Clinical practice guidelines on addressing cognitive impairment in treatable dementias

INTRODUCTION In older adults aged 60 years or above the prevalence of dementia in India is 7.4%, which translates to about 8.8 million cases of dementia.[1] With an estimated increase in the proportion of older adults aged over 60 years to approximately one-fifth of the entire population by 2050 due to increasing lifespan, the prevalence of dementia is predicted to increase tremendously.[2] A proportion of these dementias are considered to be produced by irreversible conditions, while the others by reversible conditions. The precise frequency of reversible dementias in the general population is difficult to estimate. This is because of the ambiguity surrounding the terminology used to characterize reversible dementia—the variation in the population being studied, or the existence of subclinical instances that are difficult to diagnose.[3] By and large however, the proportion of reversible dementias compared to the irreversible dementias is very low. Prevalence is highly variable, with a varied number of studies reporting a range between 0 and 40%, and average approximates to 12%. While, the prevalence of potentially reversible aetiology has been reported 18% in patients under the age of 65 years, however only 5% in those over 65 years.[3] A meta-analysis showed that although potentially reversible causes were seen in 9% of the cases, only 0.6% of dementia cases could be reversed.[4] Optimum assessment of differential diagnosis and prompt treatment are therefore of paramount importance. While therapeutic strategies are available for both reversible and irreversible dementias, the term ‘treatable dementias’ is assumed to be synonymous with ‘reversible dementias’ as they are ‘readily treatable’.[5] However, ‘treatable dementias’ include cases with conditions which are irreversible too.[6] There are definite ‘treatable aspects of irreversible dementias, such as behavioural and psychological symptoms of dementia.[6] This guideline does not cover those aspects. The process of developing this guideline began with the identification of team members and establishment of the team. The team then determined the scope of the guideline in consultation with the clinical practice committee members, in particular to make sure there are no significant overlaps between the various guidelines of the issue. A framework or a content index was then developed. A systematic literature search was then conducted using specific search terms, independently by two of its members. The final list of articles to be reviewed was then determined by the lead member. The articles retrieved were classified into various framework heads and sub-heads. All members were then involved in documenting the review and the guidelines. CAUSES OF POTENTIALLY REVERSIBLE DEMENTIAS Little (2018) proposed a mnemonic DEMENTIAS for potentially reversible causes of dementia- Drugs, Eyes/Ears (sensory isolation), Metabolic, Emotion, Normal Pressure Hydrocephalus (NPH), Tumour, Infection, Atrial Fibrillation/Alcoholism and Sleep Apnoea [Also see Figure 1].[5] We recommend adding Autoimmune (for A) also to the list.Figure 1: Treatable causes of dementiaHowever, for better understanding the reversible dementias can be broadly classified as:[6,7] 1. Intracranial (neurosurgical) disorders; 2. Intracranial (neuroinfectious) disorders; 3. Systemic (including metabolic/endocrinal) disorders; 4. toxic disorders and 5. mental and behavioural (psychiatric) disorders. Depression, alcohol-induced cognitive impairment, normal pressure hydrocephalus (NPH), Vitamin B12 deficiency alone would account for more than half of causes of reversible dementias. Other less common causes are tumours and chronic subdural hematomas, hypothyroidism and central nervous system (CNS) infections such as neurosyphilis and HIV.[8] The autoimmune dementia and encephalopathies (ADE) are becoming increasingly prevalent in early onset dementia patients; about 20-25% in dementia of early onset.[9] CLINICAL FEATURES OF POTENTIALLY REVERSIBLE DEMENTIAS Potentially reversible dementias can be identified and differentiated from irreversible dementias from their clinical presentation. A thorough history often clinches the diagnosis of the underlying condition. Tables 1a-1f show the list of disorders in each of the classified reversible dementia subtypes as mentioned above and their clinical features.Table 1a: Intracranial (neurosurgical) disorders and their clinical featuresTable 1b: Intracranial (neuroinfections) disorders and their clinical featuresTable 1c: Systemic (including metabolic/endocrinal) disorders and their clinical featuresTable 1d: Toxicity and their clinical featuresTable 1e: Drugs causing cognitive dysfunction and associated featuresTable 1f: Mental and behavioural disorders and their clinical featuresCLINICAL COURSE OF “TREATABLE DEMENTIAS” In this section, we briefly describe the course of some of the highly prevalent causes of “treatable dementia” below: Alcohol-induced (related) dementia Several lines of research suggest that chronic consumption of alcohol leads to permanent damage, both structural and functional, to the brain. Apart from the indirect contribution of thiamine deficiency to this, alcohol too has direct effects—the presentation is named ‘alcohol related dementia (ARD)’. The umbrella term ‘alcohol-related brain damage’ includes both ARD and the Wernicke–Korsakoff syndrome. Patients with ARD are mostly male, have their onset of symptoms younger compared to other dementias and lack social support. Visuospatial, memory and executive dysfunction are mainly evident.[10] Depressive cognitive disorder (Depressive pseudodementia) Depressive cognitive disorder is characterised by a cognitive impairment where its ‘risk factors overlap with those for depression’. The symptoms mimic dementia, but improve with improvements in mood; there is no neuronal degeneration noted. It is prevalent in those aged 50 or above years. The cognitive domains mainly affected are: memory, executive function and speech. Although it may be difficult to diagnose depressive cognitive disorder when there is a significant overlap of depressive and true dementia symptoms, there are aspects that help differentiate it from true dementias. The onset of cognitive impairment in depressive cognitive disorder is abrupt to acute and usually is precipitated and aggravated by stress. The symptoms show rapid progression as well as fast resolution. There is possibility of previous and family history of mood disorder episodes. More characteristically, they often tend to respond with ‘I do not know’ rather than confabulations, which are noted in other forms of dementia. Other symptoms of depression will be noted.[11]Table 2 shows the differences between depressive cognitive disorder and dementia.Table 2: Prominent differences between depressive cognitive disorder and dementiaAutoimmune dementia and encephalopathies (ADE) ADE is broadly divided in paraneoplastic (underlying cancers) and non-paraneoplastic varieties. The non-neoplastic ADEs were considered idiopathic until recently where there has been discovery of many neural-specific autoantibodies.[9] The various varieties of common autoimmune encephalitis presenting as dementia[12] are given Table 3. A detailed list of neural antibodies, in general, is given by Fernández-Fournier (2022)[13] Except for conditions like limbic encephalitis where the onset can be abrupt to acute, other conditions run a subacute to chronic course. While memory loss is the most prominent clinical presentation, other cognitive domains, especially attention is also affected. Preservation of memory with behavioural changes such as personality changes and social disinhibition may also be presented and mimic frontotemporal dementia. The course of ADE may be continuous or remitting and relapsing. Spontaneous recovery is also seen in some cases. Once the clinical suspicion is made and investigations show evidence of autoimmunity, the progression, or rather response to steroids and antibody-depleting agents (immunotherapy) is remarkably positive. Relapse after immunotherapy should be looked as a complication of immunotherapy-infectious complications such as progressive multifocal leukoencephalopathy or steroid-induced cognitive impairment.Table 3: Varieties of common autoimmune encephalitis presenting as dementiaNormal pressure hydrocephalic dementia The classical triad of NPH is gait disorder, urinary dyscontrol and dementia. The following examination and historical characteristics support hydrocephalus as the cause of dementia: a history of urinary symptoms (frequency and/or incontinence not related to the urological system), a history of typical gait (wide-based, magnetic, ‘freezing’ gait, with postural instability), and a history of meningitis or subarachnoid haemorrhage of any cause at any point in the past (e.g., head trauma or aneurysmal bleeding). A large volume lumbar puncture is typically part of the evaluation process for hydrocephalus, ideally accompanied by a filmed gait analysis both prior to and in the hours that follow. Following the evacuation of 35 to 50 cc of CSF, improvements in urine and gait are suggestive of possible dementia reversibility. Over a few years, dementia gradually worsen, albeit more subacute presentations do happen. There may be fluctuations in the course which might invite uncertainties., The neurosurgical installation of a ventriculoperitoneal or ventriculoatrial shunt may offer some reversal of dementia symptoms (especially in more obese people). Improvement in clinical outcomes is reported in 70% to 90% of those with confirmed NPH. However, there may frequently be concurrent neurodegeneration (Alzheimer’s disease, vascular or frontotemporal type) confounding the improvement. Interestingly, shunting may initially improve memory and gait abnormalities and postpone the deposition of beta-amyloid, but it is unlikely to totally stop the progression of the disease. Metabolic dementias Cortical ischemia, vascular dementia and cognitive decline have all been linked to abnormal thyroid function tests. Specifically, higher thyroid-stimulating hormone and decreased thyroxine levels have been detected. But the evidence is conflicting. And there is scant data to support that hypothyroidism is the only cause of dementia or that the use of thyroid hormone replacement therapy could reverse cognitive impairment. Similarly, hyperthyroidism is linked to an increased risk of Alzheimer’s disease brain pathology due to greater thyroxine levels; however, there is minimal evidence that treating these abnormalities may enhance cognition. It is still advised to test thyroid function in the workup of cognitive impairment, even though more evidence is required to confirm the relationship between thyroid disease and dementia and the effects of treatment. This is because thyroid disease can result in other problems, such as depression, weight loss or cardiac arrhythmias, that can affect functional trajectories in dementia.[14] Cognitive decline and dementia have been linked to both hypoparathyroidism resulting in hypocalcaemia and hyperparathyroidism resulting in hypercalcemia. Improved mentation has been linked to correction of the parathyroid abnormalities with parathyroid resection (hyperparathyroid) or calcitriol (hypoparathyroid). Importantly, lithium may stimulate PTH secretion resulting in hypercalcemia in around 10% of case and ensuing neuropsychiatric sequelae. Severe deficiencies in vitamin B12 and folate are linked to anaemia and cognitive impairment since they are essential for healthy brain development. Malabsorption combined with a decrease in oral intake is the most common cause of vitamin B12 insufficiency in elders. Vit B12 deficiency is also more often seen in those receiving proton pump inhibitors, H2 blockers and or metformin in clinical context. Folate deficiency is more commonly seen in nutritional disorders, those with duodenal pathology, patients having chronic haemolytic anaemia, patients receiving antimetabolite agents such as methotrexate. Even in the absence of anaemia, a folate shortage can result in elevated homocysteine levels, which are linked to the pathophysiology of Alzheimer’s disease and vascular disease. Regretfully, metanalyses have not discovered a statistically significant improvement in mood or cognition associated with vitamin B12 or folate replacement. Alcohol misuse is also linked to deficiencies in B12, folate and niancin (vitamin B6). As per naturalistic studies following treatment for a vitamin B12 deficiency, neuropsychiatric symptoms recovery frequently takes longer to manifest (e.g., beginning to improve in around three months and lasting up to a year). Duration of untreated period of deficiency becomes critical as it may determine the irreversibility of the symptoms. Interestingly, some experts have pointed out a period of worsening before clinical improvement during supplementation. A niacin deficiency is also linked to dementia, which is completely reversible once replenished. Intracranial Tumours Prior to twentieth-century imaging, dementia brought on by an undetected brain neoplasm was more typical. Now that neuroimaging techniques have become widely available in clinical practice, it is typically possible to quickly identify the brain lesions that cause dementia. Usually, a diffuse white matter, frontal or right hemisphere process is responsible for a subacute alteration in mentation that affects everyday functioning. Astrocytomas (glioblastomas) and meningiomas with oedema are the most prevalent because of the mass effect and increasing oedema that lead to abnormal mental status. Steroids are usually used to delay the onset of dementia caused by these lesions, which is then treated with surgery, radiation and/or chemotherapy. Other toxic disorders These dementia conditions might reverse with confiscation of the source of exposure, and subsequent clearance of the toxic substance from the body, whether by course of time or via the aid of therapeutic moieties [see Table 1d]. The dementia may reverse partially or completely if the harmful exposure is stopped. Chelation therapy helps speed up recovery from heavy metal poisoning. Sensitivity of drugs may increase (benzodiazepines or narcotics) or decrease (drugs mediated by beta-adrenergic receptors) with age. So, the response in terms of any confusion or memory or cognition in context to any medication can be unpredictable and prompt an investigation into a possible medication reaction. Most of the medications implicated in inducing dementia like those for atopy, upper respiratory infections, urinary incontinence do so via their anti-cholinergic burden. Other group of medications which cause CNS depression and are related to cognitive deficits are benzodiazepines. Traumatic brain injury-related cognitive impairment is described in clinical practice guidelines on TBI.[15] Table 4 lists the various criteria’s and tools to help clinicians to identify and de-prescribe the offending drugs. Again, dementia would significantly improve once the offending agent is stopped.Table 4: Shows Description of criteria/scales/tools to determine safe net of prescribed medications, their anticholinergic and assessment There are and test available for cognitive assessment for adults and shows the and cognitive test available for use in OF POTENTIALLY REVERSIBLE DEMENTIAS Once the suspicion for the cause for dementia a reversible is made on the clinical of the cause is by the of identification of the of the investigation that characterize those conditions is the Tables show the investigations to be for (neuroinfectious) and and disorders. also show the of the particular condition. While toxic conditions are confirmed by no are to diagnose mental and behavioural disorders; however is using the Apnoea index in Intracranial (neurosurgical) disorders, investigations and Intracranial (neuroinfections) disorders, investigations and Systemic (including metabolic/endocrinal) disorders, investigations and autoimmune dementia and analysis for neuroimaging (especially and by are The analysis shows increased white elevated elevated or for can be using available levels of are of has to be looked for shows specific to and may not be Table shows of various for investigations in cases of dementias. These on of various for investigations to identify Most of a is in the clinical course and These are in the causes of dementia. Once the cause is or is the and with Figure 2 shows treatment of various causes of dementia for 2: for to patients with dementias for two most causes that will be by are depressive cognitive disorder and dementia Depressive Cognitive of depressive cognitive disorder both and The of for treatment of depression, the for be for depressive cognitive While treatment with the of have been to be more for depression associated with cognitive These include and has also been to be cognitive agents have also been These include and agents such as and have also been Cognitive agents and other agents are to be used in with brain such as are also in cognitive impairment in While there are on risk of depressive cognitive disorder into dementia, there are of depression to cognitive impairment and dementia. of up to 70% cases with those with depressive symptoms tend to to dementia In this there is a to differentiate with depression and depressive cognitive This is made on the response to treatment. cognitive improvement in depression symptoms, the possibility of a is may not be as volume deficits are also seen in patients with depressive cognitive However, functional have been in depression and from dementia is also an while dementias. We suggest the to to the clinical practice guidelines on of in disorders, in general and cognitive impairment A very from the that disorders, disorder, depression and and disorders, have an increased risk of developing dementia in very large showed that dementia patients have higher risk of disorders both before and after dementia treatment of these disorders with an on recovery is very in the risk of of dementia. cognitive impairment disorders in various clinical practice guidelines in this is considered and to the of disorders. adding cognitive for cognitive impairment in these disorders has an Autoimmune dementia and The treatment of paraneoplastic of ADE on the treatment of the of usually the symptoms of non-paraneoplastic acute treatment is use of of once for or less oral The when there are for use of steroids or of effects to is the use of once for and then for studies have the use of as of effects for these treatment lines has to be prompt and patients treatment is and are the agents of in such as and are also dementia The treatment of ARD is In the ARD has to be differentiated from ARD is with the of treatment has to on it is also to that not all cases of ARD show recovery is is and be that of is essential for this the of of in terms of agents and in the of therapy and other forms of cognitive behavioural be only functional but also structural abnormalities tend to partially with of cognitive impairment associated with alcohol is described in the clinical practice the other dementias that might cognitive impairment related to B12 deficiency, and thyroid Vitamin B12 deficiency there is a not to like in or with a vitamin B12 should treatment. 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