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Look for the “Treatables” among dementias: It is lifesaving: An experience from a tertiary care center in India in the past 5 years

Context: The aim is to awaken our colleagues to these reversible conditions. These are live saving if understood properly are life saving for patients. That is the purpose of this article and discussed in introduction. Aim: The aim of this study is to identify possible treatable causes in patients who present with progressive cognitive decline. These patients can be identified only by high degree of suspicion, thorough clinical examination and appropriate choosing of case-based investigations. This will be highly rewarding to the patients, their family, and to the treating physician. In this article, we are sharing our experience with the treatable dementias identified which were masquerading as degenerative. Settings and Design: Retrospective study. Subjects and Methods: Retrospective study of patients seen by the authors in the past 5 years who had all the mandatory recommended investigation done was included. Patients who qualified for pseudo-dementia and small vessel disease were not included in the analysis. Statistical Analysis Used: Basic statistical elements only were used as cases in each category are small. Results: Of 1105 patients, 92 had confirmed reversible cause. Among the treatable group immune-mediated dementia formed the largest and constituted about 45.6% followed by infections 19.5%, nutritional 15.2%, and rest were by rare conditions such as Whipple's disease, cerebrotendinious xanthamatosis, mitochondrial disorders, primary demyelination, central nervous system (CNS) lymphoma, surgical conditions such as normal pressure hydrocephalus and subdural hematoma. Conclusion: About 12.1% percentage of patients with memory complaint has a reversible cause which when detected early, the quality of life of both the patient and caregiver are significantly improved. Apart from protocol-based categorization of the patients, individualized thorough clinical examinations are mandatory to identify these patients.


INTRODUCTION
Dementing illnesses are of great concern today with an increasing number of people presenting with memory complaint. In spite of continued research, results are not rewarding with reference to the degenerative dementias. [1] However, a proportion of these persons suffer from treatable dementias and every patient presenting with memory complaint should be evaluated for the same. Regular use of rating scales and neuropsychological testing will Journal of Geriatric Mental Health | Volume 6 | Issue 2 | July-December 2019 confirm memory complaint, but only a detailed history and thorough clinical evaluation will bring out the clinical clues regarding treatable dementias, confirming the significance of direct, detailed bed side assessment of every patient. [2] Dementia incidence is estimated to be about 5% in patients above 65 years and 20% in patients above 80 years. The frequency of reversible causes reported is as high as 23%. [3][4][5] The term reversible dementia was introduced in 1980 by the National institute of aging. The article "Fatal to reversible dementias" is a highly sensitizing article in this regard, which highlights the need to look at degeneration mimics. [6] Autoimmune encephalitis, can closely mimic primary mental illness, degenerative dementia, and also Creutzfeldt Jakob disease (CJD) clinically as well as by other tests like electroencephalogram (EEG), but by careful evaluation based on clinical suspicion can be easily distinguished [7] [ Table 1]. In our observation, we found that unexplained Panic, Catatonia, Excessive sleep changes, and delirium are features that help differentiate immune-mediated encephalopathy from degenerative dementias. [8] The next group of treatable causes are infections such as progressive multifocal leukoencephalopathy, human immunodeficiency virus (HIV)-associated dementia, neurosyphilis, Whipple's disease, neurocysticercosis (NCC), chronic bacterial infections, [9,10] neurometabolic diseases like mitochondrial disorders, Hashimoto's encephalopathy, chronic encephalopathy due to renal, hepatic diseases, Wernicke's encephalopathy, prolonged delirium, pseudo dementias, and chronic hyponatremia. Vascular causes include small vessel disease, [11] vasculitis, CADASIL, and toxic and metabolic disorders. Other causes are tumors of the central nervous system (CNS), normal pressure hydrocephalous (NPH) and systemic tumors with paraneoplastic manifestations. Indian studies show infections such as HIV, tuberculosis (TB), NCC, syphilis as important causes. [12] Treatable causes were more in patients under the age of 65 years and degenerative conditions above 65 years of age.
The recommended investigations apart from history and neuropsychological assessment are routine blood and urine, electrocardiogram, EEG, lumbar puncture, screening for infections, vasculitis, autoimmune and paraneoplastic conditions, imaging and brain biopsy if needed. The conditions which qualify for dementia at one time but improve or stabilize during longitudinal follow-up are the classical conditions included in the treatable category. Some useful bedside markers are the presence of skin changes such as ichthyosis, vitiligo, punched out ulcers, knuckle pigmentation, velvety skin, and rain drop pigmentation pointing to specific conditions and also nail changes of lead and arsenic poisoning. [13] History of hypophysitis points to probable sarcoid, IGG4-associated encephalopathy, histiocytosis, and TB. Patients should be evaluated for clinical features of endocrine disease such as hypothyroidism, hypopituitarism, and Addison's disease. Tendon Xanthoma points to specific conditions like cerebrotendinious xanthomatosis (CTX) and joint involvement to SLE (systemic lupus erythematosus). History of chronic diarrhea is clue to coeliac disease, CTX, Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), malabsorption syndromes, and Whipple's disease.

SUBJECTS AND METHODS
This is a retrospective study of patients with memory complaints seen in the past 5 years. Those patients with reversible dementia were evaluated for age, gender, type of dementia, and course of illness.
Those patients who had all the mandatory workup needed for the patients with memory complaint which consists of Hindi Mental status Examination, Geriatric depression scale, everyday abilities Scale for India, Hachinskis ischemic score, blood levels of Vitamin B12, thyroid function test, liver function tests, renal function test, lipid profile, HIV, venereal disease research laboratory (VDRL), magnetic resonance imaging (MRI), EEG, and case-based tests as per indication in individual cases. Those who qualified for depression induced pseudo dementia, vascular cognitive decline due to small vessel disease were not included. Those patients who had qualified for reversible causes of memory impairment were taken for the detailed assessment of the diagnosis, treatment, and follow-up. All patients or care givers have agreed in writing at the time of admission for the use of their data for teaching purpose and other academic use. However, as it is retrospective study, no special consent could be obtained. 1 1 Consent taken from all patients for utilizing their data for scientific purpose.but not taken stating this particular paper

RESULTS
Total number of patients with dementia seen in the last 5 years by the authors is 1105. There were 735 males and 370 females [ Figure 1].

Autoimmune encephalitis
It forms a very important group in this category. The Core symptoms of autoimmune encephalitis resemble mental illness, prion disease as well as dementia. The criteria forautoimmune encephalitis diagnosis are as follows: Sub-acute onset with progression of <3 months, working memory deficits, altered mental status, or psychiatric symptoms and at least one of the following like new focal CNS findings, unexplained seizure disorder, cerebrospinal fuid (CSF) pleocytosis, MRI features suggestive of encephalitis, and reasonable exclusion of alternative causes. [14,15] EEG changes help to establish organicity. [16,17] In this study, NMDA, VGKC, paraneoplastic syndromes were identified as causes of autoimmune encephalitis. All patients diagnosed, received pulse of methylprednisolone 5 g, plasmapharesis monthly for at least for 6 months, and interval therapy with either azathioprine or mycophenolate. Three patients received intravenous ımmunoglobulins.
One patient expired after 3 years of remission, following surgery for fracture hip and he developed super refractory    MRI: T1 and T2 images showed multiple areas of signal changes in the left middle cerebellar peduncle, midbrain, cerebellum, with diffuse cerebral and cerebellar atrophy; creatine peak was seen in the area of signal change. DOPA uptake scan showed poor uptake in putamen. The patient was treated with injection ceftriaxone 2 g twice a day for 2 weeks. Trimethoprim-sulfamethoxazole twice a day, doxycycline 100 mg a day and symptomatic measures. At 3 month follow-up, patient had improvement in speech, swallowing and walking, skin, and gastrointestinal features. One and half years later, patient passed away due to pneumonia.

B-cell lymphoma
A 50-year-old male presented with progressive cognitive decline of 6 months duration. He had headache and later showed bilateral pyramidal signs. His MRI revealed diffuse white matter changes and nodular areas. Histopathology revealed whitematter fragment of neuroparenchyma infiltrated by atypical lymphoid cells. High magnification showed neoplastic lymphoid cells and mitosis. Angiocentric arrangement of tumor cells was also seen. Tumor cells were positive for Leukocyte common antigen -which is a common lymphocyte marker), CD20 (B-cell marker) consistent with B-cell lymphoma. Occasional reactive intermingled lymphocytes were CD3 (T-cell marker) positive. MIB-1 labeling is high (proliferative marker). The stroma showed reactive gliosis on glial fibrillary acidic protein stain [ Figure 4]. The most common malignancies masquerading as rapidly progressive dementia are primary CNS lymphoma and intravascular large B-cell lymphoma, both rare and difficult to diagnose without brain biopsy. [16] Thorough history and radiological features are important for the diagnosis. [17,18] Mitochondrial neurogastrointestinal encephalopathy syndrome MNGIE is an autosomal recessive mitochondrial disease. It presents with polyneuropathy, opthalmoplegia, leukoencephalopathy, and starts in childhood as unexplained intestinal symptoms, and slowly progressive cognitive decline with remissions and exacerbations.
Our patient presented to us at the age of 12 with abdominal pain, diarrhea, and rapid deterioration in cognitive functions. She was investigated for coeliac disease which was noncontributory. MRI showed diffuse white matter changes and genetic evaluation confirmed MNGIE. She showed improvement with mitochondrial cocktail. Later, she was lost for follow-up for several years. She was being treated on several occasions as refractory GIT infection from other centers. She deteriorated severely in her cognitive functions, Motor functions involving both upper motor neuron and lower motor neuron in the form of extensor plantar responses and peripheral neuropathy was noticed. She was treated with mitochondrial cocktail infusion of Vitamin B1 and symptomatic measures and prognosis was explained to family [ Figure 6]. [19] Other mitochondrial diseases present with following clues: Stroke like episodes in a non-territorial fashion with encephalopathy, clues-like short stature, midline lipomas, RP (Retinits Pigmentosa), multiaxial involvement and fever induced exacerbations cross territorial diffusion restricting lesions give the clue to diagnosis.

Paraneoplastic dementias
Paraneoplastic cognitive dysfunction can be due to limbic encephalitis, Nutrional causes and also due to unknown mechanisms. In our group, we found two patients presenting with myeloneuropathy, Knuckle pigmentation, and progressive cognitive decline. Investigation for appetite loss and vomiting revealed Linitis Plastica in one patient and adenocarcinoma stomach in another patient. Cognitive functions improved with Vitamin B12 replacement. A 70-year-old male presented with progressive apathy and recent memory impairment. He in addition had loss of weight about 14 kg in 6 months and had skin tags in both feet. Evaluation showed advanced malignant thymoma, confirming paraneoplastic dementia. [10] A 64-year-old male was diagnosed as progressive supranuclear palsy syndrome in view of pseudobulbar features, apathy, extrapyramidal, and pyramidal signs. However, he had significant weight loss, palatal palsy on the left side and was smoker from the age of twelve. All investigation including whole-body positron emission tomography (PET) was normal. However, anti-Ri antibody was positive, and therefore patient was treated with large volume plasmapharesis.
Patient symptomatically improved and therefore plasmapharesis was repeated as and when patient's neurological features worsened. Two years after the onset of illness, reevaluation with PET scan showed angiosarcomatous deposit in scalp and primary remained undetected [ Figure 7]. [20,21]

Trombone tongue and neurosyphilis
Neurosyphilis commonly presents as asymptomatic, meningeal, vascular, and parenchymatous and mixed forms. It is a well-known imitator from time immemorial and these patients get labeled as psychosis which gave the condition the name the general paralysis of the insane. The points which are clues are persistent dull headache, cutaneous, and general features of syphilis such as Rhagades, leukomelanoderma, pigmented papery scar, lymphadenopathy, Argyl and Robertson Pupil. A typical dyskinesia of the lips and lower facial muscles called as "candy sign." Orofacial chorea, trombone tremor of the tongue, Grandiose delusion, mania cellular CSF and un-patterned cognitive decline withdominant frontal lobe, and subcortical feature scan be seen.
Our patient was a female in late fourth decade who was being treated as BvFTD and was suffering from the lack of initiative, aggression, poor sleep, hallucinations, delusions, wandering behavior, and double incontinence and complete dependence for Activities for daily living (ADL) on family members. Clues for the diagnosis of neurosyphilis was onset with headache and tongue tremor [Video 3]. VDRL was 1:64 titer positive and TPHA was also positive. The patient was treated with Crystalline penicillin G 24 million units intravenously and developed seizures and encephalopathy while on treatment after 4 days. Then, she was treated with ceftriaxone and symptomatic measures. Two years after treatment, her tongue tremors reduced. She became continent and independent in her ADL. She started assisting her family members in house hold activities but continued to be cognitively impaired. [22][23][24] Other infections seen in this group are Toxoplasmosis, NCC as well asTB [ Figure 8].

Cerebrotendinous xanthamatosis
CTX is a rare treatable inborn error of bile acid metabolism. Reported average duration of delay from onset of symptoms to diagnosis is about 16 years as per reports. Patients respond very well to treatment, if diagnosed before significant neurologicaldamage had occurred. Short stature, tendon xanthomas, fractures can be identified by the systematic evaluation of the whole patient. [25] Our patient is a 40-year-old married woman, born out of consanguineous parents with poor scholastic performance compared to her siblings. At the age of 29 years, she underwent both medical and surgical treatment for her swelling over both tendo-achilles without any permanent cure. Later developed hypothyroid state, dysarthria, repeated falls which led to fractures of both bones of forearm, 1 st metatarsals, clavicle, and right femur [ Figure 9]. This was followed by procedural memory problems in ADL, misplacing objects; not mingling with relatives; speaking very few words with low voice volume; unable to remember events which occurred few days ago; not interested in bathing, brushing, and dressing properly, aimless wandering, hoarding, excessive anger, and suspiciousness. At the age of 39, she was passing urine and stools in inappropriate places. With the onset of these symptoms, she was referred as a case of FTD to our center. Examination revealed a short-statured woman with haggard face, goiter, firm swellings over the both tendo-achilles, (about 7-10 cm). She had bilateral cataract and ataxia. HMSE was 18/31. Investigations revealed Vitamin D2 ergocalciferol: 1.27 ng/ml, Vitamin D3 cholecalciferol: 20.64 ng/ml, and total Vitamin D level: 21.9 ng/ml. Parathormone level was 19.7 pg/ml. Cholesterol levels include the following: Total cholesterol-221 mg/dl; high-density lipoprotein -31.1 mg/dl; low-density lipoprotein (LDL)-156 mg/dl; very LDL-34 mg/dl; phosphorus -4.6 mg/dl; calcium -9.67 mg/dl; and homocysteine-7.54 mmol/l. Cholestenol could not be done. EEG showed frontal slowwaves of theta range with a burst of asymmetrical, asynchronous, mid-positive, triphasic waves with anteroposterior gradient. Her MRI showed diffuse atrophy more pronounced over the frontal and temporal regions as well as cerebellar vermis.
X-ray of her bones showed multiple malunited fractures with severe osteopenia. Neuropsychological evaluation showed frontotemporal dysfunction. She was treated with azodeoxycholic acid and at 1-year follow-up she is stable.

Chronic cyto megalo virus encephalitis
A 45-year-old male presented with sub-acute onset of behavioral problem in the form of withdrawn behavior, confusion, excessive sleepiness, and forgetfulness of 9 months duration. Imaging showed bulky temporal lobes and T2 hyperintensities, as the symptoms were slowly progressive, possibility of mass lesion was considered and biopsy was done. Brain Biopsy showed meningeal perivascular inflammation with microglial nodules which were positive for T cell and macrophage markers [ Figure 10]. Neuronophagia characterized by T lymphocytes attacking infected neurons was seen. CMV IgG and IgM were significantly elevated in serum. Patient was treated with antiviral agent but developed status epilepticus and succumbed 6 months later. Auto immune dementias causing false-positive elevation of Measles antibody is reported. [26]

Nutritional causes
The most common cause in this group are related to Vitamin B12 deficiency who present with skin changes in the form of vitiligo, knuckle pigmentation, beefy tongue, peripheral neuropathy, frontal and temporal lobe dysfunction and myelopathy. Of 13 patients with Vitamin B12 deficiency induced dementia, 2 patients had evidenced of carcinoma stomach and 7 patients are positive for parietal cell antibody and the rest showed chronic gastritis. Myelopathy and Neuropathy was seen in 4 of the patients.

Pellagra
A 29-year-old male chronic alcoholic presented with rapidly progressive dementia with features of frontal and temporal lobe involvement. On examination, the classical velvety skin appearance of pellagra was seen with peripheral neuropathy. All patients' cognitive symptoms improved with Vitamin supplementation over a period of 3 months [ Figure 11]. Table 2 shows the general prevalence of the reversible causes.

CONCLUSION
In this study of patients seen by the team of authors, 12% of patients with cognitive complaint had a reversible cause. Therefore, it is better to rule out reversible causes before concluding patients with memory complaints as suffering from irreversible causes. Detailed history and clinical examination greatly assists in clinching the diagnosis and aids in planning treatment. Protocol-based assessment helps to confirm the presence or absence of cognitive dysfunction. Mandatory recommended laboratory tests only exclude the conditions included in that category and therefore have to be redesigned. There is no substitute for the time spent at the bedside in history taking and complete examination of the patient.

Discussion on algorithm [Flow chart 1]
All patients who are found to have memory complaint on screening should be categorized as long duration when the onset is vague and usually several months. They are mostly degenerative. Short duration ones with a fairly well-defined onset are the patients who need to be analyses for treatable cause. If they have features of raised intracranial pressure they belong to space occupying lesions. If not look for features of other parts of nervous system involvement in addition to cortex which points to vascular, infective, traumatic, or autoimmune causes. İf the disease is confined to cortex rapid presentation of degeneration is still a possibility in addition to metabolic, toxic, nutritional, and    The stroma showed reactive gliosis on GFAP stain [ Figure 4] The commonest malignancies masquerading as rapidlyprogressive dementia are primary CNS lymphoma and intravascular large B-cell lymphoma, bothrare and difficult to diagnose without brain biopsy. [16] Thorough history and radiological features are important for diagnosis [17,18]  Contd... She became continent and independent in her ADL. She started assisting her family members in house hold activities but continued to be cognitively impaired [22,23] Journal of Geriatric Mental Health | Volume 6 | Issue 2 | July-December 2019  autoimmune causes. Features of hypophysitis are seen in TB, Sarcoid, IGG4-associated syndrome, histiocytosis, etc., New-onset psychosis strongly raises suspicion of SLE and autoimmune causes. Gastrointestinal symptoms are seen in CTX, Whipples disease, mitochondrial disease, celiac, and nutrional disorders. Skin, hair, nail features point to nutrional, toxic, endocrine, vasculitis causes. This algorithm will be an easy bedside reference tool for treating doctors.
This is only a descriptive study of our patients. Long-term outcomes, detailed treatment given are not discussed as most patients are in varying stages of treatment and could not be fully evaluated.