Human prion diseases: An overview | Medicina Clínica (English Edition)

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En el esquema se muestran las mutaciones puntuales (missense) con más de 100 casos publicados en la literatura médica y el codón polimórfico 129. Estas 5 mutaciones son responsables, aproximadamente, del 85% de las enfermedades genéticas por priones. 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Una revisión general" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 564 "Ancho" => 2508 "Tamanyo" => 73598 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Schematic representation of exon 2 of the PRNP gene. The schematic shows the point mutations (missense) with more than 100 cases published in the medical literature and the polymorphic codon 129. These 5 mutations are responsible for approximately 85% of genetic prion diseases. D: aspartic acid; E: glutamate; I: isoleucine; K: lysine; L: leucine; M: methionine; N: asparagine; P: proline." ] ] ] "textoCompleto" => "IntroductionPrion diseases are a group of closely related and rapidly progressive neurodegenerative diseases affecting mammals, including humans.<a class="elsevierStyleCrossRefs" href="#bib0005">1–3</a> In these diseases, a normal brain protein known as prion protein (PrP) aggregates into an abnormal conformation.<a class="elsevierStyleCrossRefs" href="#bib0005">1–3</a> This abnormal form of the protein, known as "prion", acts as an infectious agent and can transmit the disease to other hosts. The "prion" is therefore an "infectious" protein conformation containing no nucleic acids.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> The majority of prion diseases in humans correspond to the entity known as Creutzfeldt–Jakob disease (CJD), although other clinical forms can also occur.Their diagnosis is always a challenge for clinicians. However, early detection and monitoring is crucial for care planning and public health implications. The recent introduction of techniques allowing the detection of prions in biological samples has been a remarkable achievement for the understanding of these entities. In the light of these developments, it seems appropriate to briefly review the pathogenesis, clinical and diagnostic features of these diseases, as well as their public health implications and possible therapeutics.EpidemiologyPrion diseases have a worldwide distribution, with an annual incidence of 1–2 cases per million population.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,4</a> They can occur sporadically (85–90% of cases) or by genetic transmission (10–15%).<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> In addition, there is a third form of presentation, the acquired or "infectious" form (<1%), either by dietary consumption of prion contaminated meat or by iatrogenic transmission.<a class="elsevierStyleCrossRefs" href="#bib0005">1–3</a>Sporadic cases affect subjects in a highly variable age range, from 16 to 98 years old.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> However, they typically occur later in life, with a peak in the 8th decade of life. The highest incidence of genetic forms is in the 6th decade of life.<a class="elsevierStyleCrossRefs" href="#bib0005">1–3</a>There have been 2 outbreaks transmitted through ingestion: kuru and variant CJD. The first was an epidemic disease among the Fore-speaking Aborigines in Papua New Guinea. The disease probably appeared sporadically and spread due to ritual practices of cannibalism. This custom was banned in the 1950s, so the last observed cases of kuru occurred in 2009 (incubation period of at least 50 years).<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,5</a>The CJD variant, known in the media as "mad cow disease" at the time, appeared in the UK in 1994, due to the consumption of beef contaminated with Bovine Spongiform Encephalopathy prions,<a class="elsevierStyleCrossRef" href="#bib0015">3</a> a neurological disease of cattle that can be transmitted to cattle or humans by consumption of prion-infected parts of the animal. This outbreak occurred 10 years after a massive epidemic of the disease in cattle.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a> Despite millions of people consuming this meat, only 228 patients had the disease by 2016.<a class="elsevierStyleCrossRefs" href="#bib0005">1–3</a> Currently, the incidence of variant CJD has decreased significantly due to the control of spongiform encephalopathy in cattle and vigilance to prevent contaminated meat from entering the human food chain.<a class="elsevierStyleCrossRefs" href="#bib0005">1–3</a> In addition, one case has been reported in 2020 possibly related to occupational exposure.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Finally, iatrogenic cases of CJD have occurred from dura mater grafts (228 cases) and growth hormone injections (226 cases) prior to the use of recombinant growth hormone, introduced around 1980.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> There are 3 documented cases of variant CJD transmission to blood transfusion recipients.<a class="elsevierStyleCrossRefs" href="#bib0005">1–3</a> These are the only proven cases of transmission by this mechanism; interestingly, transfusion of blood products from patients with sporadic CJD or genetic prion diseases has not transmitted the disease.<a class="elsevierStyleCrossRefs" href="#bib0005">1–3,5</a> Other iatrogenic forms of transmission are exceptional. For example, 6 cases of CJD transmitted via surgical and medical instruments; and 2 cases via corneal transplantation.<a class="elsevierStyleCrossRefs" href="#bib0010">2,5</a>PathogenesisPrP is a cell surface protein found in the brain and some other tissues whose function is unknown.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> The primary structure of PrP consists of 253 amino acid residues, and contains an unstable region in the N-terminal domain, termed octapeptide repeat region (OPR), consisting of a non-peptide (R1) followed by 4 octapeptide repeats (R2, R2, R3, R4).<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> After translation, 22 amino acid residues are removed from the N-terminal region and 23 from the C-terminal domain of the protein, and a glycosylphosphatidylinositol anchor is attached to the C-terminal domain (residue 230) for binding to the plasma membrane of the cell.<a class="elsevierStyleCrossRefs" href="#bib0040">8–10</a> PrP can also be internalised and recycled between the cell membrane and the endosome.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> The globular domain of the protein extends from amino acid residues 125–228, and contains 3 〈 helices (amino acids 144–154, 173–194, and 200–228) and 2 ® antiparallel folds (residues 128–131 and 161–164).<a class="elsevierStyleCrossRef" href="#bib0040">8</a> PrP can be glycosylated at asparagine residues 181 and 197; resulting in non-, mono- or di-glycosylated.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a>In prion diseases, aggregates of an abnormal form of PrP, known as PrPSc, accumulate in the brain (scrapie prion protein). PrP consists mainly of 〈 helices, while PrPSc has a high proportion of ®folds. This conformational change affects the biochemical properties of PrP; thus, PrPSc is relatively resistant to degradation by proteases.<a class="elsevierStyleCrossRefs" href="#bib0040">8–10</a> PrPSc has the property of 'recruiting' the normal protein (PrP) to join the abnormal protein aggregate. Neither the structure of PrPSc, nor the mechanisms for prion propagation are known exactly. A basic conceptual model proposes that the normal helical structure of the 〈 helical regions of PrP interacts directly with the regions of PrPSc in ß-fold, losing its normal helical structure 〈 and then binds to the aggregate.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> The protein aggregate, during its growth, may fracture at some point, thus creating additional particles for aggregation. In this way, the PrPSc aggregate can spread as an infectious agent. Aggregates of PrPSc constitute a proteinaceous fibrillar material, rich in folded proteins ®, known as 'amyloid', which cause central nervous system (CNS) toxicity.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,9,10</a>In prion diseases, the appearance of the abnormally conformed protein can occur by spontaneous conversion due to a modification after synthesis (translation) of the normal protein (PrP); by mutation in the gene encoding the protein; or by exogenous acquisition of the protein. In infectious or acquired food-borne forms, prions first replicate in the enteric lymphatic system and Peyer's patches.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a> Subsequently, they reach the CNS via the sympathetic nerves of the lymphoid tissue. In the CNS, prions spread synaptically.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>Pathological anatomyNo macroscopic CNS changes are usually observed in these patients, except for variable degrees of atrophy if the process has had a long course. The characteristic histopathological picture of prion diseases consists of a combination of vacuolisation (status spongiosus) of the grey matter, astrocytic gliosis and loss of neurons, without inflammation.<a class="elsevierStyleCrossRefs" href="#bib0010">2,11</a> Spongiform changes consist of the appearance of small round or oval vacuolated voids in the neuropil surrounding the neurons.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Some forms of prion diseases have their own anatomopathological features, such as the "florid plaque" found in variant CJD, which consists of an eosinophilic amyloid plaque surrounded by a halo of vacuolisation (spongiosis).<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Aggregates of PrPSc (amyloid) in the CNS can form plaques or deposits at neuronal synapses.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Prion detection is based on the resistance of PrPSc aggregates to enzymatic proteolysis. Nerve tissue is treated with proteinase K and then Western blotting for the detection of PrPSc, which, if present, has not been broken down by the enzyme. There are 2 main types of PrPSc in the nerve tissue of patients with prion diseases and they are observed in the Western blot as non-glycosylated bands of 21 KDa (type 1) or 19 KDa (type 2).<a class="elsevierStyleCrossRefs" href="#bib0045">9,12</a> Most patients with CJD have only one type of PrPSc, although both may coexist in one third of cases.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> These PrPSc types combined with the codon 129 polymorphism form the basis for the molecular classification of sporadic CJD (see below).<a class="elsevierStyleCrossRefs" href="#bib0005">1,4,8,12–14</a>GeneticsAll genetic forms of prion disease are caused by mutations in the sequence of the PRNP gene encoding the PrP2 protein. This gene is located on human chromosome 20p13; and consists of 2 exons, although the complete open reading frame of the gene is in exon 2 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> Codons 51–91 normally contain the sequences encoding a nonapeptide and 4 octapeptide repeats (OPR region).<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Among the polymorphic codons of the PRNP gene, codon 129, with 2 alleles coding for methionine or valine, is the most relevant for its clinical implications.<a class="elsevierStyleCrossRefs" href="#bib0010">2,8,15</a> Codon 129 is a factor that modifies the clinical characteristics of prion diseases. For this reason, genetic prion diseases have been classified into haplotypes based on the mutation of the PRNP gene and the polymorphic codon 129 of the mutated allele.<a class="elsevierStyleCrossRef" href="#bib0075">15</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>About 50 mutations associated with prion genetic diseases have been identified.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> It is generally considered that mutation of the PRNP gene confers on the protein an increased susceptibility to its abnormal conformation.<a class="elsevierStyleCrossRefs" href="#bib0040">8,10</a> Known mutations associated with prion diseases include more than 35 point mutations (missense) leading to amino acid substitutions; 5 mutations leading to the appearance of a premature stop codon (nonsense) in protein synthesis; and 24 base pair insertions in the OPR region that will encode between 2 and 12 octapeptides.<a class="elsevierStyleCrossRefs" href="#bib0010">2,8,9,11</a>,<a class="elsevierStyleCrossRef" href="#bib0075">15</a> In addition, deletions of 2 octapeptides in the OPR<a class="elsevierStyleCrossRefs" href="#bib0070">14–16</a> region have been described in 3 patients. The insertion or deletion of a single octapeptide is not considered pathogenic.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9,15</a> Among all these mutations, 5 point mutations are considered to be responsible for 85% of genetic prion diseases: E200 K, V210I, V180I, D178 N and P102L.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> The genetic forms of prion diseases are transmitted in an autosomal dominant pattern, generally with high, but usually incomplete, penetrance.<a class="elsevierStyleCrossRefs" href="#bib0010">2,8–10,15–17</a>Historically, genetic prion diseases have been classified into 3 clinicopathological phenotypes: (a) genetic CJD, (b) Gerstmann–Sträussler–Scheinker syndrome and (c) fatal familial insomnia.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,8</a> Base pair insertions may be associated with atypical clinical phenotypes that are difficult to classify between CJD or Gerstmann–Sträussler–Scheinker syndrome; like stop codon mutations, they may present as a dementia syndrome with variable progression.<a class="elsevierStyleCrossRefs" href="#bib0040">8,15</a>There are 23 known point mutations associated with genetic CJD.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> The most common mutation worldwide in genetic prion diseases is the substitution of glutamic acid (E) for lysine (K) at codon 200 (E200 K), which is clinically and histologically indistinguishable from sporadic CJD.<a class="elsevierStyleCrossRefs" href="#bib0005">1,8,9,11</a>,<a class="elsevierStyleCrossRefs" href="#bib0075">15,17</a> Transmission is autosomal dominant, with an estimated penetrance between 54% and 100%.<a class="elsevierStyleCrossRefs" href="#bib0025">5,8,9,15</a>Familial Gerstmann–Sträussler–Scheinker syndrome is due to more than 20 described point mutations and PRNP gene insertions. The most common of these is the substitution for leucine coding instead of proline at codon 102 (P102 L).<a class="elsevierStyleCrossRefs" href="#bib0010">2,8,9,16</a> The incidence of this disease is difficult to determine but has been estimated at 1–10 cases per 100,000,000 population.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> From a histopathological point of view, this mutation leads to the appearance of multifocal PrPSc amyloid plaques in the brain, especially in the cerebellum.<a class="elsevierStyleCrossRefs" href="#bib0010">2,8,16</a>Fatal familial insomnia is caused by the D178 N (aspartic acid substituted for asparagine) mutation associated with the allele encoding methionine at codon 129 of the mutated allele (i.e., in cis).<a class="elsevierStyleCrossRefs" href="#bib0010">2,8–10,15</a> Histopathologically, these patients show neuronal loss, gliosis and accumulation of PrPSc in the thalamus and inferior olivary nucleus. Isolated gliosis may be present in the midbrain and hypothalamus.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> In contrast, the spongiform changes characteristic of prion diseases are usually absent. However, the D178 N mutation associated with the allele coding for valine at codon 129 results in a disease that is clinically and histologically indistinguishable from sporadic CJD.<a class="elsevierStyleCrossRefs" href="#bib0040">8–10,15</a> It is now thought that the haplotype effect is not so absolute, and that the D178 N mutation may present as a clinical spectrum ranging from CJD to fatal familial insomnia.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9,18,19</a>Finally, there is a relationship between codon 129 genotype and susceptibility to prion diseases. Thus, persons homozygous (129 MM or 129 V V) for this allele are over-represented among sporadic CJD patients,<a class="elsevierStyleCrossRefs" href="#bib0010">2,8–10</a> and all variant CJD victims (but 1) have 129 M on both alleles of the PRNP gene.<a class="elsevierStyleCrossRefs" href="#bib0005">1,3,8,10</a>,<a class="elsevierStyleCrossRef" href="#bib0100">20</a>Signs and symptomsIn human prion diseases, 4 entities and some clinical variants are distinguished. These are: kuru, CJD, Gerstmann–Straüssler–Scheinker syndrome, and fatal familial insomnia.Sporadic CJD is the most common form of prion disease in humans.<a class="elsevierStyleCrossRefs" href="#bib0005">1–3</a> Clinically, it is characterised by rapidly progressive dementia, ataxia and myoclonias.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In general, a rapidly progressive dementia syndrome can be considered as a dementia syndrome with onset within 1–2 years from the onset of symptoms or a dementia syndrome with a total disease course ≤2 years.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> In approximately 25% of cases, patients or their relatives report a prodromal phase with psychiatric symptoms, such as anxiety, depression or sleep disturbances.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Cognitive impairment is the most clinically expressive neurological sign, with clear neurological function losses over a period of weeks.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Neurological motor disturbances are prominent in the form of ataxia, bradykinesia or spasticity.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> A characteristic but not pathognomonic sign of CJD is the presence of myoclonus.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Visual disturbances are common, in the form of visual deficits, distortion of visual perception or hallucinations due to involvement of the occipital cortex.<a class="elsevierStyleCrossRefs" href="#bib0005">1,13</a> In Heidenhain's variant, isolated visual symptoms, without ocular disease, precede the rest of the neurological symptomatology.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> The death of the patient occurs after a phase of akinetic mutism within 4–6 months from the onset of symptoms.<a class="elsevierStyleCrossRefs" href="#bib0005">1,4</a>There are sporadic cases of CJD showing atypical clinical manifestations.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> In some patients, without mutations in the PRNP gene, they are clinically indistinguishable from fatal familial insomnia.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Another example of clinical atypicality is variably protease-sensitive prionopathy, which presents with frontal lobe dementia.<a class="elsevierStyleCrossRefs" href="#bib0010">2,8</a> These variants may be caused by different prion "strains", in analogy to infectious diseases. Prion "strains" refer to aggregates of PrPSc with a different biochemical and neuropathological profile, and which would produce differential neurotoxicity, presumably through interaction with other factors.<a class="elsevierStyleCrossRefs" href="#bib0010">2,10,13,21</a> The result would be the presentation of different clinical phenotypes.<a class="elsevierStyleCrossRefs" href="#bib0010">2,10,13,21</a> Some researchers have pointed out that the type of PrPSc together with the genotype at codon 129 of the PRNP gene determines 6 clinicopathological subtypes of sporadic CJD,<a class="elsevierStyleCrossRefs" href="#bib0005">1,4,8,12–14</a> which are summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. As indicated in this table, the thalamic and cortical MM2 subtypes do not differ molecularly (in both the PrPSc deposition is type 2), but they do differ in terms of neuropathology and clinical phenotype.<a class="elsevierStyleCrossRefs" href="#bib0005">1,4,8,12–14</a> The MM2-thalamic subtype is also called fatal sporadic insomnia, and is clinically characterised by insomnia, psychomotor agitation, ataxia and progressive dementia. Histopathologically, thalamic and inferior olivary atrophy (similar to fatal familial insomnia) and spongiform changes may be absent. The MM2-cortical subtype presents clinically with progressive dementia, whereas spongiform degeneration can be observed in the cerebral cortex and striatum, but not in the cerebellum.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Variant CJD, acquired by consumption of meat from bovine spongiform encephalopathy-positive cattle, is clinically distinguished from sporadic CJD by the age of presentation in much younger patients (mean, 26 yrs; range, 11–74 years),<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a> psychiatric disturbances are more prominent and sensory disturbances are of early onset in the form of limb pain or paraesthesias.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a> Motor disturbances, visual disturbances and dementia develop later.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> The average duration of the disease is approximately 14 months.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Iatrogenic CJD is similar to the sporadic form, but there is an ataxic form that clinically and histopathologically resembles Gerstmann–Straüssler–Scheinker syndrome.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Kuru starts with pain in the limbs, followed by cerebellar ataxia and tremor ("kuru" means tremor in the Fore language). The onset of frank dementia occurred later in the course of the disease.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>The most common form of presentation in Gerstmann–Sträussler–Scheinker syndrome is a slowly progressive cerebellar syndrome and cerebellar signs are almost universal with disease progression.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> One group of patients may develop prominent psychiatric symptoms at onset.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> Cognitive impairment is common with disease progression, but rare as presenting symptoms.<a class="elsevierStyleCrossRefs" href="#bib0040">8,16</a> The progression is usually slower than in sporadic CJD, and the time lag between the onset of symptoms and death is usually 5–6 years.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> The fourth prion disease entity is fatal familial insomnia. In Spain, 35 cases had been diagnosed up to 2008, of which 16 were from the Basque Autonomous Community.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Clinically, the disease is characterised by severe insomnia, dysautonomia and hallucinations in the early stages, followed by ataxia, myoclonia and signs of pyramidal involvement, such as hyperreflexia.<a class="elsevierStyleCrossRefs" href="#bib0010">2,8</a> This symptomatology may be preceded by anxiety and depression. Dementia is relatively late onset.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Some familial forms of prion diseases have a very slow course that resembles familial Alzheimer's disease or Huntington's disease.<a class="elsevierStyleCrossRefs" href="#bib0010">2,9,15</a>DiagnosisFrom a clinical point of view, prion disease should be suspected in any patient with rapidly ´progressing cognitive impairment. However, its diagnosis is difficult, as many clinically overlapping and often treatable neurological processes are considered in its differential diagnosis (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). As a general rule, it should be noted that any evidence of inflammation in the cerebrospinal fluid (CSF) is contrary to a diagnosis of prion disease and an alternative diagnosis should be investigated.<a class="elsevierStyleCrossRefs" href="#bib0010">2,4</a> However, one third of patients with CJD may show a slight increase in CSF proteins and, occasionally, in oligoclonal bands.<a class="elsevierStyleCrossRef" href="#bib0020">4</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Certain findings on complementary examinations indicate prion disease. Magnetic resonance imaging (MRI) is an essential test for suspected prion disease. The MRI study should include contrast-enhanced T1-weighted sequences (to rule out alternative neurological diseases), as well as FLAIR and diffusion sequence with the apparent diffusion coefficient map.<a class="elsevierStyleCrossRefs" href="#bib0020">4,22</a> In two thirds of patients with CJD, MRI shows signal enhancement in the basal ganglia, thalamus, and sometimes in the cortical grey matter on T2, FLAIR or diffusion sequences<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,13,22</a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). On the other hand, it has been reported that a typical CJD MRI will show diffusion restriction in at least 2 cortical areas (temporal-parietal-occipital); and/or in the caudate region, caudate-putamen, or caudate-putamen-thalamus,<a class="elsevierStyleCrossRef" href="#bib0110">22</a> without white matter involvement.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>The electroencephalogram (EEG) may show large amplitude periodic three-phase complexes with a frequency of approximately 1 per second (periodic sharp wave complexes).<a class="elsevierStyleCrossRefs" href="#bib0010">2–4,11,22</a> These typical EEG findings are seen in late stages of the disease and may occur in other forms of dementia. Overall, EEG alterations have a sensitivity of 64% and a specificity of 80–91%.<a class="elsevierStyleCrossRefs" href="#bib0010">2,22</a> Elevated levels of neuronal proteins 14−3-3 (sensitivity: 61–95%; specificity: 40–92%)<a class="elsevierStyleCrossRef" href="#bib0025">5</a> and tau can be found in CSF, which also occurs in other neurological processes with neuronal injury.<a class="elsevierStyleCrossRefs" href="#bib0010">2,4,5,22</a> On the other hand, the sensitivity of these biomarkers decreases in the early stages of the disease and with the different molecular subtypes of CJD, with lower sensitivity in the MV2 and MM2 subtypes.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>Procedures for the detection of prions in vitro in clinical samples, such as real-time quaking-induced conversion (RT-QuIC) or protein-misfolding cyclic amplification (PMCA), are now available and have led to significant advances in the ante-mortem diagnosis of prion diseases.<a class="elsevierStyleCrossRefs" href="#bib0025">5,11,22,23</a> The rationale for RT-QuIC is that if CSF contains prions, incubation with recombinant PrP (with thioflavin T) will result in a conformational change of PrP in vitro leading to amyloid formation.<a class="elsevierStyleCrossRefs" href="#bib0025">5,22,23</a> Amyloid formation is detected by the emission of fluorescence by thioflavin T. In this technique, repeated cycles of substrate incubation and agitation are used to fragment the protein cluster formed; so that it can act as a template ('seed') for further abnormal folding of recombinant PrP.<a class="elsevierStyleCrossRefs" href="#bib0025">5,22,23</a> In this way, prions are continuously amplified. RT-QuIC applied to CSF samples has a sensitivity of between 92–97%<a class="elsevierStyleCrossRefs" href="#bib0025">5,10,22</a> and a specificity close to 100% in symptomatic patients; thus its positive results leave little room for a false positive diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0010">2,5,10,22</a>,<a class="elsevierStyleCrossRef" href="#bib0115">23</a> The sensitivity of the test is higher in MM1/MV1 and VV2 molecular subtypes than in other sporadic CJD subtypes.<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</a> Similarly, sensitivity is higher in genetic CJD associated with E200 K and V210I mutations than in other mutations.<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</a> RT-QuIC has also been applied to skin and olfactory mucosa samples with high sensitivity.<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</a> Given the performance of RT-QuICR, an international expert committee has recommended this test on CSF or other clinical samples as an essential diagnostic procedure in suspected CJD.<a class="elsevierStyleCrossRefs" href="#bib0020">4,11,22,23</a>Variant CJD can be difficult to diagnose, because previously noted markers, such as 14-3-3 protein or CSF prion amplification with RT-QuIC, as well as EEG alterations may be absent. A characteristic finding in patients with variant CJD is signal enhancement on MRI in the posterior nucleus of the thalamus, which will be brighter than the anterior putamen (pulvinar sign), and which is seen in more than 90% of cases.<a class="elsevierStyleCrossRefs" href="#bib0005">1,3,22</a> A very useful diagnostic test for diagnosis of variant CJD is PMCA, which shows excellent sensitivity in CSF (100%), plasma (100%) and urine (93%) in these patients, while its yield in other prion diseases is low.<a class="elsevierStyleCrossRefs" href="#bib0015">3,22,23</a> In PMCA, the fragmentation of the protein cluster to act as the 'seed' of the abnormal folding in the test cycles is sonication.<a class="elsevierStyleCrossRefs" href="#bib0055">11,22,23</a>The definitive diagnosis of prion disease is established by histopathological study and immunohistochemical staining that reveals the presence of PrPSc in brain tissue samples obtained at necropsy or through biopsy.<a class="elsevierStyleCrossRefs" href="#bib0010">2,5,22</a> Biopsy has a low sensitivity (20–60 %) and, moreover, ante-mortem diagnosis does not change the treatment. For these reasons, specialists only recommend brain biopsy for the diagnosis of alternative neurological diseases.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,5,22</a> Apart from the definitive diagnosis, there are 2 other diagnostic categories for sporadic CJD, the most common form of prion disease.<a class="elsevierStyleCrossRefs" href="#bib0025">5,22</a> According to an International Expert Committee<a class="elsevierStyleCrossRef" href="#bib0110">22</a> any progressive neuropsychiatric syndrome, in the absence of other alternative diagnoses after a thorough clinical assessment, with a positive RT-QuICR test; or a rapidly progressive cognitive disorder with 2 of the following 4 criteria, is considered probable sporadic CJD: (a) myoclonia, (b) visual or cerebellar disturbances, (c) pyramidal/extrapyramidal signs, and (d) akinetic mutism; provided he/she has a typical EEG (periodic sharp wave complexes), or a characteristic MRI, or a positive CSF 14-3-3 protein test. Characteristic MRI is considered when there is diffusion restriction in the caudate nucleus or caudate-putamen or caudate-putamen-thalamus, or in at least 2 cortical regions (temporal, occipital parietal), without white matter involvement or diffusion restriction limited to the thalamus. Finally, patients analogous to the above, with a disease duration of less than 2 years, but without EEG, MRI or 14-3-3 protein in CSF are included in the category of possible sporadic CJD.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>Given the complexity of diagnosing prion disease and the scarcity of patients, a national centre (National Prion Disorders Pathology Service Center) has been established in the USA to advise on histopathology and to facilitate prion amplification and determination of neuronal proteins in CSF.TreatmentPrion diseases are currently incurable and there is no treatment that will ameliorate the course of the disease.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> Most patients with sporadic CJD die within a year of symptom onset. Patients with other variants of prion disease may have a more protracted course. Therapeutic measures should be oriented towards the early establishment of palliative care. Authorisation for clinical autopsy should be sought from patients or relatives. Obviously, post-mortem examination, even restricted to the brain, is a risky operation and WHO recommendations should be followed to the utmost.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> Similarly, biosafety level 3 facilities are advisable for the processing of histological specimens.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>PreventionPrion diseases are potentially transmissible. The risk of contracting the disease depends on 3 factors: the likelihood of the patient suffering from prion disease, the infectivity of the fluid/tissue and the route of exposure.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Recently, the detection of prions in a cadaver donated for anatomical practice<a class="elsevierStyleCrossRef" href="#bib0125">25</a> was reported, raising concerns about accidental exposure to prions through contact with infected tissues. In general, the material with the highest prion load and the highest infectivity is nervous tissue (brain, spinal cord, eye). CSF, blood and other tissues have low infectivity. The risk of contracting the disease through dermal exposure is negligible.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Normal social contact or clinical practice (including non-invasive procedures) presents no risk.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Nor are isolation measures or contact precautions required for routine medical practice. Neurosurgical or reusable material should be destroyed or decontaminated according to WHO recommendations.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>ConclusionsPrion diseases are a group of diseases with a unique pathogenesis. The disease occurs sporadically or through genetic transmission. There is a third form of onset, acquired or infectious, through dietary consumption or contact with prion-contaminated tissues. The causative agent of the disease is an abnormally folded protein, which induces the normal protein, PrP, to transform into the disease-associated protein PrPSc. PrPSc is resistant to degradation by proteases and to physical or chemical decontamination. For this reason, special protocols are required for the complete disinfection of PrPSc from highly infective tissues. From a clinical point of view, diagnosis is difficult. Familiarity with the clinical presentation of the different phenotypes together with the appropriate use of diagnostic procedures with high sensitivity and specificity, such as MRI and RT-QuIC, allow for a confident ante-mortem diagnosis. However, definitive diagnosis requires histopathological examination of the patient's brain tissue. Standard clinical practice requires only standard preventive measures, but special protocols are needed when handling nerve tissue. There is currently no treatment available to modify the course of the disease. However, there is active research into the development of effective therapeutic strategies for prion diseases. For example, the use of antisense oligonucleotides could prevent or avoid the accumulation of prions.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> On the other hand, a fundamental pathogenic role is now attributed to neuroinflammatory mechanisms mediated by microglial activation and astrogliosis in all neurodegenerative diseases, including prion diseases.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> The study of neuroinflammation opens up the possibility of modulating glial cell activation in prion diseases, and also in other more common neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.Conflict of interestNone." "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres1915223" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1653492" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1915222" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1653491" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Epidemiology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Pathogenesis" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Pathological anatomy" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Genetics" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Signs and symptoms" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Diagnosis" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Treatment" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Prevention" ] 13 => array:2 [ "identificador" => "sec0050" "titulo" => "Conclusions" ] 14 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflict of interest" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-10-07" "fechaAceptado" => "2023-03-03" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1653492" "palabras" => array:6 [ 0 => "Creutzfeldt–Jakob disease" 1 => "Fatal familial insomnia" 2 => "Gerstmann–Sträussler–Scheinker syndrome" 3 => "Prion" 4 => "Prion diseases" 5 => "Real-time quaking-induced conversion (RT-QuIC)" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1653491" "palabras" => array:6 [ 0 => "Enfermedad de Creutzfeldt–Jakob" 1 => "Enfermedad priónica" 2 => "Insomnio familiar fatal" 3 => "Prion" 4 => "Real-time quaking-induced conversion (RT-QuIC)" 5 => "Síndrome de Gerstmann–Sträussler–Scheinker" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Prion diseases are a group of neurodegenerative diseases. The disease-causing agent is a protein (PrP), that is normally produced in the nervous system, aggregated in an abnormal form. The abnormal protein, known as prion (PrPSc), is capable of self-propagation promoting the misfolding of the normal protein (PrP). These conditions can be acquired sporadically, genetically, or infectiously either by eating meat contaminated with prions or from iatrogenic exposure. The diagnosis of these diseases is often challenging. The use of highly sensitive and specific diagnostic tools, such as MRI and RT-QuIC, may aid in the diagnosis. Neuropathological examination of brain tissue ensures a definite diagnosis. At present, no treatment significantly improves the course of prion diseases; however, an early diagnosis is of paramount importance for patient care decision planning, infection control purposes and genetic counseling." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Las enfermedades por priones constituyen un grupo de enfermedades neurodegenerativas, cuyo agente causal es una proteína normal del cerebro (PrP) que se agrega en una conformación anómala. La proteína anormal, conocida como prion (PrPSc), tiene la propiedad de auto-propagarse induciendo la plegadura anómala de la proteína normal PrP. Estas enfermedades se presentan de manera esporádica, por transmisión genética, o de forma adquirida por ingesta de carne contaminada con priones o por exposición iatrógena. Su diagnóstico resulta difícil. La utilización de exploraciones complementarias de alta sensibilidad y especificidad, como la resonancia magnética o la RT-QuIC, facilitan su diagnóstico. El diagnóstico definitivo se establece por el estudio histopatológico de muestras de tejidos. Actualmente, no se dispone de ningún tratamiento que modifique el curso de la enfermedad, pero su diagnóstico precoz es fundamental para planificar los cuidados del enfermo, adoptar las medidas de prevención necesarias y el consejo genético." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 564 "Ancho" => 2508 "Tamanyo" => 73598 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Schematic representation of exon 2 of the PRNP gene. The schematic shows the point mutations (missense) with more than 100 cases published in the medical literature and the polymorphic codon 129. These 5 mutations are responsible for approximately 85% of genetic prion diseases. D: aspartic acid; E: glutamate; I: isoleucine; K: lysine; L: leucine; M: methionine; N: asparagine; P: proline." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 864 "Ancho" => 1340 "Tamanyo" => 67432 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "MRI of a patient with probable Creutzfeldt–Jakob disease. Signal enhancement in the cortical grey matter, more significant in the right hemisphere, in FLAIR sequence (A) and in diffusion sequence (B)." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "CJD, Creutzfeldt–Jakob disease; EEG, electroencephalogram; MM2-C, MM2-cortical; MM2-T, MM2-thalamic." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variant sCJD \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Frequency (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical signs \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Neuropathology \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MM1/MV1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65−70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rapidly progressive dementia, early and prominent myoclonus, typical EEG, visual impairment common \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Classical distribution of spongiosis (cerebral cortex, striatum, thalamus and cerebellum), prominent occipital cortex involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VV2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15−20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ataxia onset, late onset dementia, atypical EEG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cortical and subcortical spongiform involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MV2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ataxia, progressive dementia, atypical EEG, long disease duration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Similar to VV2, but with amyloid plaques in the cerebellum. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MM2-T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Insomnia, psychomotor agitation, ataxia, progressive dementia, atypical EEG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Thalamic and inferior olivary atrophy, spongiosis may be absent. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MM2-C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Progressive dementia, atypical EEG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Large confluent vacuoles and perivascular PrPSc staining. Cerebral cortex and striatum affected, but not cerebellum. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VV1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Frequent onset with psychiatric symptoms, progressive dementia, atypical EEG, long course (often >2 years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral cortex and striatum affected, with preserved cerebellum. No confluent vacuoles \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Clinicopathological features of molecular variants of sporadic Creutzfeldt–Jakob disease." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neurodegenerative diseases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prion diseases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rapidly progressive Alzheimer's disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rapidly progressive Lewy body dementia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Frontotemporal dementia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Corticobasal ganglionic degeneration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Progressive supranuclear palsy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inflammatory diseases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Autoimmune encephalitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infectious encephalitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Septic encephalopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vascular diseases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stroke \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral Vasculitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral amyloid angiopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Toxic-metabolic encephalopathies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Korsakoff–Wernicke syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatic encephalopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uraemic encephalopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Poisoning (lithium, bismuth, methotrexate) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Brain neoplasms \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary cerebral lymphoma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intravascular lymphoma \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Differential diagnosis of rapidly progressive dementia." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:26 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human prion diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H. Wang" 1 => "D.D. Rhoads" 2 => "B.S. Appleby" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/QCO.0000000000000552" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Infect Dis" "fecha" => "2019" "volumen" => "32" "paginaInicial" => "272" "paginaFinal" => "276" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31008724" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prion diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P.J. 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Zerr" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41582-022-00659-0" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Neurol" "fecha" => "2022" "volumen" => "18" "paginaInicial" => "363" "paginaFinal" => "376" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35508635" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical laboratory tests used to aid in diagnosis of human prion disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. Connor" 1 => "H. Wang" 2 => "B.S. Appleby" 3 => "D.D. 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Human prion diseases: An overview

Enfermedades por priones humanas. Una revisión general

Raquel Piñar-Moralesa,b, Francisco Barrero-Hernándeza,b, Luis Aliaga-Martíneza,

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laliaga@ugr.es

Corresponding author.

a Departamento de Medicina, Facultad de Medicina. Universidad de Granada, Granada, Spain

b Servicio de Neurología, Hospital Clínico San Cecilio, Granada, Spain

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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of exon 2 of the <span class="elsevierStyleItalic">PRNP</span> gene&#46; The schematic shows the point mutations <span class="elsevierStyleItalic">&#40;missense&#41;</span> with more than 100 cases published in the medical literature and the polymorphic codon 129&#46; These 5 mutations are responsible for approximately 85&#37; of genetic prion diseases&#46; D&#58; aspartic acid&#59; E&#58; glutamate&#59; I&#58; isoleucine&#59; K&#58; lysine&#59; L&#58; leucine&#59; M&#58; methionine&#59; N&#58; asparagine&#59; P&#58; proline&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Prion diseases are a group of closely related and rapidly progressive neurodegenerative diseases affecting mammals&#44; including humans&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> In these diseases&#44; a normal brain protein known as <span class="elsevierStyleItalic">prion</span> protein &#40;PrP&#41; aggregates into an abnormal conformation&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> This abnormal form of the protein&#44; known as <span class="elsevierStyleItalic">&#34;prion&#34;</span>&#44; acts as an infectious agent and can transmit the disease to other hosts&#46; The <span class="elsevierStyleItalic">&#34;prion&#34;</span> is therefore an &#34;infectious&#34; protein conformation containing no nucleic acids&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The majority of prion diseases in humans correspond to the entity known as Creutzfeldt&#8211;Jakob disease &#40;CJD&#41;&#44; although other clinical forms can also occur&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Their diagnosis is always a challenge for clinicians&#46; However&#44; early detection and monitoring is crucial for care planning and public health implications&#46; The recent introduction of techniques allowing the detection of prions in biological samples has been a remarkable achievement for the understanding of these entities&#46; In the light of these developments&#44; it seems appropriate to briefly review the pathogenesis&#44; clinical and diagnostic features of these diseases&#44; as well as their public health implications and possible therapeutics&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">Prion diseases have a worldwide distribution&#44; with an annual incidence of 1&#8211;2 cases per million population&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;4</span></a> They can occur sporadically &#40;85&#8211;90&#37; of cases&#41; or by genetic transmission &#40;10&#8211;15&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> In addition&#44; there is a third form of presentation&#44; the acquired or &#34;infectious&#34; form &#40;&#60;1&#37;&#41;&#44; either by dietary consumption of prion contaminated meat or by iatrogenic transmission&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Sporadic cases affect subjects in a highly variable age range&#44; from 16 to 98 years old&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However&#44; they typically occur later in life&#44; with a peak in the 8th decade of life&#46; The highest incidence of genetic forms is in the 6th decade of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">There have been 2 outbreaks transmitted through ingestion&#58; kuru and variant CJD&#46; The first was an epidemic disease among the Fore-speaking Aborigines in Papua New Guinea&#46; The disease probably appeared sporadically and spread due to ritual practices of cannibalism&#46; This custom was banned in the 1950s&#44; so the last observed cases of kuru occurred in 2009 &#40;incubation period of at least 50 years&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;5</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The CJD variant&#44; known in the media as &#34;mad cow disease&#34; at the time&#44; appeared in the UK in 1994&#44; due to the consumption of beef contaminated with Bovine Spongiform Encephalopathy prions&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> a neurological disease of cattle that can be transmitted to cattle or humans by consumption of prion-infected parts of the animal&#46; This outbreak occurred 10 years after a massive epidemic of the disease in cattle&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Despite millions of people consuming this meat&#44; only 228 patients had the disease by 2016&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> Currently&#44; the incidence of variant CJD has decreased significantly due to the control of spongiform encephalopathy in cattle and vigilance to prevent contaminated meat from entering the human food chain&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> In addition&#44; one case has been reported in 2020 possibly related to occupational exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Finally&#44; iatrogenic cases of CJD have occurred from dura mater grafts &#40;228 cases&#41; and growth hormone injections &#40;226 cases&#41; prior to the use of recombinant growth hormone&#44; introduced around 1980&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> There are 3 documented cases of variant CJD transmission to blood transfusion recipients&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> These are the only proven cases of transmission by this mechanism&#59; interestingly&#44; transfusion of blood products from patients with sporadic CJD or genetic prion diseases has not transmitted the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3&#44;5</span></a> Other iatrogenic forms of transmission are exceptional&#46; For example&#44; 6 cases of CJD transmitted via surgical and medical instruments&#59; and 2 cases via corneal transplantation&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathogenesis</span><p id="par0040" class="elsevierStylePara elsevierViewall">PrP is a cell surface protein found in the brain and some other tissues whose function is unknown&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The primary structure of PrP consists of 253 amino acid residues&#44; and contains an unstable region in the N-terminal domain&#44; termed octapeptide repeat region &#40;OPR&#41;&#44; consisting of a non-peptide &#40;R1&#41; followed by 4 octapeptide repeats &#40;R2&#44; R2&#44; R3&#44; R4&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> After translation&#44; 22 amino acid residues are removed from the N-terminal region and 23 from the C-terminal domain of the protein&#44; and a glycosylphosphatidylinositol anchor is attached to the C-terminal domain &#40;residue 230&#41; for binding to the plasma membrane of the cell&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;10</span></a> PrP can also be internalised and recycled between the cell membrane and the endosome&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The globular domain of the protein extends from amino acid residues 125&#8211;228&#44; and contains 3 &#9001; helices &#40;amino acids 144&#8211;154&#44; 173&#8211;194&#44; and 200&#8211;228&#41; and 2 &#174; antiparallel folds &#40;residues 128&#8211;131 and 161&#8211;164&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> PrP can be glycosylated at asparagine residues 181 and 197&#59; resulting in non-&#44; mono- or di-glycosylated&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In prion diseases&#44; aggregates of an abnormal form of PrP&#44; known as PrP<span class="elsevierStyleSup">Sc</span>&#44; accumulate in the brain <span class="elsevierStyleItalic">&#40;scrapie prion protein&#41;</span>&#46; PrP consists mainly of &#9001;&#8239;helices&#44; while PrP<span class="elsevierStyleSup">Sc</span> has a high proportion of &#174;folds&#46; This conformational change affects the biochemical properties of PrP&#59; thus&#44; PrP<span class="elsevierStyleSup">Sc</span> is relatively resistant to degradation by proteases&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;10</span></a> PrP<span class="elsevierStyleSup">Sc</span> has the property of &#39;recruiting&#39; the normal protein &#40;PrP&#41; to join the abnormal protein aggregate&#46; Neither the structure of PrP<span class="elsevierStyleSup">Sc</span>&#44; nor the mechanisms for prion propagation are known exactly&#46; A basic conceptual model proposes that the normal helical structure of the &#9001; helical regions of PrP interacts directly with the regions of PrP<span class="elsevierStyleSup">Sc</span> in &#223;-fold&#44; losing its normal helical structure &#9001; and then binds to the aggregate&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The protein aggregate&#44; during its growth&#44; may fracture at some point&#44; thus creating additional particles for aggregation&#46; In this way&#44; the PrP<span class="elsevierStyleSup">Sc</span> aggregate can spread as an infectious agent&#46; Aggregates of PrP<span class="elsevierStyleSup">Sc</span> constitute a proteinaceous fibrillar material&#44; rich in folded proteins &#174;&#44; known as &#39;amyloid&#39;&#44; which cause central nervous system &#40;CNS&#41; toxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;9&#44;10</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In prion diseases&#44; the appearance of the abnormally conformed protein can occur by spontaneous conversion due to a modification after synthesis &#40;translation&#41; of the normal protein &#40;PrP&#41;&#59; by mutation in the gene encoding the protein&#59; or by exogenous acquisition of the protein&#46; In infectious or acquired food-borne forms&#44; prions first replicate in the enteric lymphatic system and Peyer&#39;s patches&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Subsequently&#44; they reach the CNS via the sympathetic nerves of the lymphoid tissue&#46; In the CNS&#44; prions spread synaptically&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pathological anatomy</span><p id="par0055" class="elsevierStylePara elsevierViewall">No macroscopic CNS changes are usually observed in these patients&#44; except for variable degrees of atrophy if the process has had a long course&#46; The characteristic histopathological picture of prion diseases consists of a combination of vacuolisation <span class="elsevierStyleItalic">&#40;status spongiosus&#41;</span> of the grey matter&#44; astrocytic gliosis and loss of neurons&#44; without inflammation&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;11</span></a> Spongiform changes consist of the appearance of small round or oval vacuolated voids in the neuropil surrounding the neurons&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Some forms of prion diseases have their own anatomopathological features&#44; such as the &#34;florid plaque&#34; found in variant CJD&#44; which consists of an eosinophilic amyloid plaque surrounded by a halo of vacuolisation &#40;spongiosis&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Aggregates of PrP<span class="elsevierStyleSup">Sc</span> &#40;amyloid&#41; in the CNS can form plaques or deposits at neuronal synapses&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Prion detection is based on the resistance of PrP<span class="elsevierStyleSup">Sc</span> aggregates to enzymatic proteolysis&#46; Nerve tissue is treated with proteinase K and then <span class="elsevierStyleItalic">Western blotting</span> for the detection of PrP<span class="elsevierStyleSup">Sc</span>&#44; which&#44; if present&#44; has not been broken down by the enzyme&#46; There are 2 main types of PrP<span class="elsevierStyleSup">Sc</span> in the nerve tissue of patients with prion diseases and they are observed in the <span class="elsevierStyleItalic">Western blot</span> as non-glycosylated bands of 21&#8239;KDa &#40;type 1&#41; or 19&#8239;KDa &#40;type 2&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;12</span></a> Most patients with CJD have only one type of PrP<span class="elsevierStyleSup">Sc</span>&#44; although both may coexist in one third of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> These PrP<span class="elsevierStyleSup">Sc</span> types combined with the codon 129 polymorphism form the basis for the molecular classification of sporadic CJD &#40;see below&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;8&#44;12&#8211;14</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Genetics</span><p id="par0060" class="elsevierStylePara elsevierViewall">All genetic forms of prion disease are caused by mutations in the sequence of the <span class="elsevierStyleItalic">PRNP</span> gene encoding the PrP<span class="elsevierStyleSup">2</span> protein&#46; This gene is located on human chromosome 20p13&#59; and consists of 2 exons&#44; although the complete open reading frame of the gene is in exon 2 &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> Codons 51&#8211;91 normally contain the sequences encoding a nonapeptide and 4 octapeptide repeats &#40;OPR region&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Among the polymorphic codons of the <span class="elsevierStyleItalic">PRNP</span> gene&#44; codon 129&#44; with 2 alleles coding for methionine or valine&#44; is the most relevant for its clinical implications&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#44;15</span></a> Codon 129 is a factor that modifies the clinical characteristics of prion diseases&#46; For this reason&#44; genetic prion diseases have been classified into haplotypes based on the mutation of the <span class="elsevierStyleItalic">PRNP</span> gene and the polymorphic codon 129 of the mutated allele&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">About 50 mutations associated with prion genetic diseases have been identified&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> It is generally considered that mutation of the <span class="elsevierStyleItalic">PRNP</span> gene confers on the protein an increased susceptibility to its abnormal conformation&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;10</span></a> Known mutations associated with prion diseases include more than 35 point mutations <span class="elsevierStyleItalic">&#40;missense&#41;</span> leading to amino acid substitutions&#59; 5 mutations leading to the appearance of a premature stop codon <span class="elsevierStyleItalic">&#40;nonsense&#41;</span> in protein synthesis&#59; and 24 base pair insertions in the OPR region that will encode between 2 and 12 octapeptides&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#44;9&#44;11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In addition&#44; deletions of 2 octapeptides in the OPR<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#8211;16</span></a> region have been described in 3 patients&#46; The insertion or deletion of a single octapeptide is not considered pathogenic&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9&#44;15</span></a> Among all these mutations&#44; 5 point mutations are considered to be responsible for 85&#37; of genetic prion diseases&#58; E200&#8239;K&#44; V210I&#44; V180I&#44; D178&#8239;N and P102L&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The genetic forms of prion diseases are transmitted in an autosomal dominant pattern&#44; generally with high&#44; but usually incomplete&#44; penetrance&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#8211;10&#44;15&#8211;17</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Historically&#44; genetic prion diseases have been classified into 3 clinicopathological phenotypes&#58; &#40;a&#41; genetic CJD&#44; &#40;b&#41; Gerstmann&#8211;Str&#228;ussler&#8211;Scheinker syndrome and &#40;c&#41; fatal familial insomnia&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;8</span></a> Base pair insertions may be associated with atypical clinical phenotypes that are difficult to classify between CJD or Gerstmann&#8211;Str&#228;ussler&#8211;Scheinker syndrome&#59; like stop codon mutations&#44; they may present as a dementia syndrome with variable progression&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;15</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">There are 23 known point mutations associated with genetic CJD&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> The most common mutation worldwide in genetic prion diseases is the substitution of glutamic acid &#40;E&#41; for lysine &#40;K&#41; at codon 200 &#40;E200&#8239;K&#41;&#44; which is clinically and histologically indistinguishable from sporadic CJD&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;8&#44;9&#44;11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;17</span></a> Transmission is autosomal dominant&#44; with an estimated penetrance between 54&#37; and 100&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;8&#44;9&#44;15</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Familial Gerstmann&#8211;Str&#228;ussler&#8211;Scheinker syndrome is due to more than 20 described point mutations and <span class="elsevierStyleItalic">PRNP</span> gene insertions&#46; The most common of these is the substitution for leucine coding instead of proline at codon 102 &#40;P102&#8239;L&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#44;9&#44;16</span></a> The incidence of this disease is difficult to determine but has been estimated at 1&#8211;10 cases per 100&#44;000&#44;000 population&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> From a histopathological point of view&#44; this mutation leads to the appearance of multifocal PrP<span class="elsevierStyleSup">Sc</span> amyloid plaques in the brain&#44; especially in the cerebellum&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#44;16</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Fatal familial insomnia is caused by the D178&#8239;N &#40;aspartic acid substituted for asparagine&#41; mutation associated with the allele encoding methionine at codon 129 of the mutated allele &#40;i&#46;e&#46;&#44; in <span class="elsevierStyleItalic">cis</span>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#8211;10&#44;15</span></a> Histopathologically&#44; these patients show neuronal loss&#44; gliosis and accumulation of PrP<span class="elsevierStyleSup">Sc</span> in the thalamus and inferior olivary nucleus&#46; Isolated gliosis may be present in the midbrain and hypothalamus&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> In contrast&#44; the spongiform changes characteristic of prion diseases are usually absent&#46; However&#44; the D178&#8239;N mutation associated with the allele coding for valine at codon 129 results in a disease that is clinically and histologically indistinguishable from sporadic CJD&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;10&#44;15</span></a> It is now thought that the haplotype effect is not so absolute&#44; and that the D178&#8239;N mutation may present as a clinical spectrum ranging from CJD to fatal familial insomnia&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9&#44;18&#44;19</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Finally&#44; there is a relationship between codon 129 genotype and susceptibility to prion diseases&#46; Thus&#44; persons homozygous &#40;129&#8239;MM or 129&#8239;V&#8239;V&#41; for this allele are over-represented among sporadic CJD patients&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#8211;10</span></a> and all variant CJD victims &#40;but 1&#41; have 129&#8239;M on both alleles of the <span class="elsevierStyleItalic">PRNP</span> gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3&#44;8&#44;10</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Signs and symptoms</span><p id="par0095" class="elsevierStylePara elsevierViewall">In human prion diseases&#44; 4 entities and some clinical variants are distinguished&#46; These are&#58; kuru&#44; CJD&#44; Gerstmann&#8211;Stra&#252;ssler&#8211;Scheinker syndrome&#44; and fatal familial insomnia&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Sporadic CJD is the most common form of prion disease in humans&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> Clinically&#44; it is characterised by rapidly progressive dementia&#44; ataxia and myoclonias&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In general&#44; a rapidly progressive dementia syndrome can be considered as a dementia syndrome with onset within 1&#8211;2 years from the onset of symptoms or a dementia syndrome with a total disease course &#8804;2 years&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In approximately 25&#37; of cases&#44; patients or their relatives report a prodromal phase with psychiatric symptoms&#44; such as anxiety&#44; depression or sleep disturbances&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Cognitive impairment is the most clinically expressive neurological sign&#44; with clear neurological function losses over a period of weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Neurological motor disturbances are prominent in the form of ataxia&#44; bradykinesia or spasticity&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> A characteristic but not pathognomonic sign of CJD is the presence of myoclonus&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Visual disturbances are common&#44; in the form of visual deficits&#44; distortion of visual perception or hallucinations due to involvement of the occipital cortex&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;13</span></a> In Heidenhain&#39;s variant&#44; isolated visual symptoms&#44; without ocular disease&#44; precede the rest of the neurological symptomatology&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The death of the patient occurs after a phase of akinetic mutism within 4&#8211;6 months from the onset of symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">There are sporadic cases of CJD showing atypical clinical manifestations&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In some patients&#44; without mutations in the <span class="elsevierStyleItalic">PRNP</span> gene&#44; they are clinically indistinguishable from fatal familial insomnia&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Another example of clinical atypicality is variably protease-sensitive prionopathy&#44; which presents with frontal lobe dementia&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8</span></a> These variants may be caused by different prion &#34;strains&#34;&#44; in analogy to infectious diseases&#46; Prion &#34;strains&#34; refer to aggregates of PrP<span class="elsevierStyleSup">Sc</span> with a different biochemical and neuropathological profile&#44; and which would produce differential neurotoxicity&#44; presumably through interaction with other factors&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;10&#44;13&#44;21</span></a> The result would be the presentation of different clinical phenotypes&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;10&#44;13&#44;21</span></a> Some researchers have pointed out that the type of PrP<span class="elsevierStyleSup">Sc</span> together with the genotype at codon 129 of the <span class="elsevierStyleItalic">PRNP</span> gene determines 6 clinicopathological subtypes of sporadic CJD&#44;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;8&#44;12&#8211;14</span></a> which are summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; As indicated in this table&#44; the thalamic and cortical MM2 subtypes do not differ molecularly &#40;in both the PrP<span class="elsevierStyleSup">Sc</span> deposition is type 2&#41;&#44; but they do differ in terms of neuropathology and clinical phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;8&#44;12&#8211;14</span></a> The MM2-thalamic subtype is also called fatal sporadic insomnia&#44; and is clinically characterised by insomnia&#44; psychomotor agitation&#44; ataxia and progressive dementia&#46; Histopathologically&#44; thalamic and inferior olivary atrophy &#40;similar to fatal familial insomnia&#41; and spongiform changes may be absent&#46; The MM2-cortical subtype presents clinically with progressive dementia&#44; whereas spongiform degeneration can be observed in the cerebral cortex and striatum&#44; but not in the cerebellum&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Variant CJD&#44; acquired by consumption of meat from bovine spongiform encephalopathy-positive cattle&#44; is clinically distinguished from sporadic CJD by the age of presentation in much younger patients &#40;mean&#44; 26 yrs&#59; range&#44; 11&#8211;74 years&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> psychiatric disturbances are more prominent and sensory disturbances are of early onset in the form of limb pain or paraesthesias&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Motor disturbances&#44; visual disturbances and dementia develop later&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The average duration of the disease is approximately 14 months&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Iatrogenic CJD is similar to the sporadic form&#44; but there is an ataxic form that clinically and histopathologically resembles Gerstmann&#8211;Stra&#252;ssler&#8211;Scheinker syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Kuru starts with pain in the limbs&#44; followed by cerebellar ataxia and tremor &#40;&#34;kuru&#34; means tremor in the Fore language&#41;&#46; The onset of frank dementia occurred later in the course of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The most common form of presentation in Gerstmann&#8211;Str&#228;ussler&#8211;Scheinker syndrome is a slowly progressive cerebellar syndrome and cerebellar signs are almost universal with disease progression&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> One group of patients may develop prominent psychiatric symptoms at onset&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Cognitive impairment is common with disease progression&#44; but rare as presenting symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;16</span></a> The progression is usually slower than in sporadic CJD&#44; and the time lag between the onset of symptoms and death is usually 5&#8211;6 years&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The fourth prion disease entity is fatal familial insomnia&#46; In Spain&#44; 35 cases had been diagnosed up to 2008&#44; of which 16 were from the Basque Autonomous Community&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Clinically&#44; the disease is characterised by severe insomnia&#44; dysautonomia and hallucinations in the early stages&#44; followed by ataxia&#44; myoclonia and signs of pyramidal involvement&#44; such as hyperreflexia&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8</span></a> This symptomatology may be preceded by anxiety and depression&#46; Dementia is relatively late onset&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Some familial forms of prion diseases have a very slow course that resembles familial Alzheimer&#39;s disease or Huntington&#39;s disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;9&#44;15</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Diagnosis</span><p id="par0120" class="elsevierStylePara elsevierViewall">From a clinical point of view&#44; prion disease should be suspected in any patient with rapidly &#180;progressing cognitive impairment&#46; However&#44; its diagnosis is difficult&#44; as many clinically overlapping and often treatable neurological processes are considered in its differential diagnosis &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; As a general rule&#44; it should be noted that any evidence of inflammation in the cerebrospinal fluid &#40;CSF&#41; is contrary to a diagnosis of prion disease and an alternative diagnosis should be investigated&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4</span></a> However&#44; one third of patients with CJD may show a slight increase in CSF proteins and&#44; occasionally&#44; in oligoclonal bands&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">Certain findings on complementary examinations indicate prion disease&#46; Magnetic resonance imaging &#40;MRI&#41; is an essential test for suspected prion disease&#46; The MRI study should include contrast-enhanced T1-weighted sequences &#40;to rule out alternative neurological diseases&#41;&#44; as well as FLAIR and diffusion sequence with the apparent diffusion coefficient map&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;22</span></a> In two thirds of patients with CJD&#44; MRI shows signal enhancement in the basal ganglia&#44; thalamus&#44; and sometimes in the cortical grey matter on T2&#44; FLAIR or diffusion sequences<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;13&#44;22</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; On the other hand&#44; it has been reported that a typical CJD MRI will show diffusion restriction in at least 2 cortical areas &#40;temporal-parietal-occipital&#41;&#59; and&#47;or in the caudate region&#44; caudate-putamen&#44; or caudate-putamen-thalamus&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> without white matter involvement&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">The electroencephalogram &#40;EEG&#41; may show large amplitude periodic three-phase complexes with a frequency of approximately 1 per second <span class="elsevierStyleItalic">&#40;periodic sharp wave complexes&#41;&#46;</span><a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;4&#44;11&#44;22</span></a> These typical EEG findings are seen in late stages of the disease and may occur in other forms of dementia&#46; Overall&#44; EEG alterations have a sensitivity of 64&#37; and a specificity of 80&#8211;91&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;22</span></a> Elevated levels of neuronal proteins 14&#8722;3-3 &#40;sensitivity&#58; 61&#8211;95&#37;&#59; specificity&#58; 40&#8211;92&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and tau can be found in CSF&#44; which also occurs in other neurological processes with neuronal injury&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4&#44;5&#44;22</span></a> On the other hand&#44; the sensitivity of these biomarkers decreases in the early stages of the disease and with the different molecular subtypes of CJD&#44; with lower sensitivity in the MV2 and MM2 subtypes&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Procedures for the detection of prions in vitro in clinical samples&#44; such as <span class="elsevierStyleItalic">real-time quaking-induced conversion</span> &#40;RT-QuIC&#41; or <span class="elsevierStyleItalic">protein-misfolding cyclic amplification</span> &#40;PMCA&#41;&#44; are now available and have led to significant advances in the ante-mortem diagnosis of prion diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;11&#44;22&#44;23</span></a> The rationale for RT-QuIC is that if CSF contains prions&#44; incubation with recombinant PrP &#40;with thioflavin T&#41; will result in a conformational change of PrP in vitro leading to amyloid formation&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;22&#44;23</span></a> Amyloid formation is detected by the emission of fluorescence by thioflavin T&#46; In this technique&#44; repeated cycles of substrate incubation and agitation are used to fragment the protein cluster formed&#59; so that it can act as a template &#40;&#39;seed&#39;&#41; for further abnormal folding of recombinant PrP&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;22&#44;23</span></a> In this way&#44; prions are continuously amplified&#46; RT-QuIC applied to CSF samples has a sensitivity of between 92&#8211;97&#37;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;10&#44;22</span></a> and a specificity close to 100&#37; in symptomatic patients&#59; thus its positive results leave little room for a false positive diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5&#44;10&#44;22</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> The sensitivity of the test is higher in MM1&#47;MV1 and VV2 molecular subtypes than in other sporadic CJD subtypes&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> Similarly&#44; sensitivity is higher in genetic CJD associated with E200&#8239;K and V210I mutations than in other mutations&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> RT-QuIC has also been applied to skin and olfactory mucosa samples with high sensitivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> Given the performance of RT-QuICR&#44; an international expert committee has recommended this test on CSF or other clinical samples as an essential diagnostic procedure in suspected CJD&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;11&#44;22&#44;23</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Variant CJD can be difficult to diagnose&#44; because previously noted markers&#44; such as 14-3-3 protein or CSF prion amplification with RT-QuIC&#44; as well as EEG alterations may be absent&#46; A characteristic finding in patients with variant CJD is signal enhancement on MRI in the posterior nucleus of the thalamus&#44; which will be brighter than the anterior putamen &#40;pulvinar sign&#41;&#44; and which is seen in more than 90&#37; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3&#44;22</span></a> A very useful diagnostic test for diagnosis of variant CJD is PMCA&#44; which shows excellent sensitivity in CSF &#40;100&#37;&#41;&#44; plasma &#40;100&#37;&#41; and urine &#40;93&#37;&#41; in these patients&#44; while its yield in other prion diseases is low&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;22&#44;23</span></a> In PMCA&#44; the fragmentation of the protein cluster to act as the &#39;seed&#39; of the abnormal folding in the test cycles is sonication&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;22&#44;23</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The definitive diagnosis of prion disease is established by histopathological study and immunohistochemical staining that reveals the presence of PrP<span class="elsevierStyleSup">Sc</span> in brain tissue samples obtained at necropsy or through biopsy&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5&#44;22</span></a> Biopsy has a low sensitivity &#40;20&#8211;60 &#37;&#41; and&#44; moreover&#44; ante-mortem diagnosis does not change the treatment&#46; For these reasons&#44; specialists only recommend brain biopsy for the diagnosis of alternative neurological diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;5&#44;22</span></a> Apart from the definitive diagnosis&#44; there are 2 other diagnostic categories for sporadic CJD&#44; the most common form of prion disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;22</span></a> According to an International Expert Committee<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> any progressive neuropsychiatric syndrome&#44; in the absence of other alternative diagnoses after a thorough clinical assessment&#44; with a positive RT-QuICR test&#59; or a rapidly progressive cognitive disorder with 2 of the following 4 criteria&#44; is considered probable sporadic CJD&#58; &#40;a&#41; myoclonia&#44; &#40;b&#41; visual or cerebellar disturbances&#44; &#40;c&#41; pyramidal&#47;extrapyramidal signs&#44; and &#40;d&#41; akinetic mutism&#59; provided he&#47;she has a typical EEG &#40;periodic sharp wave complexes&#41;&#44; or a characteristic MRI&#44; or a positive CSF 14-3-3 protein test&#46; Characteristic MRI is considered when there is diffusion restriction in the caudate nucleus or caudate-putamen or caudate-putamen-thalamus&#44; or in at least 2 cortical regions &#40;temporal&#44; occipital parietal&#41;&#44; without white matter involvement or diffusion restriction limited to the thalamus&#46; Finally&#44; patients analogous to the above&#44; with a disease duration of less than 2 years&#44; but without EEG&#44; MRI or 14-3-3 protein in CSF are included in the category of possible sporadic CJD&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Given the complexity of diagnosing prion disease and the scarcity of patients&#44; a national centre &#40;National Prion Disorders Pathology Service Center&#41; has been established in the USA to advise on histopathology and to facilitate prion amplification and determination of neuronal proteins in CSF&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Treatment</span><p id="par0155" class="elsevierStylePara elsevierViewall">Prion diseases are currently incurable and there is no treatment that will ameliorate the course of the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> Most patients with sporadic CJD die within a year of symptom onset&#46; Patients with other variants of prion disease may have a more protracted course&#46; Therapeutic measures should be oriented towards the early establishment of palliative care&#46; Authorisation for clinical autopsy should be sought from patients or relatives&#46; Obviously&#44; post-mortem examination&#44; even restricted to the brain&#44; is a risky operation and WHO recommendations should be followed to the utmost&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Similarly&#44; biosafety level 3 facilities are advisable for the processing of histological specimens&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Prevention</span><p id="par0160" class="elsevierStylePara elsevierViewall">Prion diseases are potentially transmissible&#46; The risk of contracting the disease depends on 3 factors&#58; the likelihood of the patient suffering from prion disease&#44; the infectivity of the fluid&#47;tissue and the route of exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Recently&#44; the detection of prions in a cadaver donated for anatomical practice<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> was reported&#44; raising concerns about accidental exposure to prions through contact with infected tissues&#46; In general&#44; the material with the highest prion load and the highest infectivity is nervous tissue &#40;brain&#44; spinal cord&#44; eye&#41;&#46; CSF&#44; blood and other tissues have low infectivity&#46; The risk of contracting the disease through dermal exposure is negligible&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Normal social contact or clinical practice &#40;including non-invasive procedures&#41; presents no risk&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Nor are isolation measures or contact precautions required for routine medical practice&#46; Neurosurgical or reusable material should be destroyed or decontaminated according to WHO recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conclusions</span><p id="par0165" class="elsevierStylePara elsevierViewall">Prion diseases are a group of diseases with a unique pathogenesis&#46; The disease occurs sporadically or through genetic transmission&#46; There is a third form of onset&#44; acquired or infectious&#44; through dietary consumption or contact with prion-contaminated tissues&#46; The causative agent of the disease is an abnormally folded protein&#44; which induces the normal protein&#44; PrP&#44; to transform into the disease-associated protein PrP<span class="elsevierStyleSup">Sc</span>&#46; PrP<span class="elsevierStyleSup">Sc</span> is resistant to degradation by proteases and to physical or chemical decontamination&#46; For this reason&#44; special protocols are required for the complete disinfection of PrP<span class="elsevierStyleSup">Sc</span> from highly infective tissues&#46; From a clinical point of view&#44; diagnosis is difficult&#46; Familiarity with the clinical presentation of the different phenotypes together with the appropriate use of diagnostic procedures with high sensitivity and specificity&#44; such as MRI and RT-QuIC&#44; allow for a confident ante-mortem diagnosis&#46; However&#44; definitive diagnosis requires histopathological examination of the patient&#39;s brain tissue&#46; Standard clinical practice requires only standard preventive measures&#44; but special protocols are needed when handling nerve tissue&#46; There is currently no treatment available to modify the course of the disease&#46; However&#44; there is active research into the development of effective therapeutic strategies for prion diseases&#46; For example&#44; the use of antisense oligonucleotides could prevent or avoid the accumulation of prions&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> On the other hand&#44; a fundamental pathogenic role is now attributed to neuroinflammatory mechanisms mediated by microglial activation and astrogliosis in all neurodegenerative diseases&#44; including prion diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The study of neuroinflammation opens up the possibility of modulating glial cell activation in prion diseases&#44; and also in other more common neurodegenerative diseases such as Alzheimer&#39;s disease or Parkinson&#39;s disease&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflict of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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            1 => "Fatal familial insomnia"
            2 => "Gerstmann&#8211;Str&#228;ussler&#8211;Scheinker syndrome"
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            4 => "Prion diseases"
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            2 => "Insomnio familiar fatal"
            3 => "Prion"
            4 => "Real-time quaking-induced conversion &#40;RT-QuIC&#41;"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Prion diseases are a group of neurodegenerative diseases&#46; The disease-causing agent is a protein &#40;PrP&#41;&#44; that is normally produced in the nervous system&#44; aggregated in an abnormal form&#46; The abnormal protein&#44; known as prion &#40;PrP<span class="elsevierStyleSup">Sc</span>&#41;&#44; is capable of self-propagation promoting the misfolding of the normal protein &#40;PrP&#41;&#46; These conditions can be acquired sporadically&#44; genetically&#44; or infectiously either by eating meat contaminated with prions or from iatrogenic exposure&#46; The diagnosis of these diseases is often challenging&#46; The use of highly sensitive and specific diagnostic tools&#44; such as MRI and RT-QuIC&#44; may aid in the diagnosis&#46; Neuropathological examination of brain tissue ensures a definite diagnosis&#46; At present&#44; no treatment significantly improves the course of prion diseases&#59; however&#44; an early diagnosis is of paramount importance for patient care decision planning&#44; infection control purposes and genetic counseling&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Las enfermedades por priones constituyen un grupo de enfermedades neurodegenerativas&#44; cuyo agente causal es una prote&#237;na normal del cerebro &#40;PrP&#41; que se agrega en una conformaci&#243;n an&#243;mala&#46; La prote&#237;na anormal&#44; conocida como prion &#40;PrP<span class="elsevierStyleSup">Sc</span>&#41;&#44; tiene la propiedad de auto-propagarse induciendo la plegadura an&#243;mala de la prote&#237;na normal PrP&#46; Estas enfermedades se presentan de manera espor&#225;dica&#44; por transmisi&#243;n gen&#233;tica&#44; o de forma adquirida por ingesta de carne contaminada con priones o por exposici&#243;n iatr&#243;gena&#46; Su diagn&#243;stico resulta dif&#237;cil&#46; La utilizaci&#243;n de exploraciones complementarias de alta sensibilidad y especificidad&#44; como la resonancia magn&#233;tica o la RT-QuIC&#44; facilitan su diagn&#243;stico&#46; El diagn&#243;stico definitivo se establece por el estudio histopatol&#243;gico de muestras de tejidos&#46; Actualmente&#44; no se dispone de ning&#250;n tratamiento que modifique el curso de la enfermedad&#44; pero su diagn&#243;stico precoz es fundamental para planificar los cuidados del enfermo&#44; adoptar las medidas de prevenci&#243;n necesarias y el consejo gen&#233;tico&#46;</p></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of exon 2 of the <span class="elsevierStyleItalic">PRNP</span> gene&#46; The schematic shows the point mutations <span class="elsevierStyleItalic">&#40;missense&#41;</span> with more than 100 cases published in the medical literature and the polymorphic codon 129&#46; These 5 mutations are responsible for approximately 85&#37; of genetic prion diseases&#46; D&#58; aspartic acid&#59; E&#58; glutamate&#59; I&#58; isoleucine&#59; K&#58; lysine&#59; L&#58; leucine&#59; M&#58; methionine&#59; N&#58; asparagine&#59; P&#58; proline&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">CJD&#44; Creutzfeldt&#8211;Jakob disease&#59; EEG&#44; electroencephalogram&#59; MM2-C&#44; MM2-cortical&#59; MM2-T&#44; MM2-thalamic&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variant sCJD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Frequency &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical signs&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Neuropathology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MM1&#47;MV1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65&#8722;70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rapidly progressive dementia&#44; early and prominent myoclonus&#44; typical EEG&#44; visual impairment common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Classical distribution of spongiosis &#40;cerebral cortex&#44; striatum&#44; thalamus and cerebellum&#41;&#44; prominent occipital cortex involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VV2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#8722;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ataxia onset&#44; late onset dementia&#44; atypical EEG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cortical and subcortical spongiform involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MV2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ataxia&#44; progressive dementia&#44; atypical EEG&#44; long disease duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Similar to VV2&#44; but with amyloid plaques in the cerebellum&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MM2-T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Insomnia&#44; psychomotor agitation&#44; ataxia&#44; progressive dementia&#44; atypical EEG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thalamic and inferior olivary atrophy&#44; spongiosis may be absent&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MM2-C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Progressive dementia&#44; atypical EEG&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Large confluent vacuoles and perivascular PrP<span class="elsevierStyleSup">Sc</span> staining&#46; Cerebral cortex and striatum affected&#44; but not cerebellum&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">VV1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Frequent onset with psychiatric symptoms&#44; progressive dementia&#44; atypical EEG&#44; long course &#40;often &#62;2 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cerebral cortex and striatum affected&#44; with preserved cerebellum&#46; No confluent vacuoles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cerebral amyloid angiopathy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Toxic-metabolic encephalopathies</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Poisoning &#40;lithium&#44; bismuth&#44; methotrexate&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Brain neoplasms</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Intravascular lymphoma&nbsp;\t\t\t\t\t\t\n
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                  """
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Differential diagnosis of rapidly progressive dementia&#46;</p>"
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                      "titulo" => "Human prion diseases"
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                          "autores" => array:3 [
                            0 => "H&#46; Wang"
                            1 => "D&#46;D&#46; Rhoads"
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                    0 => array:2 [
                      "doi" => "10.1097/QCO.0000000000000552"
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                        "paginaFinal" => "276"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31008724"
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                            0 => "P&#46;J&#46; Bosque"
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                      "LibroEditado" => array:6 [
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                    0 => array:2 [
                      "doi" => "10.3390/pathogens10111413"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34832569"
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Article information

ISSN: 23870206
Original language: English

DOI:10.1016/j.medcle.2023.06.002

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