Journal of Neurological Sciences 153 (1998) 172181

Treatable and reversible dementias: an update

Carolina Piccini*, Laura Bracco, Luigi Amaducci
Department of Neurological and Psychiatric Sciences, University of Florence, Policlinico di Careggi, 85 viale Morgagni, 50134 Florence, Italy

Abstract The ever greater emphasis on the application of a standard work-up in the clinical diagnosis of dementia and Alzheimers Disease (AD) in particular has made it easier to identify potentially treatable and / or reversible cases. The aim of this paper is to update the issue of treatable and reversible dementias. 1998 Elsevier Science B.V. Keywords: Dementia; Treatable; Reversible; Update

1. Introduction Given improving life expectancy, demographic trends make dementias a growing public health problem in developed countries with catastrophic anticipation for the future. Since the beginning of the seventies greater attention has been paid to the possibility of identifying potentially treatable and / or reversible dementias (Marsden and Harrison, 1972; Cummings et al., 1980; NIH task force, 1980; Consensus Conference, 1987; Canadian Consensus, 1991). The aim of this paper is to update new acquisitions on treatable and / or reversible dementia and to verify how they have modied the approach to the problem. One of the pioneer studies on reversible dementia has been that of Marsden and Harrison (1972; see note): among 106 patients with a presumptive diagnosis of dementia, fteen did not show any evidence of intellectual deterioration, being affected by some other illness (depression, drug intoxication or confusional state), while twenty-one of the demented patients sorted a diagnosis of conditions amenable to treatment. The Authors rst highlighted the problem of an accurate evaluation of patients in order to identify dementia cases suitable for treatment as well as not true demented cases (i.e. depression or drug intoxication).

1.1. Dementia diagnosis

Dementia is a clinical syndrome that can be produced by
*Corresponding author. Tel.: 139 55 415044; fax: 139 55 413603. 0022-510X / 98 / $19.00 1998 Elsevier Science B.V. All rights reserved. PII S0022-510X( 97 )00289-X

numerous pathological states that affect the brain. Given its syndromic nature, dementia per se does not indicate a particular disease; hence the relevance of an accurate and effective work-up in the diagnosis in order to identify all possibly treatable and reversible cases. The formulation and subsequent revision of diagnostic guidelines (DSMIV, 1994) has made possible a greater consensus in the diagnosis of dementia and especially of Alzheimers Disease (McKhann et al., 1984) reducing the number of cases of misdiagnosis. Similarly, the introduction of neuroimaging techniques has made promptly detectable some of the potentially reversible and treatable cases - i.e. brain tumours, subdural haematomas, normal pressure hydrocephalus (NPH) etc. Once the presence of dementia has been stated, the next step is to establish the presence of a potentially reversible dementia and, if any, to set an appropriate treatment. On this basis, it is now generally accepted that in management of dementia the following investigations are indicated: routine testing of haematology and biochemistry including treponemal serology, thyroid function, vitamin B12 and red cell folate , chest radiograph and neuroimaging. Brain-CT and MR scans allow us to exclude space occupying lesions and hydrocephalus, and may also indicate white matter changes associated with demyelinization or vascular disease. Specic blood tests such as screening for metabolic disorders (i.e. Wilsons Disease, metachromatic leucodistrophy and GM2 gangliosides) may be useful in selected cases. In young patients CSF examination - to exclude inammatory disorders or vasculitis as well as testing for HIV should always be considered

C. Piccini et al. / Journal of Neurological Sciences 153 (1998) 172 181

173

(Practice parameter for diagnosis, 1994; Rossor, 1994; Corey-Bloom et al., 1995).

Table 1 Factors affecting the reported decrease of reversible dementias at the level of the work-up Variables Diagnosis Diagnostic criteria, neuroimaging, referral system, setting, laboratory testing. Longitudinal evaluation, length of follow-up, comorbidity. Standardized assessment of cognitive and functional impairment.

1.2. Treatable and reversible dementias

Highly variable percentages of reversible cases have been reported in the literature, ranging from 1530% (Larson et al., 1984; Barry and Moskowitz, 1988) to values recently referred of 110% (Clareld, 1988, 1995; Arnold and Kumar, 1993; Weytingh et al., 1995). The relevant drop of percentages of reported reversible dementias may be mostly due to the fact that the clinical pattern of dementia is now better known. The diagnosis of dementia is rst of all based on clinical ndings; in fact, revising many of the reported reversible dementia cases, we could shift the diagnosis from dementia to conditions such as delirium by means of the clinical history (i.e. short length of illness before observation, abrupt onset, uctuations of symptomatology etc.), presenting symptomatology and neurological examination. On this basis, a debated point has been the non-reliability of terminology as suggested by Maletta (1990). A confusing labelling of dementing illness has been applied to different conditions, and denitions of treatable dementias appear not to be consistent from study to study. Cases due to NPH, hypothyroidism or vitamin B12 deciency appear to be more appropriately and clearly forms of dementia (secondary dementias), while pseudodementia as well as transient and abrupt onset conditions (i.e. drug intoxication) may or may not be considered dementia on the basis of the clinical patterns and of the diagnostic ability of the physician. The strict application of the standard workup is probably the biggest reason why the frequency of the treatable reversible dementias has declined allowing the early identication and treatment of reversible conditions; nevertheless methodological features of research may also have affected the reported rate of reversible dementias. During the last years, the setting of studies has shifted from in-patients to out-patients populations; reversibility has been evaluated with longitudinal follow-up rather than within cross-sectional studies; standardized and comprehensive neuropsychological testing has been introduced, instead of a subjective clinical judgment to assess the course of cognitive impairment; comorbity has been taken in greater consideration (Reier and Larson, 1988); and, nally, the increasing of the elderly population may have modied the relative percentages of reversible cases in respect to degenerative forms such as Alzheimers Disease (Friedland, 1993). Variables affecting the rates of reversible dementias reported in the literature are listed in Table 1.

Course Outcome evaluation

Many studies have been devoted to verify the incidence / prevalence of reversible dementia and the true reversibility of such cases (Larson et al., 1984; Clareld, 1988). Nevertheless nal conclusions are made difcult because of the poor comparability of the original research in terms of differences in sample size, length of follow-up, setting, referral basis, completeness of work-up and evaluation of treatment efcacy. Clareld, selecting eleven studies mostly on the basis of length of observation, found that only 11% of cases truly reversed either partly (8%) or fully (3%) (Clareld, 1988). This percentage falls at the lower end of the range usually supplied for the proportion of dementias thought to be reversible (Barry and Moskowitz, 1988) but at the upper end in the new data (Weytingh et al., 1995). The Author concludes that reversible dementias are exceedingly rare (Clareld, 1995). Nevertheless, Friedland and Hedera believe such a conclusion to bee too drastic as it does not reect the true prevalence of treatable dementia: incidence of treatable dementia in the community is likely to be higher than that reported by prevalence studies because of the relatively short duration of the illness when treated (and reversed) and since many cases may be identied and treated before they reach referral centres (Friedland, 1993; Friedland and Hedera, 1995). Furthermore, many of the studies omit reporting the age of the study population reducing the relevance of referred data: in fact, the advanced age of the population in study would cause a relatively lower occurrence of treatable dementia because of the higher prevalence of Alzheimers Disease in the very old, as in Skoog et al. (Skoog et al., 1993). Finally, we should bear in mind that the greater application of laboratory tests to clarify the diagnosis increases the possibility of nding values out of range as incidental data.

1.4. Classication
Taking into account the previous considerations (Maletta, 1990) reversible and treatable dementias can be sorted substantially into the three groups displayed in Table 2. The rst is that of dementia secondary to specic disorders, either neurological or systemic; the second refers to more acute conditions associated with alteration in alert-

1.3. True reversibility?

Once the presence of reversible dementia is recognized the further question is whether or not it truly reverses.

174

C. Piccini et al. / Journal of Neurological Sciences 153 (1998) 172 181

Table 2 Possible treatable and reversible dementias listed according to Malettas classication Secondary dementias Associated to neurological disorders Structural lesions

Normal pressure hydrocephalus, subdural haematomas, brain tumors, postconcussion syndrome.

Associated to systemic disorders Nutritional disorders Endocrin disorders

Vitamin B12 deciency, folate deciency, pellagra, thiamina deciency. Hypothyroidism, hyperthyroidism, hypoparathyroidism, adrenal and pituitary disorders, insulinoma. Systemic lupus erythematosus, vasculitis, sarcoidosis. Chronic meningitis (Tbc, fungal, parasitic), brain abscess, neurolue, Whipple disease, Lyme disease, AIDS. Primary alcoholic dementia. Chronic obstructive respiratory disorders, sleep apnea syndrome, sleep deprivation, lymbic encephalitis, radiation, hypoxia, dialysis. Drug intoxication (minor and major tranquilizers, antidepressant, narcotic analgesis, antihypertensives, cimetidina, digoxina...) Electrolitic alterations. Chemical poisoning. Depression, late-onset schizofrenia, mania delusional disorders.

Collagen / vascular disorders Infectious diseases

Alcoholic dementia Miscellaneous

Drug intoxication and metabolic disorders

Dementia due to psychiatric disorders

ness, making more questionable the diagnosis of dementia on the basis of international diagnostic criteria; nally, the third is that of so-called pseudodementias referring to psychiatric disorders, especially depression, that may appear associated with a global cognitive impairment. Nevertheless the relationship between depression and dementia has been recently further investigated, sorting different plausible hypotheses (see below). While Table 2 attempts to display an exhaustive list of possible reversibletreatable dementias our attention will be focused on emerging ndings of the latest years in terms of relevance and true reversibility of known reversible dementias as well as on the appearance of new entities.

2. Secondary dementias

2.1. Structural lesions of CNS 2.1.1. Normal pressure hydrocephalus The normal pressure hydrocephalus (NPH) is a potentially treatable dementia, clinically characterized by the presence of gait apraxia, urinary incontinence and progressive dementia (Hakims triad). The nal diagnosis is based

on the presence of at least two of NPH symptoms, signicant ventricular enlargement on brain CT, and hydrodynamic criteria (Borgesen and Gierris, 1982). Its diagnosis on clinical and neuroradiological ndings is made difcult because of the wide overlap with dementia of other types such as Alzheimers Disease. Although responsive to repeated lumbar punctures, NPH cases have reported an high variability in rate of success of shunt surgery. Selection of cases who would benet from shunting has always been difcult, and no clinical or brain imaging criteria have been entirely satisfactory (Clareld, 1989; Friedland, 1989). Successful shunting has been reported in 2580% of cases but such a response should be reviewed taking into account that there are 3040% with post-operative complications (anaesthetic complications, infections, intracranial haematomas and shunt malfunction) (Vanneste et al., 1992; Waldemar et al., 1993). The problem of prediction of surgical outcome has been tackled by using clinical signs and symptoms (Jacobs et al., 1976; Larsson et al., 1991, see note), hydrodynamic criteria (Borgesen et al., 1979; Sand et al., 1994), neuroimaging features (Bradley et al., 1996) as well as functional features in terms of cerebral blood ow and metabolism (Brooks et al., 1986; Graff-Radford et al., 1987; Waldemar et al., 1993).

C. Piccini et al. / Journal of Neurological Sciences 153 (1998) 172 181

175

The introduction of neuroimaging techniques such as brain-MR has shown greater promise toward this end. Positive CSF ow void study ndings on proton density weighted images appear to be associated with an increased probability of improving after shunt: positive predictive value was 100%, while the negative predictive value was 50% (Bradley et al., 1996). Functional brain studies evaluating cerebral ow and metabolism (SPECT / PET) have been performed for diagnosing and studying the pathophysiology of NPH (Brooks et al., 1986; Waldemar et al., 1993; Tedeschi et al., 1995). Particular attention has been devoted to the possibility of identifying characteristic SPECT / PET patterns as possible prognostic factors of shunting response (Graff-Radford et al., 1987). Different patterns of functional abnormalities have been reported from different studies: globally diminished glucose metabolism (Jagust et al., 1985; Brooks et al., 1986), subcortical low ow region associated with focal cortical ow decits (Waldemar et al., 1993) or patterns of impairment differing from patient to patient (Tedeschi et al., 1995). Such a metabolic heterogeneity may be due to the coexistence of different underlying degenerative process as displayed by histopathological ndings in studies performing shunt and biopsy but it is anyway observed also in cases with true idiopathic NPH (Tedeschi et al., 1995). It is noteworthy that some of the NPH cases with associated pathological features of different degenerative disorders were anyway positive responders to shunt operation. The acquired data unfortunately do not allow the identication of clear useful criteria for selecting patients with NPH to undergo shunting. The whole process of clinical evaluation, neuroimaging scanning and hydrodynamic tests (a lumbar infusion test, a CSF tap-test) should be routinely applied in pre-operative investigations. Recent research emphasizes the need to reconsider the NPH syndrome and its pathogenesis in order to achieve a better understanding of the disease.

or MRI-scanning. In some cases neuroimaging may show small tumours as incidental ndings and no surgery is required. The suspicion of a subdural haematoma may arise from a history of cranial trauma, often unreported because of possible memory decit of the subject. Elderly subjects may be particularly susceptible to such a condition because of cortical atrophy or concomitant illnesses. It should be remembered that they are commonly bilateral, lacking focal signs. Surgical treatment of tumours as well as evacuation of subdural haematomas can reverse the dementia syndrome, especially when the symptomatology has been of short length and was not superimposed to a degenerative disease.

2.2. Systemic disorders 2.2.1. Vitamin B12 deciency The rst description of reversible dementias is that of Thomas Addison in 1858 related to the observation that in patients with pernicious anaemia the mind occasionally wanders. At present it is well known that cobalamin deciency may also present as a neurological disorder in the absence of anaemia or macrocytosis (Lindenbaum et al., 1988, see note). Thus determination of vitamin B12 and red cell folate levels is generally recommended as routine investigations in the screening of demented patients. A review of behavioural abnormalities associated with vitamin B12 deciency suggests that dementia appear to be a quite uncommon manifestation of such a decit, while hypoactive delirium, psychomotor retardation, confusion, memory loss and depression are the more reported symptoms (Hector and Burton, 1988). Many papers have discussed the true responsibility of cobalamin deciency in the etiology of dementia (Teunisse et al., 1996). The high incidence of vitamin B12 deciency in the elderly population (Pennypacker et al., 1992) suggests that subnormal vitamin B12 level could be a coincidental nding, as indicated also by the frequent lack of responsiveness to replacement therapy. The effect of cobalamin repletion has been studied by Martin et al. (1992). The Authors performed an open trial of parenteral cobalamin therapy on patients with cognitive impairment and low serum cobalamin levels: they followed-up cases sufciently (at least six months) to allow a potential slow recovery to emerge, evaluating mental status improvement through objective neuropsychological testing. The only positive predictive factor for recovery (partial) was a short duration of cognitive symptoms before therapy (less than one year) suggesting a time-limited window of opportunity for effective intervention. Nevertheless, other authors believe that one year duration of symptoms should not be an absolute guide in deciding whether or not to treat cobalamin deciency (ONeill and Barber, 1993). In general, cobalamin repletion shows a slight improvement

2.1.2. Mass lesions Space occupying lesions such as subdural haematoma and frontal and temporal tumours may present with mental alterations including apathy, emotional lability, forgetfulness, behavioural disturbances as well as more specic cognitive decits. Such a clinical pattern may lead to a dementia diagnosis. Tumours appear to be reported in 1.5% of dementia cases (Clareld, 1988) and in 6.5% of cases with fully or partially reversed dementia (Weytingh et al., 1995). Such rates are largely affected by the referral lter bias (i.e. cases referring to a Memory Clinic). The rather slow growth of meningiomas make such tumours more plausible causes of a dementia syndrome, although different sorts have been described, e.g. prolactinoma (Brisman et al., 1993). The presence of focal signs may give raise to diagnostic doubts and the diagnosis may be readily made by brain CT

176

C. Piccini et al. / Journal of Neurological Sciences 153 (1998) 172 181

rather than a full recovery of symptoms (Larson et al., 1985; ONeill and Barber, 1993) with very few cases reported in the literature (Martin et al., 1992). Unfortunately most of the studies are not valid insofar as they are lacking a standardized evaluation of cognitive change after replacement therapy. A recent prospective longitudinal study has been conducted on effects of replacement therapy (Teunisse et al., 1996). Among 170 demented subjects, 26 cases with subnormal serum levels of vitamin B12 have been treated with cobalamin supplementation for six months and evaluated by a standardized and comprehensive assessment of dementia severity. Authors concluded that when the effects of replacement therapy were evaluated in a standardized and comprehensive way, no indications were found for the reversibility of dementia in patients with subnormal serum vitamin B12 levels. In conclusion subnormal levels of serum vitamin B12 results to be more often an incidental nding rather than a true cause of dementia.

selected cases (Stuerenburg et al., 1996). Intracerebral calcications and hyperostosis frontalis interna in demented patients may suggest an accurate search for dysparathyroidism (El Maghraoui et al., 1995). Described cases presented a good response to treatment.

2.3. Endocrine disorders 2.3.1. Thyroid and parathyroid disfunctions Thyroid diseases are known to increase in the elderly population, in particular with an high percentage of subclinical thyroid dysfunctions. Hypothyroidism may be a reversible cause of dementia (Cummings et al., 1980) while hyperthyroidism mostly appears as psychomotor agitation. Only very few cases due to hypothyroidism have been reported in the literature (Clarnette and Patterson, 1994), most displaying Alzheimers Disease when followed longitudinally (Larson et al., 1984) and with only few cases reported as completely reversed in the review of Clareld (Clareld, 1988). Such a rare occurrence of thyroid dysfunction in dementia etiology could also reect the improved diagnostic ability of general physicians. In conclusion, while conrming the need to perform thyroid screening within the work-up of dementia it appears that dementia cases due to thyroid disfunctions are rather uncommon and such a dysfunction does not exclude an underlining degenerative disorder. Idiopatic hypoparathyroidism is a rare metabolic disorder with neurological symptoms and signs such as epileptic seizures, extrapiramidal signs, papilloedema, calcications of the basal ganglia and alteration of mental status, that may be treated with 1,25-dihydroxy-cholecalciferol. The presence of dementia may generally appear as the illness progresses, while it may seldom be one of the presenting symptoms. This possibility has alerted clinicians to include hypocalcemia within the laboratory testing for the differential diagnosis of dementia (Hossain, 1970; Eraut, 1974; Slyter, 1979). A case of reversible dementia in idiopatic hypoparathyroidism associated with normocalcemia has been described, suggesting the study of serum levels of parathyroid hormone and 1,25-hydroxycholocalciferol in

2.3.2. Estrogen deciency At present, the physiological estrogen-decient state of post menopausal women appear to be a matter of great interest since it has been suspected to contribute to neurodegenerative changes associated with aging and dementia. Several studies have supported the idea that in such a condition, administration of estrogens may modify the mood as well as cognitive functions. In particular, a benecial role of estrogen replacement therapy (ERT) in preventing and delaying the onset of dementia has been suggested on the basis of an inverse relationship of dose and duration of therapy with diagnosis (Paganini-Hill and Henderson, 1994, 1996; Waring et al., 1997), although other studies do not conrm such ndings (Brenner et al., 1994; Graves et al., 1990). The rationale of such an association could be related to several observations: the effect of estrogen on neuronal survival and dendritic growth, especially in cerebral regions such as hippocampus and amygdala selectively affected in dementia (Birge, 1996), their inuence on the metabolism of amyloid precursor protein (Jaffe et al., 1994) and their ability to increase systemic as well as cerebral blood ow (Ohkura et al., 1995). Furthermore the potential neurotrophic and neuroprotective actions of estrogens on cholinergic neurons as well as their regulation of receptors and interaction with other neurotransmitters could explain their effect in enhancing response to cholinesterase inhibitors (Schneider et al., 1996) resulting from preliminary trials. An extensive review by Birge (1996) suggest that the effects of estrogen in healthy postmenopausal women remains controversial. Cognitive improvement may be difcult to disentangle from affective changes and at present ERT appears to limit its effect to selected cognitive domains such as verbal memory (Kampen and Sherwin, 1994). Nevertheless clinical trials of estrogens are justied to adequately weigh the risk and benets of ERT for the treatment and prevention of dementia. 2.4. Collagen diseases and vasculitis
Greater attention has been devoted to the presence of psychiatric disorders and cognitive impairment in collagen as well as vascular diseases. In patients affected by systemic lupus erythematosus (SLE) percentages of cognitive impairment ranging from 20 to 80% have been reported (Hay, 1994); likewise cerebral involvement appearing as mild cognitive decits have been described in vasculitis as either systemic or isolated to the CNS. Such an emphasis on cognitive impairment is partly due to the change in the course and management of SLE

C. Piccini et al. / Journal of Neurological Sciences 153 (1998) 172 181

177

patients. The introduction of immunosuppressive therapy, dialysis and renal transplantation has deeply modied the natural history of the disease, displaying the need for also taking into greater consideration the potential involvement of the CNS in the absence of clear morphological ndings at the brain-CT or MR. Dementia has rarely been reported as the rst manifestation of diseases such as SLE (Manto et al., 1993), primary Sjiogrens syndrome (Caselli et al., 1991) and giant cell (temporal) arteritis (Caselli, 1990). All the described cases were responsive to oral corticosteroids. Likewise, a case of a primary antiphospholipid syndrome with dementia was responsive to immunosuppressive therapy (Van Horn et al., 1996). A young age at onset as well as increased CSF protein may lead to a systematic investigation in order to search for collagen disease or cerebral vasculitis.

on bone marrow, and by poor penetration of the drug into the CNS. Nevertheless, HIV-1-associated dementia complex is not invariably progressive: it may improve with medical therapy or it may worsen abruptly in the presence of a severe metabolic disorder, such as hypoxemia from pneumonia (Janssen et al., 1991).

2.6. Alcoholic dementia

A deterioration of cognitive performance as well as of behaviour and personality has been reported as a consequence of long-lasting alcohol abuse. Nevertheless, a dementia attributable to a direct toxic effect of alcohol on the brain remains questionable while there is evidence of several secondary alcoholic dementias (Wernicke-Korsakoff; Marchiafava-Bignami, pellagrous encephalopathy and acquired hepatocerebral degeneration), due to factors related to alcohol abuse. The latter conditions have specic clinical patterns of presentations as well as radiologic and pathologic features, and occur also in non-alcoholics (Victor, 1994). Extensive studies of clinical-neuropathological correlations found that all alcoholics labelled as alcoholic dementia turned out to be Wernicke-Korsakoff disease, while no cases attributable only to cerebral atrophy were found (Torvik et al., 1982). The conclusion is that alcoholic dementia lacks distinctive pathology, making it difcult to be considered as an autonomous entity (Victor, 1994). Previous CT studies have evaluated the presence of brain atrophy and its reversibility in relation to withdrawal of alcohol (Artman et al., 1981). On one hand, the relation between atrophy and cognitive performance is not clear and the nature of atrophy reversibility is not understood; on the other hand reversibility with abstinence points to the possibility that cognitive impairment may be due to non structural-changes similar to that reported in nutritional and metabolic disorders. It is noteworthy that the DSM-IV lists an Alcohol-Induced Persisting Dementia no more displaying an alcoholic dementia. Abstinence and nutritious diet may improve the patients condition but dementia usually remains unresolved.

2.5. Infectious diseases

Although chronic infectious diseases (TBC, lue, toxoplasmosis, criptococcosis) have always been listed as possible cause of dementia, they have drawn new attention since the increased frequency of immunocompromise due to acquired immunodeciency syndrome (AIDS) as well as that due to immunosuppressive or steroids therapy. One of the newest arrivals within the chapter of reversible dementias has been that of the acquired immunodeciency syndrome (AIDS). AIDS has been associated with a variety of neurological complications due to opportunistic infections or to a primary infection of CNS mediated by human immunodeciency virus (HIV) (HIV encephalitis). The AIDS dementia complex (Navia et al., 1986) or, as more recently named, the human immunodeciency virus type 1 (HIV-1)- associated dementia complex (Janssen et al., 1991) is described in 20 to 30% of terminally ill patients with AIDS. Recent results (Whiley and Achim, 1994) show that all demented AIDS patients have severe HIV encephalitis while coinfections with cytomegalovirus or the presence of multinucleated giants cells are not so strongly associated with dementia. Data argue for a strong correlation between HIV encephalitis intra CNS HIV burden - and the clinical symptomatology of dementia. The hypothesis that the presence of HIV would precede the onset of dementia by a long time suggests that an aggressive antiretroviral therapy in patients with late-stage disease may inhibit development of HIV encephalitis (Whiley and Achim, 1995). Although the pathogenesis of the process causing dementia is as yet poorly understood, some new data point to a possible role of macrophages and dendritic cells as critical for the development of HIV encephalopathy (Balter, 1996; Pulliam et al., 1997); it implies that drug therapy needs to be tailored to such a site of infection. At present, the efcacy of treatment is anyway limited by toxic effects, especially

2.7. Miscellaneous
Many conditions have been reported as possible causes for dementia. Nevertheless, while some (i.e. dementia due to radiation, dialysis) may be plausible from cases history others should be searched for, such as limbic encephalitis. Limbic encephalitis is a paraneoplastic syndrome that may present as a slowly progressive cognitive impairment. The detection of antineuronal antibodies is highly specic for paraneoplastic syndrome (Anderson et al., 1988) and cerebral MR scanning may show an increased signal intensity on T2-weighted images in temporal lobes (Dirr et al., 1990). The detection of the occult carcinoma respon-

178

C. Piccini et al. / Journal of Neurological Sciences 153 (1998) 172 181

sible for the paraneoplastic disorder may reverse the neurologic syndrome, emphasizing the need for an early diagnosis (Hector and Burton, 1988). Recent studies on disturbances of breathing during sleep report that snoring and breathing stoppage in elderly were risk factors for cognitive impairment (Dehalberto et al., 1996). Deprivation of sleep (Kelly and Feigenbaum, 1992) as well as haemodinamic and / or hypoxic changes during sleep may affect cognitive performance resulting as possible causes of cognitive impairment and dementia (Bliwise, 1996). Case reports suggest that treatment of the underlying condition may reverse dementia.

4. Dementia due to psychiatric disorders

4.1. Pseudodementia
A percentage of cases referred to dementia clinics have a major psychiatric disorder, mostly depression, that may manifest with the clinical pattern of a dementia syndrome. The term pseudodementia has been used in the past to describe such cases in which features suggesting dementia are associated with a non-organic psychiatric disorder (Kiloh, 1961; Wells, 1979). Some studies have been devoted to identify clinical and neuropsychological features useful in the differential diagnosis of pseudodementia from dementia. History of affective disorders, persistently depressed or dysphoric mood, poor appetite, weight loss and hopelessness have been listed as markers of a pseudodementia (Rabins et al., 1984). The onset can be dated with some precision and the duration of symptoms before referral appears to be short (Wells, 1979). The depressive syndrome in such cases is generally severe and characterized by psychomotor retardation, hopelessness, anxiety, apathy and delusions (Reynolds et al., 1988). As far as the cognitive prole is concerned, memory appears the cognitive function mostly affected without distinction between recent and remote memory, with memory gaps and variable performances on tasks of similar difculty (Wells, 1979). Nevertheless both the clinical examination and the cognitive prole do not allow a clear cut between the two conditions and very often only the response to an effective antidepressant treatment may help the diagnosis. Longitudinal studies have sought to evaluate the evolution of patients diagnosed as having pseudodementia in terms of development of an irreversible dementia but they have reported controversial results: pseudodemented patients appear to include cases in the early stage of a dementing disorder in some studies (Alexopolous et al., 1993), while in others such a diagnosis appears consistent after a twelve years follow up (Sachdev et al., 1990). The use of the term pseudodementia appears controversial at present. In fact the ever greater attention to the clinical pattern of presentation and early symptomatology of dementia, especially Alzheimers disease, has emphasized the complexity of the relation between depression and dementia. At least four different conditions may be listed: the association of the two different diseases; depression as a reaction to the awareness of cognitive decits; both depression and cognitive impairment as markers of the involvement of a single cerebral region; or, nally, cognitive impairment as the manifestation of the mood disorder itself (Kramer and Reier, 1992). In any case the presence of depressive symptoms should be treated by an antidepressant therapy, trying to avoid tricyclic antidepressants since their anticholinergic side effects could further impair memory performance. An antidepressant therapy may help both the diagnosis of

3. Cognitive impairment due to drug intoxication or metabolic disorders Drug induced cognitive impairment has been recognized as one of the rst causes of reversible dementias in the past (NIH task force, 1980; Larson et al., 1984, 1986, 1987). In particular, elderly subjects appear to be especially susceptible to drug toxicity because of lowering of hepatic and renal functions, increase in fat / lean body ratio as well as polypharmacy due to comorbidity. Drugs that more frequently resulted to produce a dementia syndrome are: benzodiazepins, barbiturates, antidepressants, analgesics, hypotensive agents (propanolol), cimetidin, insulin. Short duration of symptoms, history of polypharmacy and the presence of a relatively mild cognitive impairment may help the diagnosis; discontinuation of drugs should improve the mental status. Although drug induced cognitive impairment is one of the most reversible and treatable cause of dementia, yet the possibility of drug toxicity in dementia patients should also be considered. Thus, in drug toxicity the main points are to differentiate delirium from dementia, to establish whether drugs have caused or exacerbated dementia giving rise to partial or full possibility of resolution of the symptomatology. Since depression and drug-intoxication often fail to meet modern criteria for dementia, no cases of drug intoxication have been reported in recent research (Walstra et al., 1997). Nevertheless it does not diminish the need of looking for these cases in the future since they appear the most responsive to treatment as reported in the review of Weytingh et al., where 13 out of 31 cases showed a full resolution of symptoms after drug discontinuation (Weytingh et al., 1995). More appropriate and careful prescribing and monitoring of drugs in elderly and demented patients could prevent such conditions. Systemic diseases like electrolyte disturbances as well as hepatic, renal and pulmonary failure may also cause transient impairment of cognition that can appear as dementia syndrome. Normal cognitive abilities should be restored by treating the underlying disease (Cummings et al., 1980).

C. Piccini et al. / Journal of Neurological Sciences 153 (1998) 172 181

179

depressive pseudodementia or improve depressive symptoms in the early phase of Alzheimers disease (Rossor, 1994). Late onset schizophrenia, anxiety states, atypical psychosis, Gansers syndrome as well as other less common psychiatric disorders have been rarely reported to simulate dementia.

5. Conclusions Checking the history of reversible and treatable dementia two main conclusions come to light. The rst is that the large adoption of standardized diagnostic guidelines improved the accuracy of dementia diagnosis, promptly identifying other disorders at the clinical level of the work-up; the second is that true reversibility appears to be quite questionable, both because of possible association of treatable disorders with degenerative dementias as well as for the possibility that they give rise to structural changes not amenable for treatment. Reversible dementia appears to be quite rare with few specic and effective treatments. Over the past twenty years attention has been shifted to preventable and treatable aspects of dementia either in reversible or irreversible cases. Treatable components such as depression, anxiety, behavioural and sleep disturbances may be successfully tackled by means of symptomatic therapy, although this does not appear effective in modifying the level of cognitive impairment (Rossor, 1994). Enhancing cholinergic transmission is an other symptomatic treatment that has been tried in the latest years (Farlow et al., 1992). Furthermore, even if reversible cases are not found, patients with dementia may present serious coexisting pathologies amenable to treatment. Therapy of excessive disability due to comorbidity is necessary to improve the patient quality of life, although not reversing the dementia syndrome (Reier and Larson, 1988). In the past, the issue of identifying reversible and treatable cases has been faced considering the need of an effective and efcient use of resources (Gordon and Freedman, 1990). Research tried to dene a more rational investigative approach in order to avoid an over-investigation of primary dementia cases. Nevertheless, at present, the greater effort of research is focused on the development of new therapies able to stop and even reverse the degenerative process. Therefore an extensive investigation of each demented patient is hopefully required.

References
Alexopolous, G.S., Meyers, B.S., Young, R.C., Mattis, S., Kakuma, T., 1993. The course of geriatric depression with reversible dementia: a controlled study. Am. J. Psychiatry 150, 16931699. Anderson, M.B., Rosenblum, M.K., Graus, F., Wiley, R.G., Posner, J.B.,

1988. Autoantibodies in paraneoplastic syndromes associated with small-cell lung cancer. Neurology 38, 13911398. Arnold, S.E., Kumar, A., 1993. Reversible dementias. Med. Clin. North Am. 77, 215230. Artman, H., Gall, M.V., Hacker, H., Herrlich, J., 1981. Reversible enlargement of cerebro-spinal uid spaces in chronic alcoholics. Am. J. Neuroradiol. 2, 2327. Balter, M., 1996. HIVs other immune-system targets: macrophages. Science 274, 14641465. Barry, P.P., Moskowitz, M.A., 1988. The diagnosis of reversible dementia in the elderly: A critical review. Arch. Intern. Med. 148, 19141918. Birge, S.J., 1996. Is there a role for estrogen replacement therapy in the prevention and treatment of dementia? J. Am. Geriatr. Soc. 44, 865870. Bliwise, D.L., 1996. Is sleep apnea a cause of reversible dementia in old age. J. Am. Geriatr. Soc. 44, 14071409. Borgesen, S.E., Gierris, F., Sorensen, S.C., 1979. Intracranial pressure and conductance to outow of cerebrospinal uid in normal-pressure hydrocephalus. J. Neurosurg. 50, 489493. Borgesen, S.E., Gierris, F., 1982. The predictive value of conductance to outow of CSF in normal pressure hydrocephalus. Brain 105, 6586. Bradley, W.G., Scalzo, D., Queralt, J., Nitz, W.N., Atkinson, D.J., Wong, P., 1996. Normal- Pressure Hydrocephalus: evaluation with cerebrospinal uid ow measurements at MR imaging. Radiology 198, 523 529. Brenner, D.E., Kukull, W.A., Stergachis, A. et al., 1994. Post-menopausal estrogen replacement therapy and the risk of Alzheimers Disease: a population-based case-control study. Am. J. Epidemiol. 140, 262267. Brisman, M.H., Fetell, M.R., Post, K.D., 1993. Reversible dementia due to macroprolactinoma. J. Neurosurg. 79, 135137. Brooks, D.J., Beaney, R.P., Powell, M., Leenders, K.L., Crockard, H.A., Thomas, D.G.T., Marshall, J., Jones, T., 1986. Studies on cerebral oxygen metabolism, blood ow, and blood volume, in patients with hydrocephalus before and after surgical decompression, using Positron Emission Tomography. Brain 109, 613628. Canadian consensus. Assessing dementia: the canadian consensus, 1991. Can. Med. Assoc. J. 144, pp. 851853. Caselli, R.J., 1990. Giant cell (temporal) arteritis: a treatable cause of multi-infarct dementia. Neurology 40, 753755. Caselli, R.J., Scheithauer, B.W., Bowles, C.A., Trenerry, M.R., Meyer, F.B., Smigielski, J.S., Rodriguez, M., 1991. The treatable dementia of Siogrens syndrome. Ann. Neurol. 30, 98101. Clareld, A.M., 1988. The reversible dementias: do they reverse? Ann. Intern. Med. 109, 476486. Clareld, A.M., 1989. Normal-Pressure Hydrocephalus: saga or swamp? JAMA 262, 25922593. Clareld, A.M., 1995. Reversible dementia (letter). Neurology 45, 601. Clarnette, R.M., Patterson, C.J., 1994. Hypothyroidism: does treatment cure dementia? J. Geriatr. Psychiatr. Neurol. 7, 2327. Consensus Conference Differential diagnosis of dementing diseases., 1987. JAMA 258, pp. 3411 3416. Corey-Bloom, J., Thal, L.J., Galasko, D., Folstein, M., Drachman, D., Raskind, M., Lanska, D.J., 1995. Diagnosis and evaluation of dementia. Neurology 45, 211218. Cummings, J., Benson, D.F., LoVerme, S., 1980. Reversible dementia. Illustrative cases, denition and review. J. Am. Geriatr. Soc. 243, 24342439. Dehalberto, M.-J., Pajot, N., Courbon, D., Alperovich, A., 1996. Breathing disorders during sleep and cognitive performance in an older community sample: the EVA study. J. Am. Geriatr. Soc. 44, 1287 1294. Diagnostic and Statistical Manual of Psychiatris Disorders 4th ed. (DSMIV)., 1994. Washington DC: APA. Dirr, L.Y., Elster, A.D., Donofrio, P.D., Smith, M., 1990. Evolution of brain MRI abnormalities in limbic encephalitis. Neurology 40, 304 306. El Maghraoui, A., Birouk, N., Zaim, A., Slassi, I., Yahyaoui, M., Chkili, T., 1995. Syndrome de Fahr et dysparathyroidie: 3 observations. La Presse Medicale 24, 13011304.

180

C. Piccini et al. / Journal of Neurological Sciences 153 (1998) 172 181 Lindenbaum, J., Healton, E.B., Savage, D.G., Brust, J.C.M., Garret, T.J., Podell, E.R., Marcell, P.D., Stabler, S.P., Allen, R.H., 1988. Neuropsychiatric disorders caused by cobalamin deciency in the absence of anemia or macrocytosis. Authors suggest that in some equivocal cases with borderline depression of serum cobalamin high serum levels of methylmalonic acid and total homocysteine that return to normal after therapy provide useful conrmatory evidence of a deciency of cobalamin. N. Engl. J. Med. 318, 17201728. Maletta, G.J., 1990. The concept of reversible dementia. How nonreliable terminology may impair effective treatment. J. Am. Geriatr. Soc. 38, 136140. Manto, M., Badot, V., Koulischer, D., Henriet, M., Guillame, B., Jacquy, J., 1993. Demence reversible et polynevrite chez une femme agee: un cas de lupus erythemateux dissemine de debut tradif. Acta Neurol. Belg. 93, 139145. Marsden, C.D., Harrison, M.J.G., 1972. Outcome of investigation of patients with presenile dementia. There was no follow-up to determine if patients actually improved after treatment. Br. Med. J. 2, 249252. Martin, D.C., Francis, J., Protetch, J., Huff, F.J., 1992. Time dependency of cognitive recovery with Cobalamin replacement: report of a pilot study. J. Am. Geriatr. Soc. 40, 168172. McKhann, G., Drachman, D., Folstein, M. et al., 1984. Clinical diagnosis of Alzheimers Disease: report of the NINCDS /ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimers Disease. Neurology 34, 939944. Navia, B.A., Jordan, B., Price, R., 1986. The AIDS dementia-complex: I. Clinical features. Ann. Neurol. 19, 517524. ONeill, D., Barber, R.D., 1993. Reversible dementia caused by vitamin B12 deciency. J. Am. Geriatr. Soc. 41, 192193. Ohkura, T., Teshima, Y., Isse, K. et al., 1995. Estrogen increases cerebral and cerebellar blood ows in postmenopausal women. Menopause 2, 1318. Paganini-Hill, A., Henderson, V.W., 1994. Estrogen deciency and risk of Alzheimers Disease in women. Am. J. Epidemiol. 140, 256261. Paganini-Hill, A., Henderson, V.W., 1996. Estrogen replacement therapy and risk of Alzheimers disease. Arch. Intern. Med. 156, 22132217. Pennypacker, L.C., Allen, R.H., Kelly, J.P., Matthews, L.M., Grisby, J., Kaye, K., Lindenbaum, J., Stabler, S.P., 1992. High prevalence of Cobalamin deciency in elderly outpatients. J. Am. Geriatr. Soc. 40, 11971204. Pulliam, L., Gascon, R., Stubblebine, M., McGuire, D., McGrath, M.S., 1997. Unique monocyte subset in patients with AIDS dementia. Lancet 349, 692695. Quality standards subcommittee of the American Academy of Neurology, 1994. Practice parameter for diagnosis and evaluation of dementia (summary statement). Neurology 44, pp. 22032206. Rabins, P., Merchant, A., Nestadt, G., 1984. Criteria for diagnosing reversible dementia caused by depression: validation by 2-year followup. Br. J. Psychiatry 144, 488492. Reier, B.V., Larson, E., 1988. Excess disability in demented elderly outpatients. The rule of the halves. J. Am. Geriatr. Soc. 36, 8283. Reynolds, C.F., Hoch, C.C., Kupfer, D.J. et al., 1988. Bedside differentiation of depressive pseudodementia from dementia. Am. J. Psychiatry 145, 10991103. Rossor, M.N., 1994. Management of neurological disorders: dementia. J. Neurol. Neursurg. Psychiatry 57, 14511456. Sachdev, P.S., Smith, J.S., Angus-Lepan, H., Rodriguez, P., 1990. Pseudodementia twelve years on. J. Neurol. Neurosurg. Psychiatry 53, 254259. Sand, T., Bovim, G., Gimse, R., Myhr, G., Helde, G., Cappelen, J., 1994. Idiopathic normal pressure hydrocephalus: the CSF tap-test may predict the clinical response to shunting. Acta Neurol. Scand. 89, 311316. Schneider, L.S., Farlow, M.R., Henderson, V.W., Pogoda, J.M., 1996. Effects of estrogen replacement theraphy on response to tacrine in patients with Alziemrs Disease. Neurology 46, 15801584. Skoog, I., Nilsson, L., Palmertz, B., Andreasson, L.-A., Svanborg, A.,

Eraut, D., 1974. Idiopathic Hypoparathyroidism presentic as dementia. Br. Med. J. 1, 429430. Farlow, M., Graon, S.I., Hershey, L.A. et al., 1992. A controlled trial of tacrine in Alzheimers Disease. JAMA 268, 25232529. Friedland, R.P., 1989. Normal-Pressure Hydrocephalus and the saga of the treatable dementias. JAMA 262, 25772581. Friedland, R.P., 1993. Alzheimers Disease: clinical features and differential diagnosis. Neurology 43 (4), S45S51. Friedland, R.P., Hedera, P., 1995. Letter in replay to Clareld. Neurology 45, 601. Gordon, M., Freedman, M., 1990. Evaluating dementia: what price testing? Can. Med. Assoc. J. 142, 13671370. Graff-Radford, N.R., Rezai, K., Godersky, J.C., Eslinger, P., Damasio, H., Kirchener, P.T., 1987. Regional cerebral blood ow in normal pressure hydrocephalus. J. Neurol. Neurosurg. Psychiatry 50, 15891596. Graves, A.B., White, E., Koepsell, T.D. et al., 1990. A case-control study on Alzheimers Disease. Ann. Neurol. 28, 766774. Hay, E.M., 1994. Psychiatric disorders and cognitive impairment in SLE. Lupus 3, 145148. Hector, M., Burton, J.R., 1988. What are psychiatric manifestations of vitamin B12 deciency? J. Am. Geriatr. Soc. 36, 11051112. Hossain, M., 1970. Neurological and psychiatric manifestations in idiopathic hypoparathyroidism: response to treatment. J. Neurol. Neurosurg. Psychiatry 33, 153156. Jacobs, L., Conti, D., Kinkel, W.R., Manning, E.J., 1976. Normal Pressure Hydrocephalus. Relationship of clinical and radiographic ndings to improvement following shunt surgery. JAMA 235, 510 512. Jagust, W.J., Friedland, R.P., Budinger, T.F., 1985. Positron emission tomography with 18F-uorodeoxyglucose differentiates normal pressure hydrocephalus from Alzheimers-type dementia. J. Neurol. Neurosurg. Psychiatry 48, 10911096. Jaffe, A.B., Toran-Allerand, D., Greengard, P., Gandy, S.E., 1994. Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J. Biol. Chem. 269, 1306413068. Janssen, R.S. and Working Group of the American Academy of Neurology AIDS Task Force, 1991. Nomenclature and research case denition for neurologic manifestation of human immunodeciency virus-type 1 (HIV-1) infection. Neurology 41, pp. 778785. Kampen, D.L., Sherwin, B.B., 1994. Estrogen use and verbal memory in healthy postmenopausal women. Obstet. Gynecol. 83, 979983. Kelly, J., Feigenbaum, L.Z., 1992. Another cause of reversible dementia: sleep deprivation due to prostatism. J. Am. Geriatr. Soc. 30, 645646. Kiloh, L.G., 1961. Pseudodementia. Acta Psychitar. Scand. 37, 336351. Kramer, S.I., Reier, B.V., 1992. Depression, dementia and revesible dementia. Clin. Geriatr. Med. 8, 289297. Larson, E.R., Reier, B.V., Featherstone, H.J., English, D., 1984. Dementia in elderly outpatients: a prospective study. Ann. Intern. Med. 100, 417423. Larson, E.R., Reier, B.V., Sumi, S.M., Caneld, C.G., Chinn, N.M., 1985. Diagnostic evaluation of 200 elderly outpatients with suspected dementia. J. Gerontol. 5, 536543. Larson, E.R., Reier, B.V., Sumi, S.M., Caneld, C.G., Chinn, N.M., 1986. Diagnostic tests in the evaluation of dementia. A prospective study of 200 elderly outpatients. Ann. Intern. Med. 146, 19171922. Larson, E.B., Kukull, W.A., Buchner, D., Reier, B.V., 1987. Adverse drug reactions associated with global cognitive impairment in elderly persons. Ann. Intern. Med. 107, 169173. Larsson, A., Wikkelso, C., Bilting, M., Stephensen, H., 1991. Clinical parameters in 74 consecutive patients shunt operated for normal pressure hydrocephalus. Mental deterioration prior to gait disturbances, long duration of dementia prior to surgery, idiopathic forms versus NPH after subaracnoid hemorrage have been previous reported as negative prognostic factors of shunt surgery. Authors conrm that NPH after subaracnoid hemorrage improved more than others and that dysphasia, incontinence and long duration of illness were prognostic unfavourable. Acta Neurol. Scand. 84, 475482.

C. Piccini et al. / Journal of Neurological Sciences 153 (1998) 172 181 1993. A population based study of dementia in 85-years-olds. N. Engl. J. Med. 328, 153158. Slyter, H., 1979. Idiopathic hypoparathyroidism presenting as dementia. Neurology 29, 393394. Stuerenburg, H.J., Hansen, H.C., Thie, A., Kunze, K., 1996. Reversible dementia in idiopathic hypoparathyroidism associated with normocalcemia. Neurology 47, 474476. Task force sponsored by the National Institute of Aging., 1980. Senility reconsidered. Treatment possibilities for mental impairment in the elderly. JAMA 244, pp. 259263. Tedeschi, E., Hasselbalch, S.G., Waldemar, G., Juhler, M., Hogh, P., Holm, S., Garde, L., Lumholdt Knudsen, L., Klinken, L., Gjerris, F., Paulson, O.B., 1995. Heterogeneous cerebral glucose metabolism in normal pressure hydrocephalus. J. Neurol. Neurosurg. Psychiatry 59, 608615. Teunisse, S., Bollen, A., van Gool, W.A., Walstra, G.J.M., 1996. Dementia and subnormal levels of vitamin B12; effects of replacement therapy on dementia. J. Neurol. 243, 522529. Torvik, A., Lindboe, C.F., Rodge, S., 1982. Brain lesions in alcoholics. A neuropathological study with clinical correlations. J. Neurol. Sci. 56, 233248. Van Horn, G., Arnett, F.C., Dimachkie, M.M., 1996. Reversible dementia and chorea in a young woman with the lupus anticoagulent. Neurology 46, 15991603.

181

Vanneste, J., Augustijn, P., Dirven, C., Tan, W.F., Goedhart, Z.D., 1992. Shunting normal pressure hydrocephalus: do the benets outweigh the risks? Neurology 42, 5459. Victor, M., 1994. Alcoholic dementia. Can. J. Neurol. Sci. 21, 8899. Waldemar, G., Schmidt, J.F., Delecluse, F., Andersen, A.R., Gierris, F., Paulson, O.B., 1993. High resolution SPECT with 99Tc-HMPAO in normal pressure hydrocephalus before and after shunt operation. J. Neurol. Neurosurg. Psychiatry 56, 655664. Walstra, G.J.M., Teunisse, S., van Gool, W.A., van Crevel, H., 1997. Reversible dementia in elderly patients referred to a memory clinic. J. Neurol. 244, 1722. Waring, S.C., Rocca, W.A., Petersen, R.C., Kokmen, E., 1997. Postmenopausal estrogen replacement therapy and Alzheimers disease: a population based study in Rochester, Minnesota. Neurology 48, A79. Wells, C.E., 1979. Pseudodementia. Am. J. Psychiatr. 136, 895900. Weytingh, M.D., Bossuyt, P.M.M., van Crevel, H., 1995. Reversible dementia: more than 10% or less than 1%. A quantitative review. J. Neurol. 242, 466471. Whiley, C.A., Achim, C.L., 1994. Human immunodeciency virus encephalitis is the pathological correlate of dementia in acquired immunodeciency syndrome. Ann. Neurol. 36, 673676. Whiley, C.A., Achim, C.L., 1995. Human immunodeciency virus encephalitis and dementia. Ann. Neurol. 38, 559560.