Neurodegenerative Disease Dementia
of blood vessel infiltrations and can present with acute stroke-like attacks or with RPD. Gliomatosis cerebri usually presents a more diffuse infiltrating pattern without enhancement during computed tomography or MRI imaging.45
Metabolic/Toxic Causes of Rapidly Progressive Dementia
The pattern of MRI white matter lesions often facilitates the diagnosis. Adult-onset metachromatic leukodystrophy might emerge as mental deterioration and psychiatric symptoms without movement deficits. Krabbe disease and X-linked adrenoleukodystrophy can present with similar features, although these conditions are usually diagnosed before adulthood.48
Adult-onset leukodystrophies usually initiate with cognitive decline, psychiatric symptoms, ataxia, dystonia and progressive gait disturbance.46,47
Lysosomal storage disorders such as
Niemann-Pick type C and Fabry’s disease often present characteristic systemic symptoms. In the presence of extrapyramidal signs, the possibility of Wilson’s or Huntington’s disease should be considered. Porphyria is suspected in the presence of painful abdominal attacks or psychiatric symptoms. Finally, mitochondrial disorders often exhibit specific features such as short stature and multiple organ deficits (CNS, peripheral nerve, muscle, heart, kidney, vision and hearing disorders).
Common metabolic disorders related to RPD include vitamin deficiency and endocrine disorders.1
Niacin deficiency or pellagra is marked by the
presence of dementia, diarrhoea and dermatitis. This entity is often an outcome of alcoholism but can also occur in nutritional deprivation, chronic infections and neoplasms, cirrhosis and malabsorption syndromes. Thiamine (vitamin B1) deficiency is common in alcoholics as well and its main clinical feature is Wernicke’s encephalopathy (memory loss, ataxia and opthalmoplegia). Vitamin B12 deficiency stems from gastrointestinal disorders and its manifestations include anaemia, degeneration of the spinal cord dorsal columns, psychiatric symptoms and cognitive decline. All of the situations mentioned above are potentially reversible. Hypothyroidism can initiate as an RPD, with mental deterioration as one of its main features. Thyroid hormone screening should be performed in all patients referred for memory impairment or executive function deficits. Hyperparathyroidism can also mimic CJD and this treatable condition should be excluded in every case of rapid cognitive decline.49
Measurement of serum calcium,
phosphorus and parathyroid hormone levels is adequate for an initial assessment, occasionally followed by advanced imaging techniques. Encephalopathy in advanced stages of renal or liver dysfunction may resemble RPD and therefore renal and liver function evaluation should be carried out in every patient.
Heavy metal intoxication (mercury, lead, aluminium, arsenic, bismuth and lithium) is a rare cause of RPD. Urine level measurements should be performed in occupationally exposed individuals. Prolonged administration of anticancer drugs such as methotrexate may result in a diffuse type of encephalopathy which is not fully reversible following the discontinuation of therapy.
Vascular Dementias
Vascular disorders are a rather uncommon cause of RPD.1,3 Multi-infarct dementia is the result of numerous diffuse minor strokes that eventually lead to memory and executive function impairment. On the other hand, isolated strategic infarcts in the thalamus anterior
242
Although rare, inherited metabolic disorders should also be taken into account during the assessment of RPD, especially in younger patients.6
corpus callosum and the striatum may lead to rapid cognitive decline as well.50
Screening for possible cardiovascular risk factors such as diabetes, hyperlipidaemia, hypertension, smoking and cardiac arrhythmias should be performed. Subcortical vascular dementia (Binswanger’s disease) represents an outcome of alterations of small brain vessels and is characterised by gradual memory deterioration, apathy and supranuclear paresis signs. Secondary causes of vessel occlusions such as thrombotic thrombocytopenic purpura and hyperviscosity syndromes (polycytaemia and Waldenstrom’s macroglobulinaemia) may cause global cerebral ischaemia with clinical manifestations resembling an RPD. Brain MRI will facilitate the assessment of vascular causes of RPD and discriminate them from CJD or neurodegenerative disorders.1
Normal Pressure Hydrocephalus
Normal pressure hydrocephalus is an important, and reversible, secondary causative factor of dementia which can take the form of an RPD.3
The clinical spectrum of normal pressure hydrocephalus involves the classic triad of memory impairment, gait disorders and urinary incontinence. Brain MRI will reveal enlargement of the ventricular system. Diagnosis can be confirmed by means of CSF pressure measurement.
Psychiatric Causes of Rapidly Progressive Dementia
Following the exclusion of all neurological and systemic causes of RPD, the possibility of pseudodementia should be considered. Patients with a history of major depression may exhibit symptoms of rapid cognitive decline. Although apathy and other depressive symptoms might prevail, this situation can mimic RPD and the differential diagnosis is often difficult.
Autoimmune Dementias
It should be noted that a number of autoimmune encephalopathies are treatable and therefore an early diagnosis could be of high importance. The hallmarks of the disorders are a rapidly progressive fluctuating course, the detection of autoantibodies in the peripheral blood and indications of inflammation in the CSF (pleocytosis, elevated protein level, increased immunoglobulin G index).51 A common clinical presentation is limbic encephalopathy initiating with disorders of short-term memory. Behavioural alterations, depression and temporal lobe seizures may accompany the memory deficits. Despite the fact that limbic encephalopathy is often paraneoplastic, even preceding the diagnosis of the underlying malignancy, in many cases the neurological disorder is non-paraneoplastic.52
Although autoimmune encephalopathies were thought to be rare in the past, it appears that they represent a relatively frequent cause of RPD.1
The differential diagnosis
of limbic encephalitis includes viral encephalitis (especially HSV), CJD, psychosis and other forms of autoimmune disorders. Affected brain areas may include the anteromedial temporal cortex, the hippocampus and the amygdala, and brain MRI shows non-enhancing signal changes in the mesial temporal lobes (see Figure 3). In cases of paraneoplastic limbic encephalitis presenting as an RPD, there is evidence of autoantibodies reacting against tumour proteins.53
It
remains unknown whether these autoantibodies have a pathogenic role or represent markers of a T-cell-mediated immune response. It seems that in most cases T-cell immunity determines the neurological outcome in paraneoplastic limbic encephalopathies. CSF possibly presents signs of inflammation and screening for tumour markers in the peripheral blood may be positive. Anti-Hu antibody is the most
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