The behavioral and psychological symptoms of dementia (BPSD) have been a difficult management area for neurologists and psychiatrists alike. The correct identification of each symptom and the underlying precipitating cause is the key to proper management—nonpharmacological as well as pharmacological. BPSD has been well documented in all types of dementia in various stages of the disease and in all dementias at an advanced stage. The proper management is not only rewarding in terms of responsiveness in an otherwise “incurable” and progressive disease, but also improves the quality of life of the patients and the caregivers alike. The caregiver burden is greatly decreased by an efficient management of BPSD. This review discusses the implications and boundaries of the term BPSD and unravels each symptom and its identification. Manifestations of psychological symptoms such as delusion, hallucination, misidentification, psychosis, depression, apathy, and anxiety are briefly described. Correct identification of behavior symptoms such as wandering, agitation, catastrophic reaction, disinhibition, and delirium has been outlined. While the subtle differences in each entity make the precise identification difficult, the different therapeutics of each make the exercise necessary. Pharmacological recommendations and side effects of medications have been mentioned thereafter. The review will help in the identification and correct pharmacological management of BPSD.
Behavior; dementia; diagnosis; psychological; therapeutics
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease. A characteristic feature of the disease is the presence of amyloid-β (Aβ) which either in its soluble oligomeric form or in the plaque-associated form is causally linked to neurodegeneration. Aβ peptide is liberated from the membrane-spanning -amyloid precursor protein by sequential proteolytic processing employing β- and γ-secretases. All these proteins involved in the production of Aβ peptide are membrane associated and hence, membrane trafficking and cellular compartmentalization play important roles. In this review, we summarize the key cellular events that lead to the progression of AD.
Alzheimer’s disease; amyloid precursor protein; β-secretase; secretase; amyloid; trafficking; endocytosis; exosomes
Primary progressive aphasia (PPA) is a focal neurodegeneration of the brain affecting the language network. Patients can have isolated language impairment for years without impairment in other areas. PPA is classified as primary progressive nonfluent aphasia (PNFA), semantic dementia (SD), and logopenic aphasia, which have distinct patterns of atrophy on neuroimaging. PNFA and SD are included under frontotemporal lobar degenerations. PNFA patients have effortful speech with agrammatism, which is frequently associated with apraxia of speech and demonstrate atrophy in the left Broca’s area and surrounding region on neuroimaging. Patients with SD have dysnomia with loss of word and object (or face) meaning with asymmetric anterior temporal lobe atrophy. Logopenic aphasics have word finding difficulties with frequent pauses in conversation, intact grammar, and word comprehension but impaired repetition for sentences. The atrophy is predominantly in the left posterior temporal and inferior parietal regions. Recent studies have described several progranulin mutations on chromosome 17 in PNFA. The three clinical syndromes have a less robust relationship to the underlying pathology, which is heterogeneous and includes tauopathy, ubiquitinopathy, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, and Alzheimer’s disease. Recent studies, however, seem to indicate that a better characterization of the clinical phenotype (apraxic, agrammatic, semantic, logopenic, jargon) increases the predictive value of the underlying pathology. Substantial advances have been made in our understanding of PPAs but developing new biomarkers is essential in making accurate causative diagnoses in individual patients. This is critically important in the development and evaluation of disease-modifying drugs.
Alzheimer’s disease; frontotemporal dementia; logopenic aphasia; neuroimaging; nonfluent aphasia; primary progressive aphasia; semantic dementia
One of the first steps toward the correct diagnosis of dementia is to segregate out the nondegenerative dementias from possible degenerative dementias. Nondegenerative dementias could be due to traumatic, endocrine, metabolic, nutritional, toxic, infective, and immunological causes. They could also be caused by tumors, subdural hematomas, and normal pressure hydrocephalus. Many of the nondegenerative dementias occur at an earlier age and often progress quickly compared to Alzheimer’s disease and other degenerative dementias. Many are treatable or preventable with simple measures. This review aims to give an overview of some of the more important endocrine, metabolic, nutritional, and toxic disorders that may lead to dementia.
Dementia; endocrine; metabolic; nutritional; reversible dementia; toxins
Frontotemporal lobar degeneration (FTLD) is a highly heterogenous group of progressive neurodegenerative disorders characterized by atrophy of prefrontal and anterior temporal cortices. Recently, the research in the field of FTLD has gained increased attention due to the clinical, neuropathological, and genetic heterogeneity and has increased our understanding of the disease pathogenesis. FTLD is a genetically complex disorder. It has a strong genetic basis and 50% of patients show a positive family history for FTLD. Linkage studies have revealed seven chromosomal loci and a number of genes including MAPT, PGRN, VCP, and CHMB-2B are associated with the disease. Neuropathologically, FTLD is classified into tauopathies and ubiquitinopathies. The vast majority of FTLD cases are characterized by pathological accumulation of tau or TDP-43 positive inclusions, each as an outcome of mutations in MAPT or PGRN, respectively. Identification of novel proteins involved in the pathophysiology of the disease, such as progranulin and TDP-43, may prove to be excellent biomarkers of disease progression and thereby lead to the development of better therapeutic options through pharmacogenomics. However, much more dissections into the causative pathways are needed to get a full picture of the etiology. Over the past decade, advances in research on the genetics of FTLD have revealed many pathogenic mutations leading to different clinical manifestations of the disease. This review discusses the current concepts and recent advances in our understanding of the genetics of FTLD.
Frontotemporal lobar degeneration; genetic risk factors; microtubule-associated protein tau; mutations; progranulin; TDP-43
The relationship between motor neurone disease (MND) and frontotemporal dementia (FTD) has been a topic of scientific exploration for over hundred years. A connection between both diseases was first postulated in 1932 and has been strengthened by a steady stream of case reports since then. By the late 20th century, the link between both diseases was firmly established, with the resulting condition often referred to as MND/FTD. Several strands of evidence support the notion of an MND/FTD overlap. First, a small but well-documented group of patients present with a full-blown FTD, associated with MND. Second, subtle but characteristic changes in frontal-executive functions and social cognition have been described in non-demented MND patients, often in association with frontal atrophy/hypoactivity on neuroimaging. Third, amyotrophic features have been documented in patients primarily diagnosed with FTD. Moreover, the same genetic defect can lead to FTD and MND phenotypes in different members of the same family. However, as the current research is moving toward a more fine-grained evaluation, an increasingly complex picture begins to emerge. Some features, such as psychotic symptoms or severe language deficits (particularly in comprehension and verb processing), seem to occur more often in MND/dementia than in the classical FTD. On the basis of the review of 100 years of literature as well as 10 years of clinical experience of longitudinal follow-up of MND/dementia patients, this review argues in favor of MND/dementia (or, more precisely, MND/dementia/aphasia) as a separate clinical entity, not sufficiently explained by a combination of MND and FTD.
Amyotrophic lateral sclerosis; cognition; frontotemporal dementia; language; motor neuron disease
Frontotemporal dementia (FTD) syndromes comprise a heterogeneous group of neurodegenerative conditions characterized by atrophy in the frontal and temporal lobes. Three main clinical variants are recognized: Behavioral variant (bv-FTD), Semantic dementia (SD), and Progressive nonfluent aphasia (PNFA). However, logopenic/phonological (LPA) variant has been recently described, showing a distinctive pattern of brain atrophy and often associated to Alzheimer’s disease pathology. The diagnosis of FTD is challenging, since there is clinical, pathological, and genetic overlap between the variants and other neurodegenerative diseases, such as motoneuron disease (MND) and corticobasal degeneration (CBD). In addition, patients with gene mutations (tau and progranulin) display an inconsistent clinical phenotype and the correspondence between the clinical variant and its pathology is unpredictable. New cognitive tests based on social cognition and emotional recognition together with advances in molecular pathology and genetics have contributed to an improved understanding. There is now a real possibility of accurate biomarkers for early diagnosis. The present review concentrates on new insights and debates in FTD.
Frontotemporal dementia; progressive nonfluent aphasia; semantic dementia; taupathies; TDP-43
Recent reports indicate that gait dysfunction can occur early in the course of cognitive decline suggesting that motor and cognitive functions in older adults may share common underlying brain substrates, pathological processes, and risk factors.
This study was designed to report the association between gait and cognition in older adults in USA and the southern Indian state of Kerala.
Materials and Methods:
Literature review of gait and cognition studies conducted in Bronx County, USA as well as preliminary results from the Kerala-Einstein study (Kozhikode city, Kerala).
Review of published studies based in the Bronx shows that both clinical and quantitative gait dysfunction are common in older adults with cognitive impairment. Furthermore, clinical and quantitative gait dysfunction in cognitively normal older adults was a strong predictor of future cognitive decline and dementia. Our preliminary study in Kozhikode city shows that timed gait is slower in older adults diagnosed with dementia and mild cognitive impairment syndrome compared to healthy older controls.
A strong association between gait and cognition is seen in seniors in USA as well as Kerala. A better understanding of the relationship between gait and cognition may help improve current diagnostic and therapeutic approaches globally.
Dementia; elderly; gait; speed
Alzheimer’s disease (AD) is the commonest progressive, dementing neurodegenerative disease in elderly, which affects innumerable people each year, and these numbers are likely to further increase as the population ages. In addition to the financial burden of AD on health care system, the disease has powerful emotional impact on caregivers and families of those afflicted. In this advancing era of AD research, with the availability of new treatment strategies having disease-modifying effects, there is growing need for the early diagnosis in AD, often hampered by paucity of biomarkers of AD. Various candidate biomarkers for AD have been developed that can detect patients with AD at an early stage. In the recent years, the search for an ideal biomarker has undergone a rapid evolution. Novel technologies in proteomics, genomics, and imaging techniques further expand the role of a biomarker not only in early diagnosis, but also in monitoring the response to various treatments. However, the availability of sensitive and specific biomarkers requires the method to be standardized so as to be able to compare the results across studies. Inspite of tremendous advances in this field the quest for an “ideal biomarker” still continues. In this review, we will discuss the various candidate markers in five spheres namely biochemical, neuroanatomical, metabolic, genetic and neuropsychological, and their current status and limitations in AD diagnosis.
Alzheimer’s disease; biomarkers; biochemical; MRI volumetry; neuropsychology; positron emission tomography; tau
Dementia and depression are mental health problems that are commonly encountered in neuropsychiatric practice in the elderly. Approximately, half of the patients with late-onset depression have cognitive impairment. The prevalence of depression in dementias has been reported to be between 9 and 68%. Depression has been both proposed to be a risk factor for dementia as well as a prodrome of dementia. This article is a selective literature review of the complex relationship between the two conditions covering definitions, epidemiology, related concepts, treatment, and emerging biomarkers. The methodological issues and the mechanisms underlying the relationship are also highlighted. The relationship between the two disorders is far from conclusive.
Alzheimer’s disease; dementia; depression; geriatric; vascular dementia
Cognitive impairment due to cerebrovascular disease is termed “Vascular Cognitive Impairment” (VCI) and forms a spectrum that includes Vascular Dementia (VaD) and milder forms of cognitive impairment referred to as Vascular Mild Cognitive Impairment (VaMCI). VCI represents a complex neurological disorder that occurs as a result of interaction between vascular risk factors such as hypertension, diabetes, obesity, dyslipidemia, and brain parenchymal changes such as macro and micro infarcts, haemorrhages, white matter changes, and brain atrophy occurring in an ageing brain. Mixed degenerative and vascular pathologies are increasingly being recognised and an interaction between the AD pathology, vascular risk factors, and strokes is now proposed. The high cardiovascular disease burden in India, increasing stroke incidence, and ageing population have contributed to large numbers of patients with VCI in India. Inadequate resources coupled with low awareness make it a problem that needs urgent attention, it is important identify patients at early stages of cognitive impairment, to treat appropriately and prevent progression to frank dementia.
Dementia; stroke; vascular cognitive impairment
Nearly 80% of the 50 million people with epilepsy worldwide reside in developing countries that are least equipped to tackle the enormous medical, social and economic challenges posed by epilepsy. These include widespread poverty, illiteracy, inefficient and unevenly distributed health care systems, and social stigma and misconceptions associated with epilepsy. Several studies have reported that a large proportion of patients with epilepsy in developing countries never receive appropriate treatment for their condition, and many, though diagnosed and initiated on treatment, soon discontinue treatment. Unaffordable cost of treatment, unavailability of antiepileptic drugs, and superstitious and cultural beliefs contribute to high epilepsy treatment gap in resource-poor countries. A significant proportion of the current burden of epilepsy in developing countries can be minimized by educating the public about the positive aspects of life with epilepsy and the primary and secondary physicians about current trends in the management of epilepsies, scaling up routine availability of low-cost antiepileptic drugs, and developing cost-effective epilepsy surgery programs.
Developing countries; epilepsy; epilepsy surgery; treatment gap
Kleine–Levin syndrome (KLS) is a rare sleep disorder mainly affecting teenage boys in which the main features are intermittent hypersomnolence, behavioral and cognitive disturbances, hyperphagia, and in some cases hypersexuality. Each episode is of brief duration varying from a week to 1–2 months and affected people are entirely asymptomatic between episodes. No definite cause has been identified, and no effective treatments are available even though illness is having well-defined clinical features. Multiple relapses occur every few weeks or months, and the condition may last for a decade or more before spontaneous resolution. In this study, PubMed was searched and appropriate articles were reviewed to highlight etiology, clinical features, and management of KLS. On the basis of this knowledge, practical information is offered to help clinicians about how to investigate a case of KLS, and what are the possible treatment modalities available currently for the treatment during an episode and interepisodic period for prophylaxis. Comprehensive research into the etiology, pathophysiology, investigation, and treatments are required to aid the development of disease-specific targeted therapies.
Hypersomnia; hypersexuality; Kleine–Levin syndrome; megaphagia; periodic
This article is part of the Guidelines for Epilepsy management in India. This article reviews the classification systems used for epileptic seizures and epilepsy and present the recommendations based on current evidence. At present, epilepsy is classified according to seizure type and epilepsy syndrome using the universally accepted International League Against Epilepsy (ILAE) classification of epileptic seizures and epilepsy syndromes. A multi-axial classification system incorporating ictal phenomenology, seizure type, epilepsy syndrome, etiology and impairments is being developed by the ILAE task force. The need to consider age-related epilepsy syndromes is particularly important in children with epilepsy. The correct classification of seizure type and epilepsy syndrome helps the individual with epilepsy to receive appropriate investigations, treatment, and information about the likely prognosis.
Epilepsy; classification; seizures
To study the electroclinical and histopathologic profile of idiopathic inflammatory myositis (IIM) with reference to prognosis and survival rate.
Materials and Methods:
Diagnosis of IIM was based on the Bohan and Peter criteria. Patients who improved and those whose condition worsened or who expired due to IIM per se at last follow-up were classified to have favorable and poor outcomes, respectively. Fisher’s exact test was used for univariate analysis of prognostic factors.
The study cohort consisted of consecutive 68 patients with IIM. The mean age at diagnosis was 36.5 years and females constituted 71%. Of these patients, 62% had definite IIM, 49% had polymyositis, 20% had dermatomyositis, and 29% had overlap syndrome. The mean follow-up period was 5.4 years. Prednisolone alone was used in 55 (80%), and azathioprine (1–3 mg/kg/day) alone in 12 (17.6%) as the initial treatment. Relapse of IIM with drug withdrawal was seen in 15 patients (22%); 70% had favorable outcome and 16% had expired. The treatment delay of ≤6 months (P = 0.001), absence of cardiac or lung involvement (P < 0.001), and positive biopsy (P = 0.033) were predictive of a favorable prognosis in the univariate analysis. In multivariate analysis, only the duration of illness of ≤6 months (P = 0.008) and the absence of cardiac or lung involvement (P = 0.001) predicted the favorable outcome at last follow-up. Cumulative survival rate was 95% at 1 year, 86% at the 5th year, and 80% at the 10th year.
Approximately, two-thirds of the patients showed good electroclinical and histopathologic correlations and an equal number improved with treatment. The treatment delay (≥6 months), presence of cardiac or pulmonary involvements, and negative muscle biopsy are bad prognostic factors.
Final outcome; myositis; prognosis; survival rate
Vitamin B12 and folate represent modifiable risk factors for dementia. They may increase the risk of Alzheimer′s dementia (AD) and vascular dementia (VaD) as their deficiency can increase the homocysteine level due to slowed methylation reaction. Homocysteine has a neurotoxic effect that could lead to neurologic disturbances. Hence, it is important to explore the status of serum B12 and folate in AD and VaD to evolve the treatment strategies for the same.
A retrospective study was conducted to assess the levels of vitamin B12, folate, and thyroid stimulating hormone (TSH) in serum and the relationship of these factors, including age and sex to cognitive decline in VaD, AD, and dementia due to other causes (DOC).
Materials and Methods:
Serum vitamin B12, folate, TSH, and total cholesterol were studied in 32 AD patients (mean age: 65 years), 12 VaD patients (mean age: 61 years), 83 DOC (mean age: 65 years), and 127 control subjects (mean age: 49 years). Results: In AD, VaD, and DOC, the levels of vitamin B12 and folate were significantly lower (P < 0.002; 0.026; 0.002 for vitamin B12 and P < 0.000 in all the 3 groups for folate) as compared with the controls. Similarly, TSH levels were significantly lower in AD and DOC (P < 0.008; 0.038) as compared with the controls.
Vitamin B12 and folate were significantly low in both AD and VaD patients. Hence, B vitamin supplementation should be considered as possible targets for the therapeutic intervention in dementia.
Alzheimer disease; dementia; folate; thyroid stimulating hormone; vascular dementia; Vitamin B12
Antemortem diagnosis of cerebral toxoplasmosis, the second most common opportunistic infection (OI) in HIV-infected individuals in developing countries is a challenge.
Materials and Methods:
Toxoplasma gondii (T.gondii) -specific serology and nested polymerase chain reaction (nPCR) were evaluated in sera and ventricular/lumbar cerebrospinal fluid (CSF) of 22 autopsy confirmed cases of cerebral toxoplasmosis with HIV and 17 controls. Frequency of concomitant T.gondii infection was investigated in 17 cases of HIV-associated tuberculous meningitis (TBM).
The sensitivity, specificity, and positive and negative predictive values of T. gondii IgG on CSF (ventricular and lumbar) and sera was 100% in histology proven cerebral toxoplasmosis (concentrations: 258 ± 50, 231 ± 36, and 646 ± 243 IU/mL, respectively); majority (94%) being high avidity type, suggesting reactivation/reinfection. The sensitivity of B1 nPCR was 100% on ventricular CSF, whereas it was only 77% on lumbar CSF. Based on histology, nPCR, and IgG serology, T. gondii co-infection with TBM was observed in 65% (11/17) of cases.
Discussion and Conclusion:
CSF IgG serology and nPCR are tests with high sensitivity and specificity for the diagnosis of cerebral toxoplasmosis. TBM and cerebral toxoplasmosis can coexist and should be considered in the background of HIV infection in developing countries.
B1 gene; cerebral toxoplasmosis; human immunodeficiency virus; T. gondii IgG; Toxoplasma gondii; tuberculous meningitis
This study was designed to identify the indications for prescription of intravenous immunoglobulin (IVIg) in neurology and the cost effectiveness of this therapy.
IVIg is a relatively costly therapy and the annual budget spent on providing this therapy for various indications at Ninewells Hospital was close to £1.5 million. In today’s economic times, a cost–benefit analysis of all therapies is prudent. This is of relevance to countries in the developing world as well where perhaps not everybody could afford such cost-intensive therapy.
Materials and Methods:
We audited 2 time periods over 12 months each in 2004–2005 and 2008–2009 to look at the patterns of utilization of IVIg over these periods. We searched the literature for alternative and cost-effective therapies for the most common indications for use of IVIg.
Fiscal costs on prescription of IVIg have rocketed up by almost 300% in this Neurology Department comparing data from 2004–2005 vs 2008–2009 and this is disproportionate to the increase in the annual admission rate (bed usage), partly because of the soaring costs of the drug available in the market and also because of the increased prescription of IVIg for numerous indications where clinical trials data are yet not so robust.
We have looked at the cost of alternative therapies and offer some proposals that if implemented could potentially save £330,000 annually from the health budget at this NHS Trust. Perhaps similar models could evolve for better cost-effective utilization of IVIg in countries in the developing world where health budgeting is more acutely relevant.
Blood transfusion service; Department of Health; United Kingdom; Intravenous immunoglobulin