological manifestations of acquired hypothyroidism include mild to moderate myopathy and sensorimotor neuropathy, which usually resolve by clinical and electrophysiological criteria, in adults treated with thyroid hormone replacement. We report a case of a 30-year-old male with severe hypothyroidism secondary to chronic autoimmune thyroiditis who presented with a 2-year history of progressive fatigue, upper and lower limb weakness, myalgia, and intermittent paraesthesia. His neurological exam demonstrated proximal and distal muscle weakness, lower limb areflexia, and relatively intact sensory modalities. The patient's biochemistry revealed unusually and profoundly raised the thyroid stimulating hormone (TSH) level of 405.5 mIU/L (reference range (RR): 0.27-4.2 mIU/L) and creatine kinase (CK) level of 20,804 U/L (RR: 45-250 U/L), while his nerve conduction studies (NCS) demonstrated severe sensorimotor polyneuropathy with both axonal and demyelinating features. Thyroid hormone replacement therapy over the first 3 months resulted in biochemical normalization of his extremely deranged thyroid function tests (TFTs) and CK levels. At 12 months, despite maintaining euthyroidism and noticeable improvement in strength, his nerve conduction studies (NCS) demonstrated the continued absence of distal motor and sensory responses in his lower limbs with only partial improvement in sensory amplitudes and conduction velocities in his upper limbs. This report highlights the potential for severe neuromuscular consequences from advanced and chronic autoimmune hypothyroidism. The patient's myopathy has resolved over a period of three months with prompt normalization of CK levels. Concerningly, the patient achieved significant but incomplete recovery from his mixed axonal and demyelinating neuropathy with residual mild distal weakness and areflexia in his lower limbs and persistent motor and sensory impairments on his NCS. The severity and incomplete resolution of our patient's neurological manifestations emphasize the importance of early diagnosis and the need for prompt therapeutic intervention for hypothyroidism.

Isolated painful trigeminal neuropathy as an unusual presentation of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids: A case report.

BACKGROUND: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system disorder, typically presenting with subacute symptoms referable to brainstem and cerebellar pathology. This is the first report of CLIPPERS presenting with a painful trigeminal neuropathy. CASE REPORT: We report an unusual case of CLIPPERS presenting with facial pain and sensory symptoms, in the absence of other brainstem or cerebellar signs. Perivascular enhancement of peri-pontine structures on neuroimaging, lymphocytic infiltrate on histopathology and rapid clinical and radiological responsiveness to glucocorticosteroids were key to diagnosis. Extensive investigations excluded various differential aetiologies. CONCLUSION: The pathogenesis of CLIPPERS is poorly understood, and the diagnostic criteria are yet to be validated. In this case, facial pain was not associated with other brainstem or cerebellar signs, broadening current understanding of how CLIPPERS may present. This has clinical implications in guiding future investigations for patients presenting with painful trigeminal neuropathy.

Prospective study of POLG mutations presenting in children with intractable epilepsy: prevalence and clinical features.

PURPOSE: To assess the frequency and clinical features of childhood-onset intractable epilepsy caused by the most common mutations in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma. METHODS: Children presenting with nonsyndromic intractable epilepsy of unknown etiology but without documented liver dysfunction at presentation were eligible for this prospective, population-based study. Blood samples were analyzed for the three most common POLG mutations. If any of the three tested mutations were found, all the exons and the exon-intron boundaries of the POLG gene were sequenced. In addition, we retrospectively reviewed the notes of patients presenting with intractable epilepsy in which we had found POLG mutations. All available clinical data were collected by questionnaire and by reviewing the medical records. KEY FINDINGS: We analyzed 213 blood DNA samples from patients fulfilling the inclusion criteria of the prospective study. Among these, five patients (2.3%) were found with one of the three common POLG mutations as homozygous or compound heterozygous states. In addition, three patients were retrospectively identified. Seven of the eight patients had either raised cerebrospinal fluid (CSF) lactate (n = 3) or brain magnetic resonance imaging (MRI) changes (n = 4) at presentation with intractable epilepsy. Three patients later developed liver dysfunction, progressing to fatal liver failure in two without previous treatment with sodium valproate (VPA). Furthermore, it is worth mentioning that one patient presented first with an autism spectrum disorder before seizures emerged. SIGNIFICANCE: Mutations in POLG are an important cause of early and juvenile onset nonsyndromic intractable epilepsy with highly variable associated manifestations including autistic features. This study emphasizes that genetic testing for POLG mutations in patients with nonsyndromic intractable epilepsies is very important for clinical diagnostics, genetic counseling, and treatment decisions because of the increased risk for VPA-induced liver failure in patients with POLG mutations. We recommend POLG gene testing for patients with intractable seizures and at least one elevated CSF lactate or suggestive brain MRI changes (predominantly abnormal T2 -weighted thalamic signal) with or without status epilepticus, epilepsia partialis continua, or liver manifestations typical for Alpers disease, especially when the disease course is progressive.

Jamar hand-held grip dynamometry in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: Few studies have evaluated the functional and electrophysiological correlates of hand-held grip dynamometry in neuromuscular disease. The practical value of normative values remains uncertain in clinical practice. We aimed to ascertain the value, clinical and electrophysiological correlates, as well as utility of normative values for grip dynamometry, in a cohort of subjects with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We performed a cross-sectional study of 31 prospectively recruited subjects with CIDP, using Jamar hand-held grip dynamometry, conventional clinical assessments and electrophysiology. RESULTS: Grip dynamometry correlated highly with motor, sensory and functional scores in the upper limbs as well as with global function. There were significant correlations with summated median/ulnar, and ulnar compound muscle action potentials. Patients' readings were significantly lower than median normative values but comparable to fifth percentile normative figures. CONCLUSIONS: Jamar grip dynamometry is a reliable measure of global neurological status in patients with CIDP, not limited to upper limb or exclusively motor function. At optimum level of function, CIDP patients had comparable dynamometry recordings to fifth percentile normative values, which may represent a realistic aim for treated subjects with the disorder, with currently available therapies.

Electrophysiological entrapment syndromes in chronic inflammatory demyelinating polyneuropathy.

We do not know if peripheral nerves are more susceptible to entrapment syndromes in chronic inflammatory demyelinating polyneuropathy (CIDP). We studied 31 prospectively recruited patients with CIDP. We determined whether entrapment zones were more frequently affected by demyelination than adjacent segments. The median, ulnar, and fibular nerves were studied at the wrist, elbow, and fibular head bilaterally. Motor conduction velocity and motor conduction block were evaluated at entrapment sites and compared with contiguous segments. Demyelination was significantly more frequent for ulnar and fibular nerves away from entrapment sites. No significant difference was observed for median nerves. CIDP is not associated with increased frequency of demyelination at entrapment sites. The presence of diffuse entrapment neuropathies at compression sites does not favor a diagnosis of CIDP. Although electrophysiological study of entrapment sites is not diagnostically useful in CIDP, it may help distinguish it from other neuropathies and confirm clinically relevant, surgically treatable compressions.

Characteristics and correlates of sensory function in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: Sensory assessments are included in clinical and research practice in chronic inflammatory demyelinating polyneuropathy (CIDP). However, their characteristics and relevance in relation to motor involvement and function have rarely been studied. OBJECTIVES: To investigate the characteristics and correlates of sensory function in CIDP. METHODS: We evaluated the sensory clinical and electrophysiological features in 31 clinically-stabilized, prospectively recruited, CIDP patients and analyzed their relation with motor strength and function as well as with electrophysiology. RESULTS: Sensory function primarily affected large fibres and was predominant in the lower limbs. Sensory Sum Scores (SSS) correlated with Medical Research Council (MRC) motor scores, Overall Neuropathy Limitation Scores (ONLS) and presence of positive sensory symptoms, in upper and lower limbs. Rydel-Seiffer vibration scores correlated with MRC and ONLS scores, in the lower limbs only. Correlations of SSS with sensory nerve action potential (SNAP) amplitudes and summated compound muscle action potential (CMAP) amplitudes, were present in the lower limbs but not in the upper limbs, whereas such correlations were ascertained in all extremities for Rydel-Seiffer scores. SNAPs correlated with ONLS scores exclusively in the legs. CONCLUSIONS: These results show that sensory involvement relates to motor function in CIDP, suggesting that the disease activity affects concurrently motor and sensory fibres in the disorder. The findings of this cross-sectional analysis may otherwise suggest the practical reliability and usefulness of clinical sensory scores, particularly the SSS, in monitoring disease progression and effects of treatment in the disorder. Further longitudinal study is required to confirm this.

Mitotic raptor promotes mTORC1 activity, G(2)/M cell cycle progression, and internal ribosome entry site-mediated mRNA translation.

The mTOR signaling complex integrates signals from growth factors and nutrient availability to control cell growth and proliferation, in part through effects on the protein-synthetic machinery. Protein synthesis rates fluctuate throughout the cell cycle but diminish significantly during the G(2)/M transition. The fate of the mTOR complex and its role in coordinating cell growth and proliferation signals with protein synthesis during mitosis remain unknown. Here we demonstrate that the mTOR complex 1 (mTORC1) pathway, which stimulates protein synthesis, is actually hyperactive during mitosis despite decreased protein synthesis and reduced activity of mTORC1 upstream activators. We describe previously unknown G(2)/M-specific phosphorylation of a component of mTORC1, the protein raptor, and demonstrate that mitotic raptor phosphorylation alters mTORC1 function during mitosis. Phosphopeptide mapping and mutational analysis demonstrate that mitotic phosphorylation of raptor facilitates cell cycle transit through G(2)/M. Phosphorylation-deficient mutants of raptor cause cells to delay in G(2)/M, whereas depletion of raptor causes cells to accumulate in G(1). We identify cyclin-dependent kinase 1 (cdk1 [cdc2]) and glycogen synthase kinase 3 (GSK3) pathways as two probable mitosis-regulated protein kinase pathways involved in mitosis-specific raptor phosphorylation and altered mTORC1 activity. In addition, mitotic raptor promotes translation by internal ribosome entry sites (IRES) on mRNA during mitosis and is demonstrated to be associated with rapamycin resistance. These data suggest that this pathway may play a role in increased IRES-dependent mRNA translation during mitosis and in rapamycin insensitivity.

The value of sensory electrophysiology in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: The purpose of this study was to evaluate the usefulness of sensory nerve conduction studies in comparison and in combination with motor conductions in diagnosing chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We retrospectively compared the electrophysiology of 20 patients with CIDP to that of 20 controls with axonal polyneuropathy, and 20 controls with myopathy. Five sensory abnormality patterns were evaluated. RESULTS: The "abnormal radial normal sural" ("ARNS") pattern showed a sensitivity of 25% for CIDP and specificity of 100% versus axonal neuropathies (p=0.047). The "abnormal sural normal radial" ("ASNR") pattern had a sensitivity of 75% for axonal neuropathy with a specificity of 80% versus CIDP (p=0.0012). Presence of ARNS or absence of ASNR patterns showed equivalent or superior sensitivity and specificity to most individual motor demyelinating defects for CIDP. Presence of ARNS or absence of ASNR patterns, integrated within three different sets of electrodiagnostic criteria for CIDP, increased sensitivity in all without significantly altering specificity. Effects were most remarkable with the American Academy of Neurology criteria (1991), which showed significantly improved sensitivity (50-85%; p=0.041), with preserved specificity of 100%. CONCLUSIONS: The use of sensory abnormality patterns appears justified in comparison and combination with motor defects in diagnosing CIDP. SIGNIFICANCE: Sensory studies may be useful in contributing to the electrodiagnosis of CIDP and their inclusion in existing electrodiagnostic criteria deserves consideration.

Transforming growth factor-beta and microRNA:mRNA regulatory networks in epithelial plasticity.

Noncoding microRNAs act as posttranscriptional repressors of gene function and are often deregulated in cancers and other diseases. Here we review recent findings on microRNA roles in tumorigenesis and report a microRNA profiling screen in transforming growth factor-beta1 (TGF-beta)-induced epithelial-mesenchymal transition (EMT) in human keratinocytes, a model of epithelial cell plasticity underlying epidermal injury and skin carcinogenesis. We describe a novel EMT-specific microRNA signature that includes induction of miR-21, a candidate oncogenic microRNA associated with carcinogenesis. By integrating the microRNA screen results with target prediction algorithms and gene expression profiling data, we outline a framework for TGF-beta-directed microRNA:messenger RNA (mRNA) regulatory circuitry and discuss its biological relevance for tumor progression.