Rapidly Progressing Dementia – Clinical Aspects and Management


than FLAIR) is highly sensitive and specific (92 and 94 %, respectively) for the diagnosis of CJD.1,30


The above characteristic findings can


be seen well before the EEG periodic abnormalities and the positivity of the 14-3-3 protein test. Similar MRI findings generally characterise the inherited prion diseases.1


These abnormalities are highly specific


for the diagnosis of CJD and have been seen only exceptionally in other pathologies, such as neurofilament inclusion body disease,1 Wilson’s disease, Wernicke’s encephalopathy, CNS vasculitis, anti-CV2-associated paraneoplastic conditions and voltage-gated potassium channel (VGKC) encephalopathy.1


The diagnosis of CJD is


based on the WHO clinical diagnostic criteria, which have recently been updated to include the above-described typical MRI findings.8 However, a definitive diagnosis of CJD can be made only after the demonstration of prions in the brain. Clinical criteria for probable sCJD require the existence of dementia with a progressive course and at least two of the following: pyramidal and/or extrapyramidal symptoms, visual or cerebellar symptoms, myoclonus, akinetic mutism and positivity in at least one out of three tests (EEG, 14-3-3 protein and MRI). No treatment has been found to be effective even for delaying the course of this rapidly fatal disease. Palliative treatment for the control of seizures and myoclonus includes sodium valproate and clonazepam.


This disease has been encountered mainly in the UK following the epidemic of bovine spongiform encephalopathy in the 1980s. Psychiatric disturbances are the most common presenting features of vCJD and typically last for months before other neurological symptoms arise, mainly cerebellar ataxia, dysesthesias, cognitive deficits leading rapidly to dementia, variable extrapyramidal disorders (dystonia, chorea) and myoclonus. The duration of the disease is somewhat longer than that of sCJD. Although MRI findings are similar to those for sCJD, more marked hyperintensity of the pulvinar compared with the anterior putamen (the ‘pulvinar sign’) is the characteristic finding.33 EEG rarely shows the typical pattern of sCJD. Diagnosis of vCJD is based on clinical, EEG and MRI findings. The WHO diagnostic criteria have been shown to be highly sensitive and specific in a recently published validation study.31


vCJD affects much younger individuals, with a mean age of 27 years.31,32


Secondary Causes of Rapidly Progressive Dementia Infectious Diseases


An early diagnosis is of high importance, as most cases of infection-related dementias are treatable. The possibility of a viral infection affecting the brain should be thoroughly investigated. Herpes simplex virus (HSV) infection can rarely exhibit a chronic course with cognitive decline, but even a clinical suspicion of such a diagnosis must lead to intravenous treatment with aciclovir. HSV encephalitis can then be confirmed by means of polymerase chain reaction for HSV 1 and 2 in the CSF.35


Although infectious CNS diseases usually present acutely, in certain cases the course is less prominent, resembling a chronic encephalopathy.1,34


A: fluid-attenuated inversion recovery (FLAIR) sequences demonstrate hyperintense signal in the striatum (caudate and putamen, R>L); B: FLAIR and C: diffusion-weighted imaging sequences demonstrate ‘cortical ribonning’ (hyperintense signal delineating the cortex) in the parietal, occipital and temporal cortices, bilaterally (B and C are of the same patient).


As far as bacterial infections are concerned, the possibility of neurosyphilis as a cause of RPD should always be excluded. Cognitive decline may coincide with psychiatric symptoms and focal neurological signs. All patients must undergo rapid plasma reagin and venereal disease research laboratory testing in the blood and CSF.38 Mycobacterium tuberculosis and other atypical Mycobacterium species occasionally cause chronic meningitis.39


In cases of pleocytosis or


elevated protein in the CSF, further investigation using Ziehl-Nielsen staining, mycobacterial culture and polymerase chain reaction is required. Lyme disease, caused by Borrelia burgdorferi, occasionally presents as an RPD, as do other neurological manifestations such as cranial nerve palsies, polyradiculopathy and psychiatric symptoms.40 Chronic fungal and parasitic CNS infections including Cryptococcus neoformans may exhibit a course resembling RPD. Whipple’s disease is a multisystem disorder caused by Tropheryma whippelli. Its clinical spectrum includes gastrointestinal symptoms such as malabsorption, fever, weight loss, arthralgias and lymphadenopathy. Neurological manifestations include ataxia, psychiatric signs and the classic triad of cognitive decline, myoclonus and opthalmoplegia. Occulomasticatory ophthalmoplegia is pathognomic of the disease. It should be noted that neurological symptoms might occur independently of malabsorption. The diagnosis can be confirmed by the detection of periodic acid-Schiff-positive inclusions on jejuna biopsy or positive polymerase chain reaction.41


Inflammatory bowel disease involvement in the


development of RPD is exceptional. Malignancies


Both primary and metastatic CNS neoplasms may present with RPD, although focal symptoms are also present in most cases. MRI is the examination of choice to identify a brain tumour, which will appear as a contrast-enhancing lesion. CNS lymphomas, either primary or metastatic, should also be considered during the investigation of a rapid cognitive decline. Primary CNS lymphomas occur often in immunodeficient patients as an outcome of HIV infection or immunosuppressive therapies.42,43


However, they may occur HIV infection is associated with


The mechanism of the disorder involves both a direct action of HIV and the coexistence of opportunistic infections (including JC infection). Measles may result in subacute sclerosing panencephalitis, a syndrome comprising progressive dementia, ataxia and seizures.37


cognitive decline either during the seroconverting period or during a later stage of advanced immunosuppression (AIDS–dementia complex).36


EUROPEAN NEUROLOGICAL REVIEW


in immunocompetent individuals as well, most commonly in older patients. Memory loss, confusion, behaviour alterations, ataxia and gait disorder are among the most common symptoms. MRI findings include isolated or multiple white matter lesions (isointense or hyperintense in T2-weighted images) that typically exhibit contrast enhancement (see Figure 1).44


CSF testing will reveal a lymphocytic


pleiocytosis and elevated protein. A transient response to corticosteroid administration might be anticipated. In most cases, biopsy is necessary to confirm the diagnosis. Intravascular lymphoma progresses in the form


241


Figure 2: Brain Magnetic Resonance Images of Two Patients with a Diagnosis of Sporadic Creutzfeld-Jacob Disease


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