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A fingerstick yields a drop of blood for testing to determine if the donor has a high enough hematocrit to safely donate blood.

A fingerstick is made to obtain a drop of blood to test the hematocrit.

In the interview process a questionnaire is filled out. The questions are designed to identify potential health problems for the donor or potential infections that may be present in the donor that could be transmitted through transfusion to another person.

The donor is interviewed and a questionnaire is filled out.

Creutzfeldt-Jakob disease, MRI scan.

This cerebral MRI scan demonstrates hyperintensity in the region of the basal ganglia and caudate bilaterally. This is a finding that, in association with a history of a rapidly progressive dementia with myoclonus and electroencephalographic changes of slow waves with spikes, suggests Creutzfeldt-Jakob disease (CJD).Creutzfeldt-Jakob disease (CJD) is rare, affecting less than one person in a million per year. Though it has been reported to occur at a variety of ages, the median age of onset is in the seventh decade, with most sporadic cases occurring between the ages of 55 and 65, but familial or infectious cases can occur in younger adults. The course of the illness can be from a few weeks to eight years. However, the average length of survival from onset of the disease is less than a year. CJD is a uniformly fatal rapidly progressive dementia. (Markus et al, 2005). The clinical features of CJD include dementia, often with psychiatric or behavioral disturbances, in 100% of cases. About 80% of cases are marked by the appearance of myoclonus. By electroencephalography (EEG), there are periodic biphasic or triphasic synchronous sharp-wave complexes that are superimposed upon a slow background rhythm. Both myoclonus and characteristic EEG changes may subside late in the course of disease. Other neurologic findings may include cerebellar signs, pyramidal tract signs, extrapyramidal signs, corticla visual defects, abnormal extraocular movements, lower motor neuron signs, vestibular dysfunction, seizures, sensory deficits, and autonomic abnormalities. (Tee et al, 2018). Routine laboratory findings are not helpful. There is no dysfunction of major organ systems besides the central nervous system. Cerebrospinal fluid (CSF) will not show an increase in cells or immunoglobulins, and occasionally a mildly elevated protein. An abnormal protein called 14-3-3 can be found in the CSF by immunoassay, but this protein may be found in association with viral encephalitis and stroke. Clinical diagnosis can be made using the real-time quaking-induced conversion (RT-QuIC) assay which detects femtogram amounts of abnormal prion protein from all subtypes of sporadic CJD. The RT-QuIC assay is run on cerebrospinal fluid (CSF) and nasal olfactory mucosa. (Bongianni et al, 2016). There are no characteristic gross pathologic features of CJD. In fact, because of the typical short course of the disease, no gross changes are seen at all. Persons living beyond 6 months to a year may have some degree of generalized cerebral atrophy. The spongiform encephalopathy of CJD is seen microscopically to exhibit many round to oval vacuoles varying in size from one to 50 microns in size in the neuropil of cortical gray matter. These vacuoles may be single or multiloculated. The vacuoles may coalesce to microcysts. Most cases of CJD also demonstrate neuronal loss and gliosis. In general, the longer the course of the disease, the more pronounced the microscopic changes will be. The PrPres can be identified in tissues with immunohistochemical staining. (Prusiner, 1998). The agent associated with CJD appears to be a prion protein (PrP), a neuronal cell surface sialoglycoprotein that is encoded by just 3 exons of the PRNP gene on chromosome 20. It is thought that the normal cellular prion protein, designated PrPc, is converted via a conformational change to an abnormal form of PrP, designated PrPSc, that is protease-resistant and can accumulate in the central nervous system of affected persons. This accumulation of abnormal protein, thus designated PrPres accounts for the degenerative changes in the cerebral cortex by inducing conformational change in the normal PrP, designated PrPC. The accumulation of PrPres leads to loss of neuronal cell function, vacuolization, and death. (Prusiner, 1998) (Markus et al, 2005). These abnormal PrP's can be transmitted from a person with spongiform encephalopathy to another person, at least by the evidence from transmission via pituitary extracts, corneal transplants, dural grafts, and contaminated electrodes. Transmission via close personal contact, in the workplace, or via transfusion of blood products does not appear to occur. How transmission occurs naturally is not clear, though an acquired mutation of the gene encoding for PrP may account for the appearance of sporadic cases. The abnormal PrP can catalyze the conversion of normal to abnormal PrP. (Prusiner, 1998). The presence of particular polymorphisms at codon 129 of PrP may have an influence on susceptibility to disease. The amino acids methionine (M) or valine (V) may be present. In healthy persons, both inherited PrP genes code for methionine. Many persons with sporadic CJD have abnormal phenotypes. However, subgroups of sporadic CJD can be found with all polymorphisms, but differing characteristics. (Mead, 2006). CJD is one form of spongiform encephalopathy; others include Kuru and fatal familial insomnia. There are other forms of which can affect mammalian species besides humans. The spongiform encephalopathy known as scrapie that is seen in sheep is poorly transmissible to other species. However, bovine spongiform encephalopathy (BSE), also called "mad cow disease", can be transmitted more readily to animals other than cattle. The relationship of human spongiform encephalopathy with animal forms of this disease is not entirely clear. An outbreak of BSE among cattle in England in the 1980's was followed by the appearance of rare cases of a CJD-like illness in the 1990's that were characterized by younger age of onset, lack of characteristic EEG findings, longer course of disease, and more extensive spongiform change with plaques in the brains of affected persons. These cases are known as variant Creutzfeldt-Jakob disease (vCJD). This suggests the possibility of a relationship, but the rarity of vCJD cases, similar to the rarity of standard CJD cases, precludes compelling epidemiologic evidence. Cases of vCJD continue to appear in regions were BSE was prevalent. (Tee et al, 2018)

Variant Creutzfeldt-Jakob disease (vCJD), high power microscopic.

Note the rounded dark pink plaques, surrounded by prominent spongiform change, that are features of variant CJD.Creutzfeldt-Jakob disease (CJD) is rare, affecting less than one person in a million per year. Though it has been reported to occur at a variety of ages, the median age of onset is in the seventh decade, with most sporadic cases occurring between the ages of 55 and 65, but familial or infectious cases can occur in younger adults. The course of the illness can be from a few weeks to eight years. However, the average length of survival from onset of the disease is less than a year. CJD is a uniformly fatal rapidly progressive dementia. (Markus et al, 2005). The clinical features of CJD include dementia, often with psychiatric or behavioral disturbances, in 100% of cases. About 80% of cases are marked by the appearance of myoclonus. By electroencephalography (EEG), there are periodic biphasic or triphasic synchronous sharp-wave complexes that are superimposed upon a slow background rhythm. Both myoclonus and characteristic EEG changes may subside late in the course of disease. Other neurologic findings may include cerebellar signs, pyramidal tract signs, extrapyramidal signs, corticla visual defects, abnormal extraocular movements, lower motor neuron signs, vestibular dysfunction, seizures, sensory deficits, and autonomic abnormalities. (Tee et al, 2018). Routine laboratory findings are not helpful. There is no dysfunction of major organ systems besides the central nervous system. Cerebrospinal fluid (CSF) will not show an increase in cells or immunoglobulins, and occasionally a mildly elevated protein. An abnormal protein called 14-3-3 can be found in the CSF by immunoassay, but this protein may be found in association with viral encephalitis and stroke. Clinical diagnosis can be made using the real-time quaking-induced conversion (RT-QuIC) assay which detects femtogram amounts of abnormal prion protein from all subtypes of sporadic CJD. The RT-QuIC assay is run on cerebrospinal fluid (CSF) and nasal olfactory mucosa. (Bongianni et al, 2016). There are no characteristic gross pathologic features of CJD. In fact, because of the typical short course of the disease, no gross changes are seen at all. Persons living beyond 6 months to a year may have some degree of generalized cerebral atrophy. The spongiform encephalopathy of CJD is seen microscopically to exhibit many round to oval vacuoles varying in size from one to 50 microns in size in the neuropil of cortical gray matter. These vacuoles may be single or multiloculated. The vacuoles may coalesce to microcysts. Most cases of CJD also demonstrate neuronal loss and gliosis. In general, the longer the course of the disease, the more pronounced the microscopic changes will be. The PrPres can be identified in tissues with immunohistochemical staining. (Prusiner, 1998). The agent associated with CJD appears to be a prion protein (PrP), a neuronal cell surface sialoglycoprotein that is encoded by just 3 exons of the PRNP gene on chromosome 20. It is thought that the normal cellular prion protein, designated PrPc, is converted via a conformational change to an abnormal form of PrP, designated PrPSc, that is protease-resistant and can accumulate in the central nervous system of affected persons. This accumulation of abnormal protein, thus designated PrPres accounts for the degenerative changes in the cerebral cortex by inducing conformational change in the normal PrP, designated PrPC. The accumulation of PrPres leads to loss of neuronal cell function, vacuolization, and death. (Prusiner, 1998) (Markus et al, 2005). These abnormal PrP's can be transmitted from a person with spongiform encephalopathy to another person, at least by the evidence from transmission via pituitary extracts, corneal transplants, dural grafts, and contaminated electrodes. Transmission via close personal contact, in the workplace, or via transfusion of blood products does not appear to occur. How transmission occurs naturally is not clear, though an acquired mutation of the gene encoding for PrP may account for the appearance of sporadic cases. The abnormal PrP can catalyze the conversion of normal to abnormal PrP. (Prusiner, 1998). The presence of particular polymorphisms at codon 129 of PrP may have an influence on susceptibility to disease. The amino acids methionine (M) or valine (V) may be present. In healthy persons, both inherited PrP genes code for methionine. Many persons with sporadic CJD have abnormal phenotypes. However, subgroups of sporadic CJD can be found with all polymorphisms, but differing characteristics. (Mead, 2006). CJD is one form of spongiform encephalopathy; others include Kuru and fatal familial insomnia. There are other forms of which can affect mammalian species besides humans. The spongiform encephalopathy known as scrapie that is seen in sheep is poorly transmissible to other species. However, bovine spongiform encephalopathy (BSE), also called "mad cow disease", can be transmitted more readily to animals other than cattle. The relationship of human spongiform encephalopathy with animal forms of this disease is not entirely clear. An outbreak of BSE among cattle in England in the 1980's was followed by the appearance of rare cases of a CJD-like illness in the 1990's that were characterized by younger age of onset, lack of characteristic EEG findings, longer course of disease, and more extensive spongiform change with plaques in the brains of affected persons. These cases are known as variant Creutzfeldt-Jakob disease (vCJD). This suggests the possibility of a relationship, but the rarity of vCJD cases, similar to the rarity of standard CJD cases, precludes compelling epidemiologic evidence. Cases of vCJD continue to appear in regions were BSE was prevalent. (Tee et al, 2018)

Creutzfeldt-Jakob disease, high power microscopic.

At high magnification, there are numerous gray matter vacuoles, along with gliosis and neuronal loss, in a patient with advanced CJD.Creutzfeldt-Jakob disease (CJD) is rare, affecting less than one person in a million per year. Though it has been reported to occur at a variety of ages, the median age of onset is in the seventh decade, with most sporadic cases occurring between the ages of 55 and 65, but familial or infectious cases can occur in younger adults. The course of the illness can be from a few weeks to eight years. However, the average length of survival from onset of the disease is less than a year. CJD is a uniformly fatal rapidly progressive dementia. (Markus et al, 2005). The clinical features of CJD include dementia, often with psychiatric or behavioral disturbances, in 100% of cases. About 80% of cases are marked by the appearance of myoclonus. By electroencephalography (EEG), there are periodic biphasic or triphasic synchronous sharp-wave complexes that are superimposed upon a slow background rhythm. Both myoclonus and characteristic EEG changes may subside late in the course of disease. Other neurologic findings may include cerebellar signs, pyramidal tract signs, extrapyramidal signs, corticla visual defects, abnormal extraocular movements, lower motor neuron signs, vestibular dysfunction, seizures, sensory deficits, and autonomic abnormalities. (Tee et al, 2018). Routine laboratory findings are not helpful. There is no dysfunction of major organ systems besides the central nervous system. Cerebrospinal fluid (CSF) will not show an increase in cells or immunoglobulins, and occasionally a mildly elevated protein. An abnormal protein called 14-3-3 can be found in the CSF by immunoassay, but this protein may be found in association with viral encephalitis and stroke. Clinical diagnosis can be made using the real-time quaking-induced conversion (RT-QuIC) assay which detects femtogram amounts of abnormal prion protein from all subtypes of sporadic CJD. The RT-QuIC assay is run on cerebrospinal fluid (CSF) and nasal olfactory mucosa. (Bongianni et al, 2016). There are no characteristic gross pathologic features of CJD. In fact, because of the typical short course of the disease, no gross changes are seen at all. Persons living beyond 6 months to a year may have some degree of generalized cerebral atrophy. The spongiform encephalopathy of CJD is seen microscopically to exhibit many round to oval vacuoles varying in size from one to 50 microns in size in the neuropil of cortical gray matter. These vacuoles may be single or multiloculated. The vacuoles may coalesce to microcysts. Most cases of CJD also demonstrate neuronal loss and gliosis. In general, the longer the course of the disease, the more pronounced the microscopic changes will be. The PrPres can be identified in tissues with immunohistochemical staining. (Prusiner, 1998). The agent associated with CJD appears to be a prion protein (PrP), a neuronal cell surface sialoglycoprotein that is encoded by just 3 exons of the PRNP gene on chromosome 20. It is thought that the normal cellular prion protein, designated PrPc, is converted via a conformational change to an abnormal form of PrP, designated PrPSc, that is protease-resistant and can accumulate in the central nervous system of affected persons. This accumulation of abnormal protein, thus designated PrPres accounts for the degenerative changes in the cerebral cortex by inducing conformational change in the normal PrP, designated PrPC. The accumulation of PrPres leads to loss of neuronal cell function, vacuolization, and death. (Prusiner, 1998) (Markus et al, 2005). These abnormal PrP's can be transmitted from a person with spongiform encephalopathy to another person, at least by the evidence from transmission via pituitary extracts, corneal transplants, dural grafts, and contaminated electrodes. Transmission via close personal contact, in the workplace, or via transfusion of blood products does not appear to occur. How transmission occurs naturally is not clear, though an acquired mutation of the gene encoding for PrP may account for the appearance of sporadic cases. The abnormal PrP can catalyze the conversion of normal to abnormal PrP. (Prusiner, 1998). The presence of particular polymorphisms at codon 129 of PrP may have an influence on susceptibility to disease. The amino acids methionine (M) or valine (V) may be present. In healthy persons, both inherited PrP genes code for methionine. Many persons with sporadic CJD have abnormal phenotypes. However, subgroups of sporadic CJD can be found with all polymorphisms, but differing characteristics. (Mead, 2006). CJD is one form of spongiform encephalopathy; others include Kuru and fatal familial insomnia. There are other forms of which can affect mammalian species besides humans. The spongiform encephalopathy known as scrapie that is seen in sheep is poorly transmissible to other species. However, bovine spongiform encephalopathy (BSE), also called "mad cow disease", can be transmitted more readily to animals other than cattle. The relationship of human spongiform encephalopathy with animal forms of this disease is not entirely clear. An outbreak of BSE among cattle in England in the 1980's was followed by the appearance of rare cases of a CJD-like illness in the 1990's that were characterized by younger age of onset, lack of characteristic EEG findings, longer course of disease, and more extensive spongiform change with plaques in the brains of affected persons. These cases are known as variant Creutzfeldt-Jakob disease (vCJD). This suggests the possibility of a relationship, but the rarity of vCJD cases, similar to the rarity of standard CJD cases, precludes compelling epidemiologic evidence. Cases of vCJD continue to appear in regions were BSE was prevalent. (Tee et al, 2018)

Creutzfeldt-Jakob disease, medium power microscopic.

At medium power, there are numerous gray matter vacuoles, along with gliosis and neuronal loss, in a patient with advanced CJD.Creutzfeldt-Jakob disease (CJD) is rare, affecting less than one person in a million per year. Though it has been reported to occur at a variety of ages, the median age of onset is in the seventh decade, with most sporadic cases occurring between the ages of 55 and 65, but familial or infectious cases can occur in younger adults. The course of the illness can be from a few weeks to eight years. However, the average length of survival from onset of the disease is less than a year. CJD is a uniformly fatal rapidly progressive dementia. (Markus et al, 2005). The clinical features of CJD include dementia, often with psychiatric or behavioral disturbances, in 100% of cases. About 80% of cases are marked by the appearance of myoclonus. By electroencephalography (EEG), there are periodic biphasic or triphasic synchronous sharp-wave complexes that are superimposed upon a slow background rhythm. Both myoclonus and characteristic EEG changes may subside late in the course of disease. Other neurologic findings may include cerebellar signs, pyramidal tract signs, extrapyramidal signs, corticla visual defects, abnormal extraocular movements, lower motor neuron signs, vestibular dysfunction, seizures, sensory deficits, and autonomic abnormalities. (Tee et al, 2018). Routine laboratory findings are not helpful. There is no dysfunction of major organ systems besides the central nervous system. Cerebrospinal fluid (CSF) will not show an increase in cells or immunoglobulins, and occasionally a mildly elevated protein. An abnormal protein called 14-3-3 can be found in the CSF by immunoassay, but this protein may be found in association with viral encephalitis and stroke. Clinical diagnosis can be made using the real-time quaking-induced conversion (RT-QuIC) assay which detects femtogram amounts of abnormal prion protein from all subtypes of sporadic CJD. The RT-QuIC assay is run on cerebrospinal fluid (CSF) and nasal olfactory mucosa. (Bongianni et al, 2016). There are no characteristic gross pathologic features of CJD. In fact, because of the typical short course of the disease, no gross changes are seen at all. Persons living beyond 6 months to a year may have some degree of generalized cerebral atrophy. The spongiform encephalopathy of CJD is seen microscopically to exhibit many round to oval vacuoles varying in size from one to 50 microns in size in the neuropil of cortical gray matter. These vacuoles may be single or multiloculated. The vacuoles may coalesce to microcysts. Most cases of CJD also demonstrate neuronal loss and gliosis. In general, the longer the course of the disease, the more pronounced the microscopic changes will be. The PrPres can be identified in tissues with immunohistochemical staining. (Prusiner, 1998). The agent associated with CJD appears to be a prion protein (PrP), a neuronal cell surface sialoglycoprotein that is encoded by just 3 exons of the PRNP gene on chromosome 20. It is thought that the normal cellular prion protein, designated PrPc, is converted via a conformational change to an abnormal form of PrP, designated PrPSc, that is protease-resistant and can accumulate in the central nervous system of affected persons. This accumulation of abnormal protein, thus designated PrPres accounts for the degenerative changes in the cerebral cortex by inducing conformational change in the normal PrP, designated PrPC. The accumulation of PrPres leads to loss of neuronal cell function, vacuolization, and death. (Prusiner, 1998) (Markus et al, 2005). These abnormal PrP's can be transmitted from a person with spongiform encephalopathy to another person, at least by the evidence from transmission via pituitary extracts, corneal transplants, dural grafts, and contaminated electrodes. Transmission via close personal contact, in the workplace, or via transfusion of blood products does not appear to occur. How transmission occurs naturally is not clear, though an acquired mutation of the gene encoding for PrP may account for the appearance of sporadic cases. The abnormal PrP can catalyze the conversion of normal to abnormal PrP. (Prusiner, 1998). The presence of particular polymorphisms at codon 129 of PrP may have an influence on susceptibility to disease. The amino acids methionine (M) or valine (V) may be present. In healthy persons, both inherited PrP genes code for methionine. Many persons with sporadic CJD have abnormal phenotypes. However, subgroups of sporadic CJD can be found with all polymorphisms, but differing characteristics. (Mead, 2006). CJD is one form of spongiform encephalopathy; others include Kuru and fatal familial insomnia. There are other forms of which can affect mammalian species besides humans. The spongiform encephalopathy known as scrapie that is seen in sheep is poorly transmissible to other species. However, bovine spongiform encephalopathy (BSE), also called "mad cow disease", can be transmitted more readily to animals other than cattle. The relationship of human spongiform encephalopathy with animal forms of this disease is not entirely clear. An outbreak of BSE among cattle in England in the 1980's was followed by the appearance of rare cases of a CJD-like illness in the 1990's that were characterized by younger age of onset, lack of characteristic EEG findings, longer course of disease, and more extensive spongiform change with plaques in the brains of affected persons. These cases are known as variant Creutzfeldt-Jakob disease (vCJD). This suggests the possibility of a relationship, but the rarity of vCJD cases, similar to the rarity of standard CJD cases, precludes compelling epidemiologic evidence. Cases of vCJD continue to appear in regions were BSE was prevalent. (Tee et al, 2018)

Creutzfeldt-Jakob disease, high power microscopic.

An area of vacuoles that are coalescing to microcysts are seen in the gray matter of a patient with CJD of more prolonged duration.Creutzfeldt-Jakob disease (CJD) is rare, affecting less than one person in a million per year. Though it has been reported to occur at a variety of ages, the median age of onset is in the seventh decade, with most sporadic cases occurring between the ages of 55 and 65, but familial or infectious cases can occur in younger adults. The course of the illness can be from a few weeks to eight years. However, the average length of survival from onset of the disease is less than a year. CJD is a uniformly fatal rapidly progressive dementia. (Markus et al, 2005). The clinical features of CJD include dementia, often with psychiatric or behavioral disturbances, in 100% of cases. About 80% of cases are marked by the appearance of myoclonus. By electroencephalography (EEG), there are periodic biphasic or triphasic synchronous sharp-wave complexes that are superimposed upon a slow background rhythm. Both myoclonus and characteristic EEG changes may subside late in the course of disease. Other neurologic findings may include cerebellar signs, pyramidal tract signs, extrapyramidal signs, corticla visual defects, abnormal extraocular movements, lower motor neuron signs, vestibular dysfunction, seizures, sensory deficits, and autonomic abnormalities. (Tee et al, 2018). Routine laboratory findings are not helpful. There is no dysfunction of major organ systems besides the central nervous system. Cerebrospinal fluid (CSF) will not show an increase in cells or immunoglobulins, and occasionally a mildly elevated protein. An abnormal protein called 14-3-3 can be found in the CSF by immunoassay, but this protein may be found in association with viral encephalitis and stroke. Clinical diagnosis can be made using the real-time quaking-induced conversion (RT-QuIC) assay which detects femtogram amounts of abnormal prion protein from all subtypes of sporadic CJD. The RT-QuIC assay is run on cerebrospinal fluid (CSF) and nasal olfactory mucosa. (Bongianni et al, 2016). There are no characteristic gross pathologic features of CJD. In fact, because of the typical short course of the disease, no gross changes are seen at all. Persons living beyond 6 months to a year may have some degree of generalized cerebral atrophy. The spongiform encephalopathy of CJD is seen microscopically to exhibit many round to oval vacuoles varying in size from one to 50 microns in size in the neuropil of cortical gray matter. These vacuoles may be single or multiloculated. The vacuoles may coalesce to microcysts. Most cases of CJD also demonstrate neuronal loss and gliosis. In general, the longer the course of the disease, the more pronounced the microscopic changes will be. The PrPres can be identified in tissues with immunohistochemical staining. (Prusiner, 1998). The agent associated with CJD appears to be a prion protein (PrP), a neuronal cell surface sialoglycoprotein that is encoded by just 3 exons of the PRNP gene on chromosome 20. It is thought that the normal cellular prion protein, designated PrPc, is converted via a conformational change to an abnormal form of PrP, designated PrPSc, that is protease-resistant and can accumulate in the central nervous system of affected persons. This accumulation of abnormal protein, thus designated PrPres accounts for the degenerative changes in the cerebral cortex by inducing conformational change in the normal PrP, designated PrPC. The accumulation of PrPres leads to loss of neuronal cell function, vacuolization, and death. (Prusiner, 1998) (Markus et al, 2005). These abnormal PrP's can be transmitted from a person with spongiform encephalopathy to another person, at least by the evidence from transmission via pituitary extracts, corneal transplants, dural grafts, and contaminated electrodes. Transmission via close personal contact, in the workplace, or via transfusion of blood products does not appear to occur. How transmission occurs naturally is not clear, though an acquired mutation of the gene encoding for PrP may account for the appearance of sporadic cases. The abnormal PrP can catalyze the conversion of normal to abnormal PrP. (Prusiner, 1998). The presence of particular polymorphisms at codon 129 of PrP may have an influence on susceptibility to disease. The amino acids methionine (M) or valine (V) may be present. In healthy persons, both inherited PrP genes code for methionine. Many persons with sporadic CJD have abnormal phenotypes. However, subgroups of sporadic CJD can be found with all polymorphisms, but differing characteristics. (Mead, 2006). CJD is one form of spongiform encephalopathy; others include Kuru and fatal familial insomnia. There are other forms of which can affect mammalian species besides humans. The spongiform encephalopathy known as scrapie that is seen in sheep is poorly transmissible to other species. However, bovine spongiform encephalopathy (BSE), also called "mad cow disease", can be transmitted more readily to animals other than cattle. The relationship of human spongiform encephalopathy with animal forms of this disease is not entirely clear. An outbreak of BSE among cattle in England in the 1980's was followed by the appearance of rare cases of a CJD-like illness in the 1990's that were characterized by younger age of onset, lack of characteristic EEG findings, longer course of disease, and more extensive spongiform change with plaques in the brains of affected persons. These cases are known as variant Creutzfeldt-Jakob disease (vCJD). This suggests the possibility of a relationship, but the rarity of vCJD cases, similar to the rarity of standard CJD cases, precludes compelling epidemiologic evidence. Cases of vCJD continue to appear in regions were BSE was prevalent. (Tee et al, 2018)

Creutzfeldt-Jakob disease, high power microscopic.

A few small vacuoles are seen in the gray matter of a patient with CJD of rapid onset and short duration.Creutzfeldt-Jakob disease (CJD) is rare, affecting less than one person in a million per year. Though it has been reported to occur at a variety of ages, the median age of onset is in the seventh decade, with most sporadic cases occurring between the ages of 55 and 65, but familial or infectious cases can occur in younger adults. The course of the illness can be from a few weeks to eight years. However, the average length of survival from onset of the disease is less than a year. CJD is a uniformly fatal rapidly progressive dementia. (Markus et al, 2005). The clinical features of CJD include dementia, often with psychiatric or behavioral disturbances, in 100% of cases. About 80% of cases are marked by the appearance of myoclonus. By electroencephalography (EEG), there are periodic biphasic or triphasic synchronous sharp-wave complexes that are superimposed upon a slow background rhythm. Both myoclonus and characteristic EEG changes may subside late in the course of disease. Other neurologic findings may include cerebellar signs, pyramidal tract signs, extrapyramidal signs, corticla visual defects, abnormal extraocular movements, lower motor neuron signs, vestibular dysfunction, seizures, sensory deficits, and autonomic abnormalities. (Tee et al, 2018). Routine laboratory findings are not helpful. There is no dysfunction of major organ systems besides the central nervous system. Cerebrospinal fluid (CSF) will not show an increase in cells or immunoglobulins, and occasionally a mildly elevated protein. An abnormal protein called 14-3-3 can be found in the CSF by immunoassay, but this protein may be found in association with viral encephalitis and stroke. Clinical diagnosis can be made using the real-time quaking-induced conversion (RT-QuIC) assay which detects femtogram amounts of abnormal prion protein from all subtypes of sporadic CJD. The RT-QuIC assay is run on cerebrospinal fluid (CSF) and nasal olfactory mucosa. (Bongianni et al, 2016). There are no characteristic gross pathologic features of CJD. In fact, because of the typical short course of the disease, no gross changes are seen at all. Persons living beyond 6 months to a year may have some degree of generalized cerebral atrophy. The spongiform encephalopathy of CJD is seen microscopically to exhibit many round to oval vacuoles varying in size from one to 50 microns in size in the neuropil of cortical gray matter. These vacuoles may be single or multiloculated. The vacuoles may coalesce to microcysts. Most cases of CJD also demonstrate neuronal loss and gliosis. In general, the longer the course of the disease, the more pronounced the microscopic changes will be. The PrPres can be identified in tissues with immunohistochemical staining. (Prusiner, 1998). The agent associated with CJD appears to be a prion protein (PrP), a neuronal cell surface sialoglycoprotein that is encoded by just 3 exons of the PRNP gene on chromosome 20. It is thought that the normal cellular prion protein, designated PrPc, is converted via a conformational change to an abnormal form of PrP, designated PrPSc, that is protease-resistant and can accumulate in the central nervous system of affected persons. This accumulation of abnormal protein, thus designated PrPres accounts for the degenerative changes in the cerebral cortex by inducing conformational change in the normal PrP, designated PrPC. The accumulation of PrPres leads to loss of neuronal cell function, vacuolization, and death. (Prusiner, 1998) (Markus et al, 2005). These abnormal PrP's can be transmitted from a person with spongiform encephalopathy to another person, at least by the evidence from transmission via pituitary extracts, corneal transplants, dural grafts, and contaminated electrodes. Transmission via close personal contact, in the workplace, or via transfusion of blood products does not appear to occur. How transmission occurs naturally is not clear, though an acquired mutation of the gene encoding for PrP may account for the appearance of sporadic cases. The abnormal PrP can catalyze the conversion of normal to abnormal PrP. (Prusiner, 1998). The presence of particular polymorphisms at codon 129 of PrP may have an influence on susceptibility to disease. The amino acids methionine (M) or valine (V) may be present. In healthy persons, both inherited PrP genes code for methionine. Many persons with sporadic CJD have abnormal phenotypes. However, subgroups of sporadic CJD can be found with all polymorphisms, but differing characteristics. (Mead, 2006). CJD is one form of spongiform encephalopathy; others include Kuru and fatal familial insomnia. There are other forms of which can affect mammalian species besides humans. The spongiform encephalopathy known as scrapie that is seen in sheep is poorly transmissible to other species. However, bovine spongiform encephalopathy (BSE), also called "mad cow disease", can be transmitted more readily to animals other than cattle. The relationship of human spongiform encephalopathy with animal forms of this disease is not entirely clear. An outbreak of BSE among cattle in England in the 1980's was followed by the appearance of rare cases of a CJD-like illness in the 1990's that were characterized by younger age of onset, lack of characteristic EEG findings, longer course of disease, and more extensive spongiform change with plaques in the brains of affected persons. These cases are known as variant Creutzfeldt-Jakob disease (vCJD). This suggests the possibility of a relationship, but the rarity of vCJD cases, similar to the rarity of standard CJD cases, precludes compelling epidemiologic evidence. Cases of vCJD continue to appear in regions were BSE was prevalent. (Tee et al, 2018)

Amyotrophic lateral sclerosis, muscle biopsy, microscopic, trichrome stain.

A muscle biopsy demonstrates the typical "grouped atrophy" of muscle fibers that occurs with denervation. Microscopic, trichrome stain.Amyotrophic lateral sclerosis (ALS) is also known as Lou Gehrig's disease after the famous Yankee first baseman who had this disease. ALS results from loss of motor neurons. This is most striking in the anterior horn cells of spinal cord with loss of lower motor neurons, marked initially by muscle fasciculations. ALS may also involve upper motor neurons including cranial motor nuclei and Betz cells of neocortex, evidenced by spasticity of muscles. The loss motor innervation eventually leads to muscle atrophy. Astrocytosis is seen in response to the loss of motor neurons. With loss of upper motor neurons there is lateral column degeneration with gliosis, the so-called "sclerosis" of the lateral columns of spinal cord. Males are affected more commonly than females. The patients present in middle age with weakness of the extremities and may go on to develop bulbar signs and symptoms. Sphincter control, sensation, intellectual function are not affected by ALS. The course is usually 2 to 6 years after diagnosis, but patients presenting with bulbar signs and symptoms have a shorter life span because of swallowing difficulties and aspiration. The etiology is unknown. Familial cases may be association with mutations in the superoxide dismutase-1 (SOD1) gene. (Walling, 1999) (Saberi et al, 2015)

Amyotrophic lateral sclerosis, microscopic, Luxol fast blue stain.

There is lateral column degeneration of the spinal cord microscopically in this case of ALS, as seen with Luxol fast blue stain.Amyotrophic lateral sclerosis (ALS) is also known as Lou Gehrig's disease after the famous Yankee first baseman who had this disease. ALS results from loss of motor neurons. This is most striking in the anterior horn cells of spinal cord with loss of lower motor neurons, marked initially by muscle fasciculations. ALS may also involve upper motor neurons including cranial motor nuclei and Betz cells of neocortex, evidenced by spasticity of muscles. The loss motor innervation eventually leads to muscle atrophy. Astrocytosis is seen in response to the loss of motor neurons. With loss of upper motor neurons there is lateral column degeneration with gliosis, the so-called "sclerosis" of the lateral columns of spinal cord. Males are affected more commonly than females. The patients present in middle age with weakness of the extremities and may go on to develop bulbar signs and symptoms. Sphincter control, sensation, intellectual function are not affected by ALS. The course is usually 2 to 6 years after diagnosis, but patients presenting with bulbar signs and symptoms have a shorter life span because of swallowing difficulties and aspiration. The etiology is unknown. Familial cases may be association with mutations in the superoxide dismutase-1 (SOD1) gene. (Walling, 1999) (Saberi et al, 2015)

Amyotrophic lateral sclerosis. microscopic.

There is loss of anterior horn cells apparent in this H and E stained section of spinal cord in this microscopic section in a case of ALS.Amyotrophic lateral sclerosis (ALS) is also known as Lou Gehrig's disease after the famous Yankee first baseman who had this disease. ALS results from loss of motor neurons. This is most striking in the anterior horn cells of spinal cord with loss of lower motor neurons, marked initially by muscle fasciculations. ALS may also involve upper motor neurons including cranial motor nuclei and Betz cells of neocortex, evidenced by spasticity of muscles. The loss motor innervation eventually leads to muscle atrophy. Astrocytosis is seen in response to the loss of motor neurons. With loss of upper motor neurons there is lateral column degeneration with gliosis, the so-called "sclerosis" of the lateral columns of spinal cord. Males are affected more commonly than females. The patients present in middle age with weakness of the extremities and may go on to develop bulbar signs and symptoms. Sphincter control, sensation, intellectual function are not affected by ALS. The course is usually 2 to 6 years after diagnosis, but patients presenting with bulbar signs and symptoms have a shorter life span because of swallowing difficulties and aspiration. The etiology is unknown. Familial cases may be association with mutations in the superoxide dismutase-1 (SOD1) gene. (Walling, 1999) (Saberi et al, 2015)

Amyotrophic lateral sclerosis, gross.

A normal spinal cord is shown compared to the cord of a patient with ALS to highlight the difference in size of the nerve roots. The atrophy is apparent in the ALS cord.Amyotrophic lateral sclerosis (ALS) is also known as Lou Gehrig's disease after the famous Yankee first baseman who had this disease. ALS results from loss of motor neurons. This is most striking in the anterior horn cells of spinal cord with loss of lower motor neurons, marked initially by muscle fasciculations. ALS may also involve upper motor neurons including cranial motor nuclei and Betz cells of neocortex, evidenced by spasticity of muscles. The loss motor innervation eventually leads to muscle atrophy. Astrocytosis is seen in response to the loss of motor neurons. With loss of upper motor neurons there is lateral column degeneration with gliosis, the so-called "sclerosis" of the lateral columns of spinal cord. Males are affected more commonly than females. The patients present in middle age with weakness of the extremities and may go on to develop bulbar signs and symptoms. Sphincter control, sensation, intellectual function are not affected by ALS. The course is usually 2 to 6 years after diagnosis, but patients presenting with bulbar signs and symptoms have a shorter life span because of swallowing difficulties and aspiration. The etiology is unknown. Familial cases may be association with mutations in the superoxide dismutase-1 (SOD1) gene. (Walling, 1999) (Saberi et al, 2015)

Lewy bodies, microscopic.

A rounded pink cytoplasmic Lewy body is seen microscopically with H and E stain at the left, while immunohistochemical staining with antibody to ubiquitin reveals the appearance at the right.There is a spectrum of clinical disorders with features of a movement disorder and a pathophysiology linked to abnormalities in alpha-synuclein. These alpha-synucleinopathies include not only Parkinson disease but also Lewy body disease and multiple system atrophy. Parkison-like findings can be present with the tauopathies of progressive supranuclear palsy and corticobasal degeneration. These disorders are defined by predominantly alpha-synuclein or tau protein accumulating in neurons and glia. (Dickson, 2018). Most cases of Parkinson disease (PD) are sporadic. This syndrome covers several diseases of different etiologies which affect primarily the pigmented neuronal groups including the substantia nigra, locus ceruleus, dorsal motor nucleus of cranial nerve X and the substantia innominata. There is loss of dopaminergic neurons predominantly in the substantia nigra pars compacta and the presence of intracellular Lewy bodies composed of alpha-synuclein. Idiopathic PD commonly begins in late middle age and the course is slowly progressive. Movement problems include a festinating gait, cogwheel rigidity of the limbs, poverty of voluntary movement, and a pill rolling type of tremor at rest. In time the facies become mask-like. Usually mental deterioration does not occur but some patients may become demented as the disease progresses. The pigmented neurons are slowly lost as the disease progresses and melanin pigment can be seen within the background neuropil or within macrophages. Astrocytosis occurs secondary to neuronal loss. (Takahashi and Wakabayashi, 2001) (Eriksen et al, 2005) (Choong and Mochizuki, 2022). Some patients with Parkinsonian symptoms also have dementia, and in these patients there are Lewy bodies in the cerebral cortex, as well as the substantia nigra. This can be termed Lewy body dementia, and it is in the differential diagnosis for Alzheimer disease. Pathologically, Lewy bodies in association with Parkinson disease are found within the cytoplasm of pigmented neurons. For a diagnosis of Lewy body dementia, the Lewy bodies must be found in the neocortex. These are homogeneous pink bodies on H&E stains with a surrounding halo. Immunohistochemical staining with antibody to alpha-synuclein is positive in these Lewy bodies. (Kosaka, 2000). There are genetic markers for PD. Mutations in the PARK2 gene encoding for the protein parkin have been identified in some rare familial forms of PD. An autosomal dominant form with mutations in the alpha-synuclein gene has also been described. Additional genes with mutations associated with PD include DJ1 and PINK1. (Eriksen et al, 2005). Multiple system atrophy (MSA) has overlapping features which may include movement disorder (parkinsonism), autonomic dysfunction, and cerebellar ataxia. Past literature may refer to names such as striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. Most patients with MSA exhibit symptoms similar to Parkinson disease, but with alpha-synucleinopathy in oligodendroglial cells and not neurons. The clinical appearance is that of a sporadic, progressive, adult-onset disorder with autonomic dysfunction (orthostatic hypotension or urinary incontinence/retention, parkinsonism cerebellar dysfunction, and corticospinal tract signs. MSA is characterized microscopically by the appearance of glial cytoplasmic inclusions. Tau positive inclusions are present. (Bigio, 2013)(Dickson, 2018)

Parkinson disease, microscopic.

A normally pigmented substantia nigra is seen on the left, but the patient with Parkinson's disease has decreased neurons and pigment as seen microscopically at the right.There is a spectrum of clinical disorders with features of a movement disorder and a pathophysiology linked to abnormalities in alpha-synuclein. These alpha-synucleinopathies include not only Parkinson disease but also Lewy body disease and multiple system atrophy. Parkison-like findings can be present with the tauopathies of progressive supranuclear palsy and corticobasal degeneration. These disorders are defined by predominantly alpha-synuclein or tau protein accumulating in neurons and glia. (Dickson, 2018). Most cases of Parkinson disease (PD) are sporadic. This syndrome covers several diseases of different etiologies which affect primarily the pigmented neuronal groups including the substantia nigra, locus ceruleus, dorsal motor nucleus of cranial nerve X and the substantia innominata. There is loss of dopaminergic neurons predominantly in the substantia nigra pars compacta and the presence of intracellular Lewy bodies composed of alpha-synuclein. Idiopathic PD commonly begins in late middle age and the course is slowly progressive. Movement problems include a festinating gait, cogwheel rigidity of the limbs, poverty of voluntary movement, and a pill rolling type of tremor at rest. In time the facies become mask-like. Usually mental deterioration does not occur but some patients may become demented as the disease progresses. The pigmented neurons are slowly lost as the disease progresses and melanin pigment can be seen within the background neuropil or within macrophages. Astrocytosis occurs secondary to neuronal loss. (Takahashi and Wakabayashi, 2001) (Eriksen et al, 2005) (Choong and Mochizuki, 2022). Some patients with Parkinsonian symptoms also have dementia, and in these patients there are Lewy bodies in the cerebral cortex, as well as the substantia nigra. This can be termed Lewy body dementia, and it is in the differential diagnosis for Alzheimer disease. Pathologically, Lewy bodies in association with Parkinson disease are found within the cytoplasm of pigmented neurons. For a diagnosis of Lewy body dementia, the Lewy bodies must be found in the neocortex. These are homogeneous pink bodies on H&E stains with a surrounding halo. Immunohistochemical staining with antibody to alpha-synuclein is positive in these Lewy bodies. (Kosaka, 2000). There are genetic markers for PD. Mutations in the PARK2 gene encoding for the protein parkin have been identified in some rare familial forms of PD. An autosomal dominant form with mutations in the alpha-synuclein gene has also been described. Additional genes with mutations associated with PD include DJ1 and PINK1. (Eriksen et al, 2005). Multiple system atrophy (MSA) has overlapping features which may include movement disorder (parkinsonism), autonomic dysfunction, and cerebellar ataxia. Past literature may refer to names such as striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. Most patients with MSA exhibit symptoms similar to Parkinson disease, but with alpha-synucleinopathy in oligodendroglial cells and not neurons. The clinical appearance is that of a sporadic, progressive, adult-onset disorder with autonomic dysfunction (orthostatic hypotension or urinary incontinence/retention, parkinsonism cerebellar dysfunction, and corticospinal tract signs. MSA is characterized microscopically by the appearance of glial cytoplasmic inclusions. Tau positive inclusions are present. (Bigio, 2013)(Dickson, 2018)

Parkinson disease, gross.

A normally pigmented substantia nigra is seen grossly in the midbrain on the right, but the midbrain on the left from the patient with Parkinson's disease shows a pale substantia nigra.There is a spectrum of clinical disorders with features of a movement disorder and a pathophysiology linked to abnormalities in alpha-synuclein. These alpha-synucleinopathies include not only Parkinson disease but also Lewy body disease and multiple system atrophy. Parkison-like findings can be present with the tauopathies of progressive supranuclear palsy and corticobasal degeneration. These disorders are defined by predominantly alpha-synuclein or tau protein accumulating in neurons and glia. (Dickson, 2018). Most cases of Parkinson disease (PD) are sporadic. This syndrome covers several diseases of different etiologies which affect primarily the pigmented neuronal groups including the substantia nigra, locus ceruleus, dorsal motor nucleus of cranial nerve X and the substantia innominata. There is loss of dopaminergic neurons predominantly in the substantia nigra pars compacta and the presence of intracellular Lewy bodies composed of alpha-synuclein. Idiopathic PD commonly begins in late middle age and the course is slowly progressive. Movement problems include a festinating gait, cogwheel rigidity of the limbs, poverty of voluntary movement, and a pill rolling type of tremor at rest. In time the facies become mask-like. Usually mental deterioration does not occur but some patients may become demented as the disease progresses. The pigmented neurons are slowly lost as the disease progresses and melanin pigment can be seen within the background neuropil or within macrophages. Astrocytosis occurs secondary to neuronal loss. (Takahashi and Wakabayashi, 2001) (Eriksen et al, 2005) (Choong and Mochizuki, 2022). Some patients with Parkinsonian symptoms also have dementia, and in these patients there are Lewy bodies in the cerebral cortex, as well as the substantia nigra. This can be termed Lewy body dementia, and it is in the differential diagnosis for Alzheimer disease. Pathologically, Lewy bodies in association with Parkinson disease are found within the cytoplasm of pigmented neurons. For a diagnosis of Lewy body dementia, the Lewy bodies must be found in the neocortex. These are homogeneous pink bodies on H&E stains with a surrounding halo. Immunohistochemical staining with antibody to alpha-synuclein is positive in these Lewy bodies. (Kosaka, 2000). There are genetic markers for PD. Mutations in the PARK2 gene encoding for the protein parkin have been identified in some rare familial forms of PD. An autosomal dominant form with mutations in the alpha-synuclein gene has also been described. Additional genes with mutations associated with PD include DJ1 and PINK1. (Eriksen et al, 2005). Multiple system atrophy (MSA) has overlapping features which may include movement disorder (parkinsonism), autonomic dysfunction, and cerebellar ataxia. Past literature may refer to names such as striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. Most patients with MSA exhibit symptoms similar to Parkinson disease, but with alpha-synucleinopathy in oligodendroglial cells and not neurons. The clinical appearance is that of a sporadic, progressive, adult-onset disorder with autonomic dysfunction (orthostatic hypotension or urinary incontinence/retention, parkinsonism cerebellar dysfunction, and corticospinal tract signs. MSA is characterized microscopically by the appearance of glial cytoplasmic inclusions. Tau positive inclusions are present. (Bigio, 2013)(Dickson, 2018)

Huntington disease, microscopic.

Microscopically, the caudate nucleus in Huntington's disease demonstrates loss of neurons along with gliosis.Huntington disease (HD) is a genetic disorder of increased CAG tandem repeat sequences in the huntingtin gene, resulting in pathologically elongated CAG‐repeat sequences which are translated into abnormally long polyglutamine stretches in the mutated huntingtin protein. The abnormal protein aggregates into intra‐neuronal inclusions, predominantly in the neostriatum with neuronal loss of GABA‐ergic medium spiny stellate projections neurons. (Rüb et al, 2016). The HD mode of inheritance appears as autosomal dominant, with onset usually between the ages of 20 and 50 years, but most often in the 40's, with a course that averages 15 years to death. The abnormal gene, huntingtin (HTT), with increased CAG repeats encodes for a protein with a gain of toxic function through protein misfolding. Individuals without the disease have less than 36 repeats. In persons with more than 40 CAG repeats HD is present in over 99% of cases. Persons with 36 to 40 repeats have decreased penetrance and may be unaffected themselves but may transmit the disease to offspring. The greater the number of repeats, the earlier the onset of the disease. Spontanenous new mutations are uncommon. (McColgan and Tabrizi, 2018). Affected persons may initially have diminished cognitive function, as well as behaviorial proglems including personality changes and psychiatric symptoms such as depression, schizophrenia‐like symptoms, disinhibition, restlessness, and irritability. The movement disorder may initially start with choreiform movements, followed by dystonia and then diminished movement with progressive neuronal loss in the caudate nucleus and putamen. (Rüb et al, 2016). Pathologically there is diffuse atrophy of the caudate and putamen, along with lesser atrophy of globus pallidus and nucleus accumbens. Microscopically there is severe loss of small spiny neurons in the caudate and putamen with subsequent astrocytosis. With the loss of cells, the head of the caudate becomes shrunken and there is "ex vacuo" dilatation of the anterior horns of the lateral ventricles. There is a loss of gamma aminobutyric acid (GABA), acetylcholine and substance P. (Purdon et al, 1994)

Huntington disease, gross.

Huntington's disease is shown grossly in this coronal section of the brain. It demonstrates atrophy of the caudate with resultant increase in size of lateral ventricles.Huntington disease (HD) is a genetic disorder of increased CAG tandem repeat sequences in the huntingtin gene, resulting in pathologically elongated CAG‐repeat sequences which are translated into abnormally long polyglutamine stretches in the mutated huntingtin protein. The abnormal protein aggregates into intra‐neuronal inclusions, predominantly in the neostriatum with neuronal loss of GABA‐ergic medium spiny stellate projections neurons. (Rüb et al, 2016). The HD mode of inheritance appears as autosomal dominant, with onset usually between the ages of 20 and 50 years, but most often in the 40's, with a course that averages 15 years to death. The abnormal gene, huntingtin (HTT), with increased CAG repeats encodes for a protein with a gain of toxic function through protein misfolding. Individuals without the disease have less than 36 repeats. In persons with more than 40 CAG repeats HD is present in over 99% of cases. Persons with 36 to 40 repeats have decreased penetrance and may be unaffected themselves but may transmit the disease to offspring. The greater the number of repeats, the earlier the onset of the disease. Spontanenous new mutations are uncommon. (McColgan and Tabrizi, 2018). Affected persons may initially have diminished cognitive function, as well as behaviorial proglems including personality changes and psychiatric symptoms such as depression, schizophrenia‐like symptoms, disinhibition, restlessness, and irritability. The movement disorder may initially start with choreiform movements, followed by dystonia and then diminished movement with progressive neuronal loss in the caudate nucleus and putamen. (Rüb et al, 2016). Pathologically there is diffuse atrophy of the caudate and putamen, along with lesser atrophy of globus pallidus and nucleus accumbens. Microscopically there is severe loss of small spiny neurons in the caudate and putamen with subsequent astrocytosis. With the loss of cells, the head of the caudate becomes shrunken and there is "ex vacuo" dilatation of the anterior horns of the lateral ventricles. There is a loss of gamma aminobutyric acid (GABA), acetylcholine and substance P. (Purdon et al, 1994)

Multi-infarct dementia, gross.

Grossly, this composite view of the brain demonstrates multiple remote cystic infarcts in various locations. This process took several years.Multi-infarct dementia (MID) can cause a dementia similar to Alzheimer disease (AD). However, no pathologic findings are present characteristic of AD. Instead, there are multiple ischemic lesions in the cerebral cortex that cumulatively result in loss of enough neurons to produce dementia. The cognitive impairment results from multiple lesions and infarcts in both white and gray matter that follow occlusions in cerebral arteries and arterioles. Most patients with MID have an incremental loss of mental function following each vascular event. Focal neurologic deficits can be present, depending upon the size and location of the infarcts. In some cases, though, there is gradual loss of mental function. Pathologically, marked cerebral arterial atherosclerosis and/or thromboembolic disease can account for the appearance of many infarcts, typically small and scattered.

Progressive supranuclear palsy, globose tangle, Bielschowsky stain, microscopic.

Pictured here at high magnification with Bielschowsky silver stain is a globose tangle in a neuron of the brainstem in a patient with progressive supranuclear palsy.Frontotemporal dementia, also called frontal lobar degeneration (FTLD) or non-specific frontal lobe dementia, has a slow, insidious onset marked in the early stages by personality changes, then progressive loss of speech (fluent or nonfluent aphasia), apathy, and finally mutism. Changes can include impulsive behaviors and disinhibition, poor insight into consquences of behavior, repetitive behaviors, loss of personal hygiene, and loss of social graces. The mean age of onset is in the 6th decade. Most cases are sporadic but 40% may be familial. The gross pathologic findings include cerebral atrophy predominantly in a frontal lobe and sometimes temporal lobe distribution. (Younes and Miller, 2020). Microscopically, there is a spongy vacuolization of layer 2 of the frontal and temporal cortex, along with loss of neurons and gliosis, and no increase in neuritic plaques. Pick bodies may appear in 15% of cases. Some cases have been linked to mutations in the tau gene. Inclusions, both straight filaments and neurofibrillary tangles with paired helical filaments, of mutant tau protein are present. The more common variations of FTLD are given below. (Bigio, 2013)(Arvanitakis, 2010). Pick disease is a distinctive but uncommon form of frontotemporal dementia which can appear similar to Alzheimer disease. The cerebral atrophy typically involves the frontal and temporal lobes and is so striking that it is "knife-like" in appearance. This atrophy may be asymmetrical. Microscopically, there is marked loss of cortical neurons with gliosis. Hallmarks include ballooned or swollen Pick cells and Pick bodies, neuronal intracytoplasmic inclusions of randomly arranged tau filaments that are highlighted by silver stain. Mutations are found in the gene encoding for tau protein, associated with microtubules. The abnormal tau may be present in the microscopically apparent Pick bodies, which have partially degraded tau fibrils (called ubiquitinated, since they are positive with immunohistochemical staining for ubiquitin). (Bigio, 2013)(Perl, 2000). Corticobasal degeneration (CBD) is classified as an akinetic rigid movement disorder consisting of progessive asymmetric rigidity and apraxia with late development of cognitive decline. However, a wider clinical spectrum, including dementia as an early finding, is possible. Postmortem gross pathologic findings include asymmetrical cortical atrophy of the posterior frontal, parietal, and the peri-Rolandic cortex contralateral to the limbs most severly affected in life. Histologic findings include focal/asymmetric neocortical atrophy, predominantly in the frontoparietal region, and ballooned achromatic neurons. Basal ganglia and nigral degeneration are often but not always present. The etiology is unknown but molecular studies indicate glial and neuronal accumulation of the tau protein as threadlike inclusions in affected areas. There is substantial pathological and clinical overlap with other neurodegenerative disorders such as Creutzfeld-Jakob disease, progessive supranuclear palsy, Alzheimer disease, and Pick disease. This can make unequivocal diagnosis difficult. (Bigio, 2013)(Boeve, 2007)(Younes and Miller, 2020). Progressive supranuclear palsy (PSP) is classically marked by a supranuclear gaze palsy along with rigidity, but patients with this disorder may present with dementia that appears similar to Alzheimer disease. Clinical features include a gradually progressive onset at age 40 or later along with vertical supranuclear palsy and prominent postural instability with falls in the first year of disease onset, and no evidence of other diseases that could explain the foregoing features, as indicated by mandatory exclusion criteria. The pathologic diagnosis is made by the microscopic findings of globose neurofibrillary tangles and variable neuron loss with gliosis of the globus pallidus, subthalamic nucleus, periaqueductal grey matter of pons, and substantia nigra. Mutant tau protein is present in inclusions. (Bigio, 2013)(Boeve, 2007)(Younes and Miller, 2020)

Pick disease, gross.

Pick's disease is demonstrated grossly in this coronal section in which there is marked atrophy with ex vacuo ventricular dilation.Frontotemporal dementia, also called frontal lobar degeneration (FTLD) or non-specific frontal lobe dementia, has a slow, insidious onset marked in the early stages by personality changes, then progressive loss of speech (fluent or nonfluent aphasia), apathy, and finally mutism. Changes can include impulsive behaviors and disinhibition, poor insight into consquences of behavior, repetitive behaviors, loss of personal hygiene, and loss of social graces. The mean age of onset is in the 6th decade. Most cases are sporadic but 40% may be familial. The gross pathologic findings include cerebral atrophy predominantly in a frontal lobe and sometimes temporal lobe distribution. (Younes and Miller, 2020). Microscopically, there is a spongy vacuolization of layer 2 of the frontal and temporal cortex, along with loss of neurons and gliosis, and no increase in neuritic plaques. Pick bodies may appear in 15% of cases. Some cases have been linked to mutations in the tau gene. Inclusions, both straight filaments and neurofibrillary tangles with paired helical filaments, of mutant tau protein are present. The more common variations of FTLD are given below. (Bigio, 2013)(Arvanitakis, 2010). Pick disease is a distinctive but uncommon form of frontotemporal dementia which can appear similar to Alzheimer disease. The cerebral atrophy typically involves the frontal and temporal lobes and is so striking that it is "knife-like" in appearance. This atrophy may be asymmetrical. Microscopically, there is marked loss of cortical neurons with gliosis. Hallmarks include ballooned or swollen Pick cells and Pick bodies, neuronal intracytoplasmic inclusions of randomly arranged tau filaments that are highlighted by silver stain. Mutations are found in the gene encoding for tau protein, associated with microtubules. The abnormal tau may be present in the microscopically apparent Pick bodies, which have partially degraded tau fibrils (called ubiquitinated, since they are positive with immunohistochemical staining for ubiquitin). (Bigio, 2013)(Perl, 2000). Corticobasal degeneration (CBD) is classified as an akinetic rigid movement disorder consisting of progessive asymmetric rigidity and apraxia with late development of cognitive decline. However, a wider clinical spectrum, including dementia as an early finding, is possible. Postmortem gross pathologic findings include asymmetrical cortical atrophy of the posterior frontal, parietal, and the peri-Rolandic cortex contralateral to the limbs most severly affected in life. Histologic findings include focal/asymmetric neocortical atrophy, predominantly in the frontoparietal region, and ballooned achromatic neurons. Basal ganglia and nigral degeneration are often but not always present. The etiology is unknown but molecular studies indicate glial and neuronal accumulation of the tau protein as threadlike inclusions in affected areas. There is substantial pathological and clinical overlap with other neurodegenerative disorders such as Creutzfeld-Jakob disease, progessive supranuclear palsy, Alzheimer disease, and Pick disease. This can make unequivocal diagnosis difficult. (Bigio, 2013)(Boeve, 2007)(Younes and Miller, 2020). Progressive supranuclear palsy (PSP) is classically marked by a supranuclear gaze palsy along with rigidity, but patients with this disorder may present with dementia that appears similar to Alzheimer disease. Clinical features include a gradually progressive onset at age 40 or later along with vertical supranuclear palsy and prominent postural instability with falls in the first year of disease onset, and no evidence of other diseases that could explain the foregoing features, as indicated by mandatory exclusion criteria. The pathologic diagnosis is made by the microscopic findings of globose neurofibrillary tangles and variable neuron loss with gliosis of the globus pallidus, subthalamic nucleus, periaqueductal grey matter of pons, and substantia nigra. Mutant tau protein is present in inclusions. (Bigio, 2013)(Boeve, 2007)(Younes and Miller, 2020)

Pick disease, gross.

Pick's disease with the gross appearance of lobar atrophy is seen here involving the frontal lobe. Note the "knife like" gyri.Frontotemporal dementia, also called frontal lobar degeneration (FTLD) or non-specific frontal lobe dementia, has a slow, insidious onset marked in the early stages by personality changes, then progressive loss of speech (fluent or nonfluent aphasia), apathy, and finally mutism. Changes can include impulsive behaviors and disinhibition, poor insight into consquences of behavior, repetitive behaviors, loss of personal hygiene, and loss of social graces. The mean age of onset is in the 6th decade. Most cases are sporadic but 40% may be familial. The gross pathologic findings include cerebral atrophy predominantly in a frontal lobe and sometimes temporal lobe distribution. (Younes and Miller, 2020). Microscopically, there is a spongy vacuolization of layer 2 of the frontal and temporal cortex, along with loss of neurons and gliosis, and no increase in neuritic plaques. Pick bodies may appear in 15% of cases. Some cases have been linked to mutations in the tau gene. Inclusions, both straight filaments and neurofibrillary tangles with paired helical filaments, of mutant tau protein are present. The more common variations of FTLD are given below. (Bigio, 2013)(Arvanitakis, 2010). Pick disease is a distinctive but uncommon form of frontotemporal dementia which can appear similar to Alzheimer disease. The cerebral atrophy typically involves the frontal and temporal lobes and is so striking that it is "knife-like" in appearance. This atrophy may be asymmetrical. Microscopically, there is marked loss of cortical neurons with gliosis. Hallmarks include ballooned or swollen Pick cells and Pick bodies, neuronal intracytoplasmic inclusions of randomly arranged tau filaments that are highlighted by silver stain. Mutations are found in the gene encoding for tau protein, associated with microtubules. The abnormal tau may be present in the microscopically apparent Pick bodies, which have partially degraded tau fibrils (called ubiquitinated, since they are positive with immunohistochemical staining for ubiquitin). (Bigio, 2013)(Perl, 2000). Corticobasal degeneration (CBD) is classified as an akinetic rigid movement disorder consisting of progessive asymmetric rigidity and apraxia with late development of cognitive decline. However, a wider clinical spectrum, including dementia as an early finding, is possible. Postmortem gross pathologic findings include asymmetrical cortical atrophy of the posterior frontal, parietal, and the peri-Rolandic cortex contralateral to the limbs most severly affected in life. Histologic findings include focal/asymmetric neocortical atrophy, predominantly in the frontoparietal region, and ballooned achromatic neurons. Basal ganglia and nigral degeneration are often but not always present. The etiology is unknown but molecular studies indicate glial and neuronal accumulation of the tau protein as threadlike inclusions in affected areas. There is substantial pathological and clinical overlap with other neurodegenerative disorders such as Creutzfeld-Jakob disease, progessive supranuclear palsy, Alzheimer disease, and Pick disease. This can make unequivocal diagnosis difficult. (Bigio, 2013)(Boeve, 2007)(Younes and Miller, 2020). Progressive supranuclear palsy (PSP) is classically marked by a supranuclear gaze palsy along with rigidity, but patients with this disorder may present with dementia that appears similar to Alzheimer disease. Clinical features include a gradually progressive onset at age 40 or later along with vertical supranuclear palsy and prominent postural instability with falls in the first year of disease onset, and no evidence of other diseases that could explain the foregoing features, as indicated by mandatory exclusion criteria. The pathologic diagnosis is made by the microscopic findings of globose neurofibrillary tangles and variable neuron loss with gliosis of the globus pallidus, subthalamic nucleus, periaqueductal grey matter of pons, and substantia nigra. Mutant tau protein is present in inclusions. (Bigio, 2013)(Boeve, 2007)(Younes and Miller, 2020)

Diffuse Lewy body disease, microscopic.

At the left, an H&E stain demonstrates a rounded pink cytoplasmic Lewy body in a neuron of the cerebral cortex from a patient with diffuse Lewy body disease, which can be a cause for dementia. Lewy bodies can also be seen in substantia nigra with Parkinson's disease. An immunohistochemical stain for ubiquitin, seen at the right, helps demonstrate the Lewy bodies more readily by the brown reaction product within them.Lewy body dementia (LBD) is a clinicopathological syndrome that may account for up to 20% of all cases of dementia in older patients, typically in their seventh and eighth decades. Diseases with Lewy bodies should also be considered in the differential diagnosis of a wide range of clinical presentations including episodic disturbances of consciousness, syncope, sleep disorders, and unexplained delirium. (Weintraub and Irwin, 2022). There are three major syndromes associated with the appearance of Lewy bodies. These are: the movement disorder known as Parkinson disease, multiple system atrophy with autonomic nervous system failure, and dementia. Parkinsonism, the most common syndrome with Lewy bodies, is a disease developing in middle age. In older persons, a mixture of cognitive, autonomic, and motor dysfunction is more common. Some older persons with dementia who are thought to have Alzheimer disease may actually have diffuse Lewy body disease, and some of those persons may be developing a movement disorder resembling Parkinson disease. Conversely, some patients initially presenting with Parkinson disease may develop manifestations of Lewy body dementia. When cognitive impairment is present with LBD, some neuropathologic features of Alzeimer dementia are usually present as well. (Mehta and Schneider, 2023). The clinical presentation of Lewy body disease varies according to the site of Lewy body formation and associated neuronal loss. In Parkinson disease, the Lewy bodies are found in the substantia nigra of the midbrain, coupled with the loss of pigmented neurons. In persons with the dementia of diffuse Lewy body disease, there are Lewy bodies in the neocortex. Some persons have the Lewy bodies in both locations. The basal ganglia and diencephalon may also be involved in some cases. (Mehta and Schneider, 2023). Lewy bodies are spherical, neuronal intracytoplasmic, eosinophilic inclusions comprised of abnormally truncated and phosphorylated alpha-synuclein neurofilament protein. With idiopathic Parkinson disease, Lewy bodies are typically found in the substantia nigra, nucleus basalis of Meynert, dorsal raphe, locus ceruleus, dorsal motor nucleus of the vagus nerve, and hypothalamus. In cases Lewy body dementia, cortical Lewy bodies are prominent, but there are typically findings of Alzheimer disease as well. The presence of alpha-synuclein inclusions within glial cells is characteristic of multiple system atrophy. (Kövari et al, 2009) (Mehta and Schneider, 2023)

Alzheimer disease, neurofibrillary tangle, with Bielschowsky silver stain, microscopic.

Alzheimer's disease, neurofibrillary tangle. The tangles are best demonstrated with Bielschowsky silver stain as shown here, microscopic.Alzheimer disease (AD) is becoming more common in developed nations as the population includes more and more older persons. There is no known cause for the disease. It is often not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's. At age 60 less than 1% of persons have AD, but by age 85 a fourth to a third of persons have evidence for AD. Thus, in aging populations, AD becomes more prevalent. Familial cases with a defined inheritance pattern account for about 10% of Alzheimer disease. The so-called "early onset" cases of AD in persons in their 30's, 40's, and 50's may have a genetic basis, linked to the APP, PSEN1, and PSEN2 genes. AD cases linked to an APP genetic defect on chromosome 21 may explain the appearance of Alzheimer disease in persons with Down syndrome surviving to middle age. APP encodes for amyloid precursor protein, resulting in fibrillar aggregates of beta-amyloid that is toxic to neurons. About half of early onset AD cases are linked to mutations in the presenilin 1 gene on chromosome 14, presenilin 2 gene on chromosome 1, but these defects account for less than 0.5% of cases. (Lane et al 2018). The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects. A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE). The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases. However, the presence of apoE4 is neither necessary nor sufficient for development of AD, so testing for it is not warranted. Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in some AD cases. The abnormal tau may account for helical filaments found in neurofibrillary tangles. (Lane et al 2018). Regardless of the cause, the diagnosis of AD is made clinically by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. Biomarkers for prediction of progression to AD in persons with mild cognitive impairment have been studied. The amyloid PET scan has a high sensitivity and specificity for AD and may be useful when clinical findings are atypical or the patient is young. Additional markers include CSF Aß42 and tau, temporoparietal hypometabolism on 18F-FDG PET scan, and measurement of hippocampal volume. Patients with all of these markers progressed to AD, while persons without any markers did not. (Galluzzi, et al, 2013)(Johnson, et al, 2013). The definitive diagnosis of AD is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation. The pathognomonic microscopic features of AD are: an increased number of beta-amyloid-containing neuritic plaques and neurofibrillary tangles composed of abnormally phosphorylated tau protein aggregates in cerebral cortex. (Mehta and Schneider, 2023). Neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers relative to age in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Neurofibrillary tangles consist of hyperphosphorylated tau protein filaments within neurons. Other microscopic findings with AD include amyloid angiopathy and granolovacuolar degeneration. (Mirra et al, 1993). Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer disease. Many treatment strategies are based upon reducing the loss of acetylcholine. However, such medications appear to be able to produce moderate symptomatic benefits but not to stop disease progression. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer disease is pneumonia, typically an aspiration pneumonia. (Klafki et al, 2006). Biomarkers of AD can be employed to suggest the diagnosis, but are not definitive. Positron emission tomography (PET) scans can employ radiolabeled F-fluorodeoxyglucosse (F-FDG PET), tau protein PET, and amyloid PET. The latter is the most sensitive and specific. CSF markers include detection of tau protein. (Frisoni et al, 2017)

Alzheimer disease, neurofibrillary tangle, H and E stain, microscopic.

Alzheimer's disease, neurofibrillary tangle. The neurons demonstrate intracytoplasmic proliferation of twisted filaments producing the visible "neurofibrillary tangle" under the microscope. These are commonly found in the pyramidal cells of the Hippocampus and the cerebral cortex. H and E stain, microscopic.Alzheimer disease (AD) is becoming more common in developed nations as the population includes more and more older persons. There is no known cause for the disease. It is often not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's. At age 60 less than 1% of persons have AD, but by age 85 a fourth to a third of persons have evidence for AD. Thus, in aging populations, AD becomes more prevalent. Familial cases with a defined inheritance pattern account for about 10% of Alzheimer disease. The so-called "early onset" cases of AD in persons in their 30's, 40's, and 50's may have a genetic basis, linked to the APP, PSEN1, and PSEN2 genes. AD cases linked to an APP genetic defect on chromosome 21 may explain the appearance of Alzheimer disease in persons with Down syndrome surviving to middle age. APP encodes for amyloid precursor protein, resulting in fibrillar aggregates of beta-amyloid that is toxic to neurons. About half of early onset AD cases are linked to mutations in the presenilin 1 gene on chromosome 14, presenilin 2 gene on chromosome 1, but these defects account for less than 0.5% of cases. (Lane et al 2018). The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects. A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE). The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases. However, the presence of apoE4 is neither necessary nor sufficient for development of AD, so testing for it is not warranted. Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in some AD cases. The abnormal tau may account for helical filaments found in neurofibrillary tangles. (Lane et al 2018). Regardless of the cause, the diagnosis of AD is made clinically by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. Biomarkers for prediction of progression to AD in persons with mild cognitive impairment have been studied. The amyloid PET scan has a high sensitivity and specificity for AD and may be useful when clinical findings are atypical or the patient is young. Additional markers include CSF Aß42 and tau, temporoparietal hypometabolism on 18F-FDG PET scan, and measurement of hippocampal volume. Patients with all of these markers progressed to AD, while persons without any markers did not. (Galluzzi, et al, 2013)(Johnson, et al, 2013). The definitive diagnosis of AD is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation. The pathognomonic microscopic features of AD are: an increased number of beta-amyloid-containing neuritic plaques and neurofibrillary tangles composed of abnormally phosphorylated tau protein aggregates in cerebral cortex. (Mehta and Schneider, 2023). Neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers relative to age in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Neurofibrillary tangles consist of hyperphosphorylated tau protein filaments within neurons. Other microscopic findings with AD include amyloid angiopathy and granolovacuolar degeneration. (Mirra et al, 1993). Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer disease. Many treatment strategies are based upon reducing the loss of acetylcholine. However, such medications appear to be able to produce moderate symptomatic benefits but not to stop disease progression. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer disease is pneumonia, typically an aspiration pneumonia. (Klafki et al, 2006). Biomarkers of AD can be employed to suggest the diagnosis, but are not definitive. Positron emission tomography (PET) scans can employ radiolabeled F-fluorodeoxyglucosse (F-FDG PET), tau protein PET, and amyloid PET. The latter is the most sensitive and specific. CSF markers include detection of tau protein. (Frisoni et al, 2017)

Alzheimer disease, senile plaque, with Congo red stain, microscopic.

Alzheimer's disease, senile plaque. Older plaques contain a central amyloid core, seen here with Congo red stain, microscopic.Alzheimer disease (AD) is becoming more common in developed nations as the population includes more and more older persons. There is no known cause for the disease. It is often not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's. At age 60 less than 1% of persons have AD, but by age 85 a fourth to a third of persons have evidence for AD. Thus, in aging populations, AD becomes more prevalent. Familial cases with a defined inheritance pattern account for about 10% of Alzheimer disease. The so-called "early onset" cases of AD in persons in their 30's, 40's, and 50's may have a genetic basis, linked to the APP, PSEN1, and PSEN2 genes. AD cases linked to an APP genetic defect on chromosome 21 may explain the appearance of Alzheimer disease in persons with Down syndrome surviving to middle age. APP encodes for amyloid precursor protein, resulting in fibrillar aggregates of beta-amyloid that is toxic to neurons. About half of early onset AD cases are linked to mutations in the presenilin 1 gene on chromosome 14, presenilin 2 gene on chromosome 1, but these defects account for less than 0.5% of cases. (Lane et al 2018). The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects. A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE). The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases. However, the presence of apoE4 is neither necessary nor sufficient for development of AD, so testing for it is not warranted. Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in some AD cases. The abnormal tau may account for helical filaments found in neurofibrillary tangles. (Lane et al 2018). Regardless of the cause, the diagnosis of AD is made clinically by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. Biomarkers for prediction of progression to AD in persons with mild cognitive impairment have been studied. The amyloid PET scan has a high sensitivity and specificity for AD and may be useful when clinical findings are atypical or the patient is young. Additional markers include CSF Aß42 and tau, temporoparietal hypometabolism on 18F-FDG PET scan, and measurement of hippocampal volume. Patients with all of these markers progressed to AD, while persons without any markers did not. (Galluzzi, et al, 2013)(Johnson, et al, 2013). The definitive diagnosis of AD is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation. The pathognomonic microscopic features of AD are: an increased number of beta-amyloid-containing neuritic plaques and neurofibrillary tangles composed of abnormally phosphorylated tau protein aggregates in cerebral cortex. (Mehta and Schneider, 2023). Neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers relative to age in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Neurofibrillary tangles consist of hyperphosphorylated tau protein filaments within neurons. Other microscopic findings with AD include amyloid angiopathy and granolovacuolar degeneration. (Mirra et al, 1993). Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer disease. Many treatment strategies are based upon reducing the loss of acetylcholine. However, such medications appear to be able to produce moderate symptomatic benefits but not to stop disease progression. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer disease is pneumonia, typically an aspiration pneumonia. (Klafki et al, 2006). Biomarkers of AD can be employed to suggest the diagnosis, but are not definitive. Positron emission tomography (PET) scans can employ radiolabeled F-fluorodeoxyglucosse (F-FDG PET), tau protein PET, and amyloid PET. The latter is the most sensitive and specific. CSF markers include detection of tau protein. (Frisoni et al, 2017)

Alzheimer disease, thioflavin stain, microscopic.

The thioflavin stain viewed with fluorescence microscopy highlights the neuritic plaques of Alzheimer's disease with amyloid deposition which fluoresces bright green, as shown here.Alzheimer disease (AD) is becoming more common in developed nations as the population includes more and more older persons. There is no known cause for the disease. It is often not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's. At age 60 less than 1% of persons have AD, but by age 85 a fourth to a third of persons have evidence for AD. Thus, in aging populations, AD becomes more prevalent. Familial cases with a defined inheritance pattern account for about 10% of Alzheimer disease. The so-called "early onset" cases of AD in persons in their 30's, 40's, and 50's may have a genetic basis, linked to the APP, PSEN1, and PSEN2 genes. AD cases linked to an APP genetic defect on chromosome 21 may explain the appearance of Alzheimer disease in persons with Down syndrome surviving to middle age. APP encodes for amyloid precursor protein, resulting in fibrillar aggregates of beta-amyloid that is toxic to neurons. About half of early onset AD cases are linked to mutations in the presenilin 1 gene on chromosome 14, presenilin 2 gene on chromosome 1, but these defects account for less than 0.5% of cases. (Lane et al 2018). The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects. A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE). The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases. However, the presence of apoE4 is neither necessary nor sufficient for development of AD, so testing for it is not warranted. Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in some AD cases. The abnormal tau may account for helical filaments found in neurofibrillary tangles. (Lane et al 2018). Regardless of the cause, the diagnosis of AD is made clinically by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. Biomarkers for prediction of progression to AD in persons with mild cognitive impairment have been studied. The amyloid PET scan has a high sensitivity and specificity for AD and may be useful when clinical findings are atypical or the patient is young. Additional markers include CSF Aß42 and tau, temporoparietal hypometabolism on 18F-FDG PET scan, and measurement of hippocampal volume. Patients with all of these markers progressed to AD, while persons without any markers did not. (Galluzzi, et al, 2013)(Johnson, et al, 2013). The definitive diagnosis of AD is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation. The pathognomonic microscopic features of AD are: an increased number of beta-amyloid-containing neuritic plaques and neurofibrillary tangles composed of abnormally phosphorylated tau protein aggregates in cerebral cortex. (Mehta and Schneider, 2023). Neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers relative to age in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Neurofibrillary tangles consist of hyperphosphorylated tau protein filaments within neurons. Other microscopic findings with AD include amyloid angiopathy and granolovacuolar degeneration. (Mirra et al, 1993). Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer disease. Many treatment strategies are based upon reducing the loss of acetylcholine. However, such medications appear to be able to produce moderate symptomatic benefits but not to stop disease progression. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer disease is pneumonia, typically an aspiration pneumonia. (Klafki et al, 2006). Biomarkers of AD can be employed to suggest the diagnosis, but are not definitive. Positron emission tomography (PET) scans can employ radiolabeled F-fluorodeoxyglucosse (F-FDG PET), tau protein PET, and amyloid PET. The latter is the most sensitive and specific. CSF markers include detection of tau protein. (Frisoni et al, 2017)

Alzheimer disease, Bielschowsky silver stain, microscopic.

In the neuropil of the cerebral cortex there is fragmentation of neurites (neuronal processes) within gray matter producing the characteristic "senile plaques." These are degenerative presynaptic endings. The plaques may also contain a few astrocytes, and microglia. Bielschowsky silver stain, microscopic.Alzheimer disease (AD) is becoming more common in developed nations as the population includes more and more older persons. There is no known cause for the disease. It is often not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's. At age 60 less than 1% of persons have AD, but by age 85 a fourth to a third of persons have evidence for AD. Thus, in aging populations, AD becomes more prevalent. Familial cases with a defined inheritance pattern account for about 10% of Alzheimer disease. The so-called "early onset" cases of AD in persons in their 30's, 40's, and 50's may have a genetic basis, linked to the APP, PSEN1, and PSEN2 genes. AD cases linked to an APP genetic defect on chromosome 21 may explain the appearance of Alzheimer disease in persons with Down syndrome surviving to middle age. APP encodes for amyloid precursor protein, resulting in fibrillar aggregates of beta-amyloid that is toxic to neurons. About half of early onset AD cases are linked to mutations in the presenilin 1 gene on chromosome 14, presenilin 2 gene on chromosome 1, but these defects account for less than 0.5% of cases. (Lane et al 2018). The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects. A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE). The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases. However, the presence of apoE4 is neither necessary nor sufficient for development of AD, so testing for it is not warranted. Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in some AD cases. The abnormal tau may account for helical filaments found in neurofibrillary tangles. (Lane et al 2018). Regardless of the cause, the diagnosis of AD is made clinically by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. Biomarkers for prediction of progression to AD in persons with mild cognitive impairment have been studied. The amyloid PET scan has a high sensitivity and specificity for AD and may be useful when clinical findings are atypical or the patient is young. Additional markers include CSF Aß42 and tau, temporoparietal hypometabolism on 18F-FDG PET scan, and measurement of hippocampal volume. Patients with all of these markers progressed to AD, while persons without any markers did not. (Galluzzi, et al, 2013)(Johnson, et al, 2013). The definitive diagnosis of AD is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation. The pathognomonic microscopic features of AD are: an increased number of beta-amyloid-containing neuritic plaques and neurofibrillary tangles composed of abnormally phosphorylated tau protein aggregates in cerebral cortex. (Mehta and Schneider, 2023). Neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers relative to age in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Neurofibrillary tangles consist of hyperphosphorylated tau protein filaments within neurons. Other microscopic findings with AD include amyloid angiopathy and granolovacuolar degeneration. (Mirra et al, 1993). Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer disease. Many treatment strategies are based upon reducing the loss of acetylcholine. However, such medications appear to be able to produce moderate symptomatic benefits but not to stop disease progression. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer disease is pneumonia, typically an aspiration pneumonia. (Klafki et al, 2006). Biomarkers of AD can be employed to suggest the diagnosis, but are not definitive. Positron emission tomography (PET) scans can employ radiolabeled F-fluorodeoxyglucosse (F-FDG PET), tau protein PET, and amyloid PET. The latter is the most sensitive and specific. CSF markers include detection of tau protein. (Frisoni et al, 2017)

Alzheimer disease, gross.

Alzheimer's disease with cerebral atrophy on coronal section of the brain shows the characteristic hydrocephalus ex vacuo, or ventricular dilation resulting from loss of cortex, gross.Alzheimer disease (AD) is becoming more common in developed nations as the population includes more and more older persons. There is no known cause for the disease. It is often not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's. At age 60 less than 1% of persons have AD, but by age 85 a fourth to a third of persons have evidence for AD. Thus, in aging populations, AD becomes more prevalent. Familial cases with a defined inheritance pattern account for about 10% of Alzheimer disease. The so-called "early onset" cases of AD in persons in their 30's, 40's, and 50's may have a genetic basis, linked to the APP, PSEN1, and PSEN2 genes. AD cases linked to an APP genetic defect on chromosome 21 may explain the appearance of Alzheimer disease in persons with Down syndrome surviving to middle age. APP encodes for amyloid precursor protein, resulting in fibrillar aggregates of beta-amyloid that is toxic to neurons. About half of early onset AD cases are linked to mutations in the presenilin 1 gene on chromosome 14, presenilin 2 gene on chromosome 1, but these defects account for less than 0.5% of cases. (Lane et al 2018). The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects. A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE). The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases. However, the presence of apoE4 is neither necessary nor sufficient for development of AD, so testing for it is not warranted. Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in some AD cases. The abnormal tau may account for helical filaments found in neurofibrillary tangles. (Lane et al 2018). Regardless of the cause, the diagnosis of AD is made clinically by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. Biomarkers for prediction of progression to AD in persons with mild cognitive impairment have been studied. The amyloid PET scan has a high sensitivity and specificity for AD and may be useful when clinical findings are atypical or the patient is young. Additional markers include CSF Aß42 and tau, temporoparietal hypometabolism on 18F-FDG PET scan, and measurement of hippocampal volume. Patients with all of these markers progressed to AD, while persons without any markers did not. (Galluzzi, et al, 2013)(Johnson, et al, 2013). The definitive diagnosis of AD is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation. The pathognomonic microscopic features of AD are: an increased number of beta-amyloid-containing neuritic plaques and neurofibrillary tangles composed of abnormally phosphorylated tau protein aggregates in cerebral cortex. (Mehta and Schneider, 2023). Neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers relative to age in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Neurofibrillary tangles consist of hyperphosphorylated tau protein filaments within neurons. Other microscopic findings with AD include amyloid angiopathy and granolovacuolar degeneration. (Mirra et al, 1993). Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer disease. Many treatment strategies are based upon reducing the loss of acetylcholine. However, such medications appear to be able to produce moderate symptomatic benefits but not to stop disease progression. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer disease is pneumonia, typically an aspiration pneumonia. (Klafki et al, 2006). Biomarkers of AD can be employed to suggest the diagnosis, but are not definitive. Positron emission tomography (PET) scans can employ radiolabeled F-fluorodeoxyglucosse (F-FDG PET), tau protein PET, and amyloid PET. The latter is the most sensitive and specific. CSF markers include detection of tau protein. (Frisoni et al, 2017)

Alzheimer disease, gross.

Shown here is the brain with more pronounced atrophy with Alzheimer's disease seen superiorly and laterally, gross.Alzheimer disease (AD) is becoming more common in developed nations as the population includes more and more older persons. There is no known cause for the disease. It is often not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's. At age 60 less than 1% of persons have AD, but by age 85 a fourth to a third of persons have evidence for AD. Thus, in aging populations, AD becomes more prevalent. Familial cases with a defined inheritance pattern account for about 10% of Alzheimer disease. The so-called "early onset" cases of AD in persons in their 30's, 40's, and 50's may have a genetic basis, linked to the APP, PSEN1, and PSEN2 genes. AD cases linked to an APP genetic defect on chromosome 21 may explain the appearance of Alzheimer disease in persons with Down syndrome surviving to middle age. APP encodes for amyloid precursor protein, resulting in fibrillar aggregates of beta-amyloid that is toxic to neurons. About half of early onset AD cases are linked to mutations in the presenilin 1 gene on chromosome 14, presenilin 2 gene on chromosome 1, but these defects account for less than 0.5% of cases. (Lane et al 2018). The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects. A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE). The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases. However, the presence of apoE4 is neither necessary nor sufficient for development of AD, so testing for it is not warranted. Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in some AD cases. The abnormal tau may account for helical filaments found in neurofibrillary tangles. (Lane et al 2018). Regardless of the cause, the diagnosis of AD is made clinically by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. Biomarkers for prediction of progression to AD in persons with mild cognitive impairment have been studied. The amyloid PET scan has a high sensitivity and specificity for AD and may be useful when clinical findings are atypical or the patient is young. Additional markers include CSF Aß42 and tau, temporoparietal hypometabolism on 18F-FDG PET scan, and measurement of hippocampal volume. Patients with all of these markers progressed to AD, while persons without any markers did not. (Galluzzi, et al, 2013)(Johnson, et al, 2013). The definitive diagnosis of AD is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation. The pathognomonic microscopic features of AD are: an increased number of beta-amyloid-containing neuritic plaques and neurofibrillary tangles composed of abnormally phosphorylated tau protein aggregates in cerebral cortex. (Mehta and Schneider, 2023). Neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers relative to age in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Neurofibrillary tangles consist of hyperphosphorylated tau protein filaments within neurons. Other microscopic findings with AD include amyloid angiopathy and granolovacuolar degeneration. (Mirra et al, 1993). Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer disease. Many treatment strategies are based upon reducing the loss of acetylcholine. However, such medications appear to be able to produce moderate symptomatic benefits but not to stop disease progression. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer disease is pneumonia, typically an aspiration pneumonia. (Klafki et al, 2006). Biomarkers of AD can be employed to suggest the diagnosis, but are not definitive. Positron emission tomography (PET) scans can employ radiolabeled F-fluorodeoxyglucosse (F-FDG PET), tau protein PET, and amyloid PET. The latter is the most sensitive and specific. CSF markers include detection of tau protein. (Frisoni et al, 2017)

Alzheimer disease, gross.

Alzheimer's disease leads to cerebral atrophy. Shown here is the external surface of the brain with widened sulci and narrowed gyri, mostly over the frontal and parietal regions, gross.Alzheimer disease (AD) is becoming more common in developed nations as the population includes more and more older persons. There is no known cause for the disease. It is often not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's. At age 60 less than 1% of persons have AD, but by age 85 a fourth to a third of persons have evidence for AD. Thus, in aging populations, AD becomes more prevalent. Familial cases with a defined inheritance pattern account for about 10% of Alzheimer disease. The so-called "early onset" cases of AD in persons in their 30's, 40's, and 50's may have a genetic basis, linked to the APP, PSEN1, and PSEN2 genes. AD cases linked to an APP genetic defect on chromosome 21 may explain the appearance of Alzheimer disease in persons with Down syndrome surviving to middle age. APP encodes for amyloid precursor protein, resulting in fibrillar aggregates of beta-amyloid that is toxic to neurons. About half of early onset AD cases are linked to mutations in the presenilin 1 gene on chromosome 14, presenilin 2 gene on chromosome 1, but these defects account for less than 0.5% of cases. (Lane et al 2018). The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects. A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE). The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases. However, the presence of apoE4 is neither necessary nor sufficient for development of AD, so testing for it is not warranted. Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in some AD cases. The abnormal tau may account for helical filaments found in neurofibrillary tangles. (Lane et al 2018). Regardless of the cause, the diagnosis of AD is made clinically by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. Biomarkers for prediction of progression to AD in persons with mild cognitive impairment have been studied. The amyloid PET scan has a high sensitivity and specificity for AD and may be useful when clinical findings are atypical or the patient is young. Additional markers include CSF Aß42 and tau, temporoparietal hypometabolism on 18F-FDG PET scan, and measurement of hippocampal volume. Patients with all of these markers progressed to AD, while persons without any markers did not. (Galluzzi, et al, 2013)(Johnson, et al, 2013). The definitive diagnosis of AD is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation. The pathognomonic microscopic features of AD are: an increased number of beta-amyloid-containing neuritic plaques and neurofibrillary tangles composed of abnormally phosphorylated tau protein aggregates in cerebral cortex. (Mehta and Schneider, 2023). Neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers relative to age in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Neurofibrillary tangles consist of hyperphosphorylated tau protein filaments within neurons. Other microscopic findings with AD include amyloid angiopathy and granolovacuolar degeneration. (Mirra et al, 1993). Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer disease. Many treatment strategies are based upon reducing the loss of acetylcholine. However, such medications appear to be able to produce moderate symptomatic benefits but not to stop disease progression. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer disease is pneumonia, typically an aspiration pneumonia. (Klafki et al, 2006). Biomarkers of AD can be employed to suggest the diagnosis, but are not definitive. Positron emission tomography (PET) scans can employ radiolabeled F-fluorodeoxyglucosse (F-FDG PET), tau protein PET, and amyloid PET. The latter is the most sensitive and specific. CSF markers include detection of tau protein. (Frisoni et al, 2017)

A 77-year-old male presented with facial redness and discomfort for the past year.

Physical examination shows thickened and bumpy nasal skin; and pink patches with telangiectasia and red papules on the face, most prominently on the medial cheeks and forehead. This is rhinophyma, and he also has associated papulopustular rosacea. General skincare (emollients, soap substitutes) and lifestyle advice is important in managing rosacea in general. Keeping a symptom diary to identify and avoid triggers (eg, foods, hot beverages, spices, alcohol) for flare-ups can be helpful. Cool compresses are often used for flushing and various topical or systemic medications may be considered for symptom control. Sunscreens may help as many sufferers experience exacerbation with sunshine. This patient was prescribed the tetracycline antibiotic doxycycline, and advised to avoid spicy foods, alcohol, caffeine, and stress. He was also recommended to seek plastic surgery consultation to consider cosmetic facial resurfacing. Oral isotretinoin has also been reported to be useful in treating rhinophyma; the drug reduces the enlarged sebaceous glands that characterize rhinophyma. See: Rhinophyma.

This 70-year-old presented with a scaly, tender, itchy nodule on the back of her right hand.

This is a cutaneous squamous cell carcinoma (SCC). SCC is a common skin cancer derived from keratinocytes. It is invasive and can sometimes metastasise and be fatal. The mortality rate is around 25%. SCC usually begins as a tender erythematous papule or nodule. It usually has surface scales. It tends to grow faster than basal cell carcinomas (BCCs). Some SCCs can bleed or ulcerate. They are usually located on sun-exposed sites such as the face, lips, ears, bald scalp, forearms, hands, and lower legs. Most SCCs arise from actinic keratoses (AK) or SCC in situ. SCCs are five times more common in solid organ transplant recipients who are on systemic immunosuppressants. The longer the period of immunosuppression, the greater the risk of SCC development. Education regarding this risk of skin cancer, its early presenting features, and rapid access to specialists is essential. Vigilant sun protection is essential for high-risk patients. Patients should be advised to minimise sun/ultraviolet (UV) light exposure and wear sun protective clothing such as a wide-brimmed hat, long-sleeved shirt, and long pants. They should also apply SPF 50+ sunscreen with UVA and UVB blocking properties regularly when outdoors. Oral acitretin has been shown to reduce SCC development in solid organ transplant recipients by 2030%. See: Cutaneous squamous cell carcinoma.

15-year-old with discolouration on abdomen and neck

Physical examination shows: She was diagnosed with confluent and reticulated papillomatosis. This uncommon skin condition has an unclear cause. Current studies support a bacterial aetiology (a gram-positive actinomycete Dietzia papillomatosis) and the condition responds well to antibiotics. Differential diagnoses include tinea versicolor (excluded by direct mycology) and acanthosis nigricans. Confluent and reticulated papillomatosis usually clears with a tetracycline antibiotic. This patient was prescribed minocycline, and the rash resolved. See: Confluent and reticulated papillomatosis.

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Physical examination shows monomorphic pink papules and fine pustules with areas of redness and telangiectasia. She was diagnosed with papulopustular rosacea. Alcohol, spicy foods, hot beverages, and alcohol are frequently cited food triggers. Sunshine usually makes rosacea worse, though in a small minority it actually helps. Drugs that cause flushing may make rosacea worse. General skincare and lifestyle advice is important in managing rosacea. Keeping a symptom diary to identify and avoid triggers for flare-ups can be helpful. Cool compresses are often used for flushing and various topical or systemic medications may be considered for symptom control. This patient was prescribed oral doxycycline and advised to avoid sun exposure (see: Sun protection). Her symptoms responded gratifyingly. See: Rosacea.

45-year-old with progressive facial discolouration

Physical examination shows reticulate red-brown hyperpigmentation with telangiectasia and atrophy on the lateral cheeks and sides of the neck. This is poikiloderma of Civatte, which is typically seen on sun-exposed areas such as the lateral cheeks and sides of the neck, and spares the shaded area under the chin. This is a common and benign skin condition more frequently seen in post-menopausal women. Poikiloderma is characterised by hyperpigmentation, telangiectasia, and atrophy within the same lesion. In some instances, photosensitising fragrance constituents in personal care products may be responsible. Use a UVA- and UVB-blocking sunscreen, and avoid perfumed products on the affected area. Hydroquinone and retinoid creams may help. Intense pulsed light or pulsed dye laser are both advocated to reduce both the telangiectasia and hyperpigmentation. See: Poikiloderma of Civatte.

33-year-old with pink scaly facial papules

This is chronic perioral dermatitis. It usually consists of erythematous papules arranged around the chin and nasolabial folds. Similar lesions may develop at the outer canthi. Occasionally pustules develop, and it may be mistaken for a bacterial infectionor acne. In the latter condition comedones (blackheads and whiteheads) are present. In perioral dermatitis, topical products, especially topical steroids, should generally be stopped as they can worsen the condition. Mild cases may resolve with this zero-therapy approach. In moderate or severe cases, oral tetracycline antibiotics result in rapid resolution and a gratified patient! Topical pimecrolimus is an alternative. This patient was prescribed trimethoprim as she was allergic to tetracyclines, and instructed to use gentle facial products, avoid fragrances and sun exposure, and refrain from using topical steroids. See: Periorificial dermatitis.

60-year-old with multiple crusted plaques on the scalp

The most likely diagnosis is erosive pustular dermatosis of the scalp. It is more common in elderly men with a sun-damaged bald scalp, a history of actinic keratoses, and/or a history of SCCs or basal cell carcinomas (BCCs) of the scalp. It is usually diagnosed by its characteristic clinical appearance. Initially, a small area of the scalp becomes red, crusted, and irritated. Crusting and superficial pustulation usually overlies a moist, eroded surface. Extensive disease can result in scarring and extensive alopecia. SCC can develop in the scars. Potent or ultrapotent topical steroids will suppress the inflammatory changes. Gradual reduction in the potency of topical steroid used over a 6-month period may result in cure. Failure to respond to this should prompt biopsyto exclude malignancy. There is some evidence for using oral zinc sulfate, topical calcipotriol, and topical dapsone. Oral retinoids may also be tried. Maintenance therapy with sun protection and intermittent moderate-potency topical steroids can provide long-term relief. See:Erosive pustular dermatosis.

This 18-year-old male presented to ED with a 1 week history of widespread target shaped lesions on his trunk, legs, and arms as well as severe oral mucositis. The rash had initially started around his eyes, progressing to a widespread eruption of discrete lesions affecting his hands, trunk and limbs, with  erosion of his oral and genital mucosa. He had very poor oral intake for 3 days prior to admission.

Erythema multiforme is an immune-mediated condition generally characterised by target lesions which can blister centrally, and can also include erosions or bullae in the mucosae of the mouth, genitals, or conjunctivae. The target skin lesions may be pruritic and mucosal erosions can be very painful. The patient may experience fatigue, myalgias, and fevers Viral infections such asherpes simplexvirus (HSV) are often, although not always, involved in the development of this condition. SJS/TEN tends to produce coalescing lesions affecting more than 10% of the body surface area and is usually drug induced. Mycoplasma pneumonia-induced rash and mucositis has recently been distinguished from erythema multiforme; the skin lesions are less prominent and it carries a better prognosis than erythema multiforme triggered by other agents. Erythema multiforme is generally self-limiting and symptoms usually resolve in 46 weeks. Oralantihistaminesortopical steroidsmay be used for itch if required. It may recur with subsequent attacks of herpes simplex if this is the trigger and if frequent suppressive antiviral therapy may be indicated. In erythema multiforme major with severe mucosal erosion, support of oral intake (eg, lidocaine oral gel and nutritional supplements) may be necessary. Prednisoneis often used in practice to reduce the length of the illness and its severity, but its use is not strongly evidence-based. See:Erythema multiforme.

30-year-old woman with chronic axillary and submammary plaques

This is Hailey-Hailey disease. It is also calledbenign familial pemphigus. It is an autosomal dominant genodermatosis. It is due to a mutation in theATP2C1gene, causing dysfunction of a Golgi-associated protein and interfering with cellular calcium signalling. The onset of disease is usually during the second or third decade, but sometimes delayed into the fourth or fifth decade. It mainly affects the major body folds such as the axillary, inframammary, and groin folds, and sometimes the trunk. Widespread separation of the epidermal keratinocytes (acantholysis) resulting in a dilapidated brick wall appearance. There may be mild dyskeratosis. Direct immunofluorescenceis negative in Hailey-Hailey disease. There is currently no cure for Hailey-Hailey disease. Avoidance of triggers and symptom management are the mainstay of management. General measures include wearing lightweight clothing, antiseptic washes or bleach baths, and humectants. Symptom management options may include intermittenttopicalorintralesional steroids, topicalcalcineurin inhibitors,botulinum toxininjections, and low dose naltrexone. See:Benign familial pemphigus.

13-year-old with a facial flush

The diagnosis iskeratosis pilaris rubra. This condition is a variant ofkeratosis pilaris, and there are often typical lesions of keratosis pilaris on the upper arms and thighs. There may also be discernible pigmentation as well as redness on the cheeks, and it may extend onto the neck (often referred to as erythromelanosis faciei et coli). It is easier to discern in pale skin individuals. It is often associated withatopic eczemaand ichthyosis vulgaris. Emollients containingurea,lactic acidorsalicylic acid,ortopical retinoidsmay diminish the scale. Definitive treatments to reduce the redness includepulsed dye laserto help with erythema orlaser-assistedhair removalfor ingrown hairs. Differential diagnoses include: For more information, seeKeratosis pilaris.

A 3-year-old boy presented with multiple pigmented skin lesions on his trunk. The initial lesion started on his left knee at 6 months of age. The lesions became more erythematous on hot days or in warm temperature environments, and were otherwise asymptomatic.

Urticaria pigmentosa, also known asmaculopapular cutaneous mastocytosis, is due to abnormal collection of mast cells in the skin causing brown patches and freckles. It is the commonest type of cutaneousmastocytosis. It commonly affects infants, with first patches appearing at a few months of age. In young children, it is common for the patches to blister when rubbed. 50 to 70% of cases undergo spontaneous resolution before adolescence. Most children with urticaria pigmentosa do not require any treatment. Treatment modalities include: Children with urticaria pigmentosa may developanaphylaxisor anaphylactoid reactions to bee and wasp stings, hence it is advisable for them to carry an injectableadrenaline(epinephrine) kit.

He previously worked as a farmer and spent a lot of time under the sun during his working years.

Cutaneous squamous cell carcinoma(SCC) usually begins as a tender erythematous papule or nodule that may have a variable amount of hyperkeratosis. Older lesions may ulcerate. It is generally located on sun-exposed sites and usually enlarges over a period of months. They can arise in old scars, and in areas that have been subject to irradiation. Cutaneous SCC nearly always requiressurgical excision. Other methods of removal include: Cutaneous SCC can bleed or ulcerate if the lesion continues to grow. It can also become a nidus forinfectionsuch ascellulitis. Cutaneous SCC can also be invasive. In some cases, it may metastasise to both the lymph nodes and beyond, and be fatal.

A 65-year-old man presented with a one week history of a widespread, itchy, painful rash affecting various parts of his body. The itchy weals progressed and expanded over a few hours and were persistent, lasting 48 hrs, painful, and resulted in some bruising.

There are annular, indurated, urticated plaques, with petechiae and purpura centrally in some areas. There are also targetoid lesions. Given the morphology and history of the rash, the differential diagnoses included: With the histology showing leukocytoclastic vasculitisin specimen one (arm), the likely diagnosis is urticarial vasculitis. Weals lasting more than 24 hrs, bruising, and pain with itch are typical clinical findings. Treatment is based on the systemic effects and the extent of cutaneous involvement. As this patient was very symptomatic, he was started on a weaning course of prednisoneand antihistamines (cetirizine 20 mg twice daily). Other potential treatment options for urticarial vasculitis include dapsone, colchicine, hydroxychloroquine, or immunosuppressive medications such as ciclosporin or azathioprine. Consideration should be given to possible underlying causes such as SLE, Sjogren syndrome, gammopathies, leukaemia, internal cancers, hepatitis B and the use of some drugs, although many cases are idiopathic.

A 34-year-old woman with trisomy 21 presented with a rapidly worsening rash of 4 months. The rash was associated with marked scratching that started on her hands then spread throughout the body. She had no preceding skin disorders.

Crusted scabies is a highly contagious hyperinfestation with Sarcoptes scabiei var hominis a parasitic mites, presenting in immunocompromised patients. It is previously known as Norwegian scabies. It is estimated that individuals with crusted scabies have up to 4,000 mites/g of skin. Patients are often infested with over 1 million mites. The majority of patients with normal scabies are infested with only with around 1020 mites. Scabies is readily diagnosed clinically and confirmed by identification of mites or eggs on dermoscopic or microscopic examination of burrows or scale in crusted disease. Treatment requires oral ivermectinand topical insecticides: Family members, carers, and close contacts should also be screened for scabies and treated accordingly. Regardless of examination findings, all family members who have had close contact with the index case should be treated with a topical scabicide and should repeat treatment in one week. Risk factors for crusted scabies include:

A 30-year-old male patient hailing from Bihar, India, presented with multiple hypopigmented hypoesthetic patches over his trunk along with the pictured erythematous skin lesion with a punched-out centre.

The swiss cheese pattern is consistent with mid-borderline leprosy. Diagnosis can be confirmed via skin biopsyfor histopathology, and slit-skin smear for bacterial index (Bl) and morphological index (MI). After confirming the diagnosis, multi-drug therapy (MDT) should be initiated according to the type/grading of leprosy. For more information, see our page on leprosy.

A 12-week-old girl presented with a persistent rash on the thigh and armpit since her birth. Her parents had noted that she appeared persistently irritable, with no social smile, and was unable to fix on and follow objects or faces. She had a normal antenatal and birth history.

The likely diagnosis is incontinentia pigmenti (IP). It is a rare genetic condition characterised by skin, eyes, teeth, and CNS abnormalities. The characteristic skin lesions of IP present at birth or develop in the first few weeks of life in about 90% of patients and tend to be linear or follow the lines of Blaschko. Incontinentia pigmenti is an X-linked dominant disorder, caused by mutation in the NF-kB essential modulator (NEMO or IKBKG) gene, which encodes for a protein that protects against TNF-alpha-induced apoptosis. Male patients with milder NEMO mutations may present with hypohidrotic ectodermal dysplasia with immunodeficiency. IP has 4 stages (some of which may be absent or overlapping) of cutaneous finding that follow the lines of Blaschko(with the exception of stage 4).

A 58-year-old male presents with a six month history of erythroderma, non-responsive to topical and oral steroids. He is otherwise well and has no mucosal lesions or ocular involvement.

This rash shows the classical deck chair sign, a clinical pattern characterised by selective sparing of skin folds and flexures in an erythematous eruption. Often widespread papules coalesce to form plaques,the papular component can be seen in the images. Deck chair sign is characteristic of papuloerythroderma of Ofuji (PEO). It has also been observed in: A high index of suspicion is needed to rule out associated malignancy. Comprehensive investigations including skin biopsy, tumour markers, and imaging are recommended.

Blisters after protracted sepsis

Diagnosis: Linear IgA bullous disease (LABD) LABD is an autoimmune vesiculobullous disease. It can be idiopathic; secondary to medications or infections; or associated with some underlying disease (eg, inflammatory bowel disease, rheumatoid arthritis, malignancy). Vancomycin is the most common drug associated with LABD. Lesions typically appear 24 hours to 15 days after the first dose. Differential diagnoses: Blisters are sometimes seen showing thestring of beads sign with a large central blister surrounded by smaller peripheral ones as depicted in the image. The gold standard for diagnosis is direct immunofluorescence of perilesional skin which demonstrates linear deposition of IgA at the dermoepidermal junction. Skin biopsy shows subepidermal blisters with a predominantly neutrophilic dermal infiltrate. In the case of drug-induced LABD, many cases will resolve with withdrawal of the offending agent. In more severe or idiopathic cases, treatment options include:

A 25-year-old male was referred to our skin cancer clinic with a one year history of an asymptomatic, slowly enlarging lesion in the right postauricular area. A biopsy showed focal hypergranulosis, basal cell liquefactive degeneration, and a dense upper dermal infiltrate of lymphocytes and melanophages.

Clinically this resembles milia en plaque. However, the lesion is slightly infiltrated and other granulomatous conditions (eg, sarcoid) may be considered. Histology confirmed lichen planus follicularis tumidus, a very rare variant of lichen planus. A full skin check is needed for other signs of cutaneous or mucosal lichen planus. The retro-auricular site is the location of predilection. Lichen planus follicularis tumidus is in essence a chronic-relapsing disease, and very resistant to treatment. Ultrapotent topical steroids, systemic steroids, and retinoids (topicalor oral isotretinoin) have been suggested. In the case of our patient, the lesion was surgically excised.

Farmer with enlarging finger lesion

This is an orf of the finger and a result of a zoonotic infection that often occurs in a person who have been handling sheep (such as lambing season in this farmer) or goats. Orf lesions are generally solitary or few in number, and can be tender. They occur most commonly on the fingers, hands or forearms but can appear on the face. Patients are largely asymptomatic although some may have some systemic upset or associated lymphadenopathy. In immunosuppressed individuals, they can develop into larger, persistent, or fungating lesions. Orf is caused by the parapoxvirus, Orfviridae. This infection is usually diagnosed clinically but can be confirmed on a viral swab, skin biopsy, or vesicular fluid by polymerase chain reaction (PCR). It can also be identified by electron microscopy. Orf is a self-limiting condition that usually resolves in 6 to 12 weeks. Secondary bacterial infectionand regional adenitis may require antibiotics. Orf can also be associated with immunologic reactions such as erythema multiforme, other non-specific toxic erythemas, and pemphigoid. The lesion should be covered to prevent transmission. It is highly transmissible between animals but human-to-human transmission is rare. It is advisable to use gloves or wash hands with antiseptics thoroughly when handling infected animals. People can develop recurrent orf infections, but some immunity to the virus is acquired after the first infection so that it is less severe on subsequent occasions.

This 78-year-old lady presented with a new reddish-orange spreading rash on the right side of her face overnight. The affected skin was raised with a demarcated border and areas of blistering. Her white cell count and C-reactive protein were very raised and she described an episode of fever and rigors.

This rash and history is classical for erysipelas. Erysipelas is a superficial form of cellulitis, a potentially serious bacterial infection affecting the skin. Erysipelas affects the upper dermis and extends into the superficial cutaneous lymphatics. Almost all erysipelas are caused by Group A beta-haemolytic streptococci (Streptococcus pyogenes). Staphylococcus aureus, including methicillin-resistant strains (MRSA), Streptococcus pneumoniae, Klebsiella pneumoniae, Yersinia enterocolitica, and Haemophilus influenzae have also been found rarely to cause erysipelas. Oral or intravenous penicillin is the antibiotic of first choice. Erythromycin, roxithromycin, or pristinamycin may be used in patients with penicillin allergy. Vancomycin may be used for facial erysipelas caused by MRSA and treatment duration is usually for 10 to 14 days. Erysipelas tend to recur in up to one-third of patients due to existing lymphoedema or poor lymphatic drainage as a complication of the condition.

An otherwise healthy 3-week-old girl presented to the children’s assessment unit with a rapidly progressing red patch on the left lateral periorbital region.

Infantile haemangioma of the periorbital region, caused by the rapid growth of capillary blood vessels on the surface of the skin. Infantile haemangiomas characteristically develop in the first few weeks of life, up to three months of age. In view of its rapid progression and proximity to the eye, this patient underwent an MRI of the brain to exclude any extension in the orbit or brain. If the haemangioma is not in a high risk area, patients may not need further investigation or treatment. Infantile haemangiomas can be managed by observation only, as most will undergo spontaneous resolution by the age of 6, but may be treated with an oral beta-blocker. This causes resolution of the lesion by contracting the blood vessels and decreasing blood flow to the area. Treatment duration is dependent on the response, but can continue for up to 18 months. The indications for beta blockade include obliteration of the visual axis by the haemangioma, severe organ dysfunction as a result of the haemangioma, bleeding (often in the napkin area due to trauma) and cosmetic concerns. Some thin lesions may be amenable to the topical beta blocker timolol.

This 11-year-old female presented with disseminated flaccid blisters which were easily torn, exposing a red oozing dermis. These blisters mainly affected the mucosal membrane of the eyes, mouth, and genitalia, in addition to the skin of the face, trunk, and proximal extremities two days prior to presentation.

Drug-induced epidermal necrolysis. Differential diagnoses include: Since the lesions affected >30% of the body surface area with a history of taking supplements, and there was no malignancy suspected, the diagnosis suggests drug induced toxic epidermal necrolysis. This is a dermatological emergency. Eye care: Mouth care: Nutrition: Airway: Genitourinary care: Prevent recurrence: Systemic corticosteroids (12 mg/kg/day for 35 days) and ciclosporin could be used, although this remains controversial. The skin lesions will ultimately heal and any pigmentary changes will resolve. Potential long term problems include:

52-year-old with expanding abdominal plaques

A skin biopsy was obtained including subcutaneous fat, which demonstrated collagen bundles extending into the reticular dermis, enclosing the eccrine glands and blood vessels. With the clinical and histological findings, the likely diagnosis is plaque morphoea (morphea). There are many subtypes of morphoea such as plaque, linear, generalised, and pansclerotic. It is important to evaluate the patient for systemic symptoms and with laboratory tests such as ANA, anti-histone antibodies, and anti-SS DNA antibodies. In patients with superficial circumscribed lesions, topical treatments are appropriatesuch as: For patients with more widespread lesions and deep morphoea, consider: Rapidly progressive lesions require treatment with systemic corticosteroids or methotrexate. Morphoea can be chronically active or relapsing and remitting. Deep tissue involvement (eg, subcutaneous tissue, muscle, or bone) can lead to deformity and dysfunction.

A 6-hour-old male neonate presented with a shiny membrane covering his body since birth. The baby was born at term and was the second child in the family with the same skin abnormality.

The likely diagnosis is collodion baby, a rare congenital disorder due to a mutation of certain genes which manifest as a tight, clear sheath covering their skin called a collodion membrane, that usually dries and peels off during the first few weeks of life. The most common underlying diseases: Other rarer conditions that may present with a collodion membrane include: 10% of collodion babies have normal underlying skin a mild presentation known as self-healing collodion baby. Management requires the expertise of a dermatologist and the paediatric team. The baby is initially kept in a humidified, neutral-temperature environment like an incubator. Other supportive treatments such as intravenous fluid and tube feeding may also be required to maintain hydration and nutrition. The skin should be kept soft to try and reduce scaling. The collodion membrane must not be debrided. Treatment may include: Collodion babies are at high risk of complications. The cracking and peeling of the membrane increases the risk of infectionfrom microorganisms. These infants are also at risk for: Prognosis depends upon the particular underlying condition.

This 40-year-old man has had three attacks of lesions which affect both his palms and soles. These attacks have occurred over the last three months, and last about 10 days.

This is recurrent erythema multiforme. He has some target-like lesionsthat are characteristic of this eruption. Recurrent disease is usually triggered either by intermittent drug exposure, or herpes simplex infections which may be overt or covert. It is important to accurately elucidate drug exposure history and seek symptoms of cold sores which can occur around the mouth, on the genitalia, or even affecting the uterine cervix. The lesions of erythema multiforme can be treated by a super potent topical steroid which will reduce symptoms and hasten resolution. If evidence of herpes simplex as a trigger can be found, then suppressive long-term oral aciclovir may be an option if the eruption is sufficiently problematic and frequent to merit this. If a drug is suspected it should be avoided.

This 25-year-old man has got round, brown, scaly patches over his chest. It has been diagnosed as a fungal infection but has not responded to oral terbinafine for two weeks.

The superficial brown scaly patches are highly suggestive of a yeast infection called pityriasis versicolor it is due to a yeast called Malasseziaand not a dermatophyte fungus. The best way to confirm the diagnosis is by taking skin scrapings. The yeast pseudohyphae and spores are said to resemble spaghetti and meatballs when looked at using a potassium hydroxide wet preparation on microscopy. Unfortunately it does not respond to oral terbinafine, which is highly active against dermatophyte fungi but not the causative yeast. It can be treated by using topical azole shampoos or creams, or a short course of oral itraconazole. See: Pityriasis versicolor.

This elderly lady has a rash affecting both lower legs. It is weepy and itchy. She has not responded to a week of oral antibiotics.

This is bilateral lower leg eczema, and it is often multifactorial. There is often underlying venous incompetence, compounded by both irritantor allergic contact dermatitis. It is often bilateral, which cellulitis is almost never! Rest, elevation, potassium permanganate compresses or soaks, a topical steroid to suppress the eczema, and compression. Doppler ankle brachial pressure index (ABPI) should be measured to assess the safety of high compression bandaging. Consideration should be given to what is being used topically, and patch testingis indicated to exclude an allergic contact dermatitis to a medicament dressing or bandage. See: Venous eczema.

This 15-year-old boy has intensely itchy, excoriated, and weepy patches on both legs. They have not responded to oral flucloxacillin.

The picture looks like acute discoid eczema there are exuding, excoriated, weepy well-defined plaques on the lower legs. Affected individuals are often atopic. Wet exuding lesions can be dried out with the use of one in 10,000 potassium permanganate soaks. Thereafter, a potent steroidand antibiotic combination cream will be needed to suppress the eczema and prevent the development of secondary staphylococcal superinfection. See: Discoid eczema.

A 23-year-old female presents with a six-week history of an erythematous rash starting around the feet then spreading cephalically until covering 60% of the skin surface, predominantly over the torso.

There is a patchy and confluent erythematous rash studded with fine pseudo pustules andperipheral circular peeling seen over the abdomen. The likely cause is lamotrigine-induced generalised pustular psoriasis (GPP). Lamotrigine is a widely used antiepileptic commonly producing cutaneous side effects (incidence 10%). However, this is the first report of lamotrigine-induced GPP. Other differential diagnoses would include: After stopping the offending drug (lamotrigine in this case), the first-line treatment for generalised pustular psoriasis (GPP) would include acitretin, ciclosporin, or methotrexate. If this is insufficient, a biologic agentcould be considered. It is important to note that glucocorticosteroidstypically flare pustular psoriasis, particularly on withdrawal, so are contraindicated for GPP.

This 15-year-old boy has just returned from a holiday in Thailand. He had a beach “tattoo” undertaken 10 days ago. Within a few days he developed persisting, itchy, red areas where the tattoo had been applied.

The likely cause of his reaction to the beach henna tattoo is an allergic contact dermatitis to the black dye chemical paraphenylenediamine (PPD). Although the tattoo solution does contain some henna, this is much less likely to be the sensitiser. The reaction will settle with the use of a topical steroid. However, he is now sensitised to PPD, and should he use a PPD-containing hair dye in the future, he will have a reaction to this. PPD-allergic individuals may also react to some azo clothing dyes, PABA-containing sunscreens, amine local anaesthetics(benzocaine and procaine), sulfonamides, and sulfone drugs. See: Tattoo-associated skin reactions.

This man has had recurring sore lesions always on the left side of his palate.

There are clustered erosions on the left side of the palate. (They started with a prodrome of soreness and then vesicles developed, which have now eroded.) The recurrent nature of the eruption occurring in the same area of the palate and the clustering of the vesicles and later erosions is typical of herpes simplexvirus (HSV) infection, usually HSV type 1. By taking viral swabs this can be subjected to either viral culture or PCR. Aciclovir 200 mg five times a day for 5 days and chlorhexidine mouthwash twice a day for 5 days are reasonable options for an acute attack. Repetitive frequent recurrences may need long term suppressive aciclovir.

19-year-old female presented with:

This is systemic lupus erythematosus (SLE)overlapping with psoriasis. There are no randomised controlled trials for concomitant SLE and psoriasis, as limited cases are reported worldwide. Apremilast 30 mg oral twice daily and methylprednisolone25 mg oral once daily along with sunscreen and topical steroids were used. She responded very well and is now in complete clinical remission. Antimalarials were avoided as although these can be very helpful for the joint and skin manifestations of SLE, they can cause an exacerbation of psoriasis. Interleukin (IL) 17A inhibitors may help both diseases; TNF antagonists may exacerbate SLE.

50-year-old lady with erythroderma

Pityriasis rubra pilaris (PRP) is a group of papulosquamous dermatoses. There are 5 major types of PRP, plus an HIV-associated type has been described. The distinction is mostly based on age of onset and distribution. Adult classic form (type 1) is the most common form. Localised PRP can be treated with topical emollients and medium-potency topical corticosteroids. Extensive or disabling PRP usually requires systemic treatment. Treatment options include:

A 47-year old man with a recent acute myeloid leukaemia relapse presented with multiple purple lesions on the anterior chest and forearms. The lesions were not itchy or tender.

Sweet syndrome(acute febrile neutrophilic dermatosis). It is a type of neutrophilic dermatosis. Sweet syndrome usually has an acute onset of erythematous, oedematous plum coloured papules and plaques that are tender but not pruritic, with the face and trunk being the common areas to be affected. Lesions may occur in the mouth and conjunctivitis and episcleritis are well reported. There is often peripheral blood neutrophilia and fever. A dense neutrophilic dermal infiltrate with disintegration of neutrophils producing nuclear dust. There should not be inflammatory changes in the blood vessels, which distinguishes it from a leukocytoclastic vasculitis. The exact cause for neutrophilic dermatosis is unknown. Sweet syndrome can be caused by underlying disorders such as: In mild disease, neutrophilic dermatosis may respond to topical corticosteroids. In moderate-to-severe disease, the treatment options are:

A 52-year old gentleman presented with widespread rash of one week's duration - it started 3 days following commencement of oral flucloxacillin and fluconazole for oral thrush and possible candida infection at the groin.

Acute generalised exanthematous pustulosis (AGEP), also known as toxic pustuloderma. AGEP is an uncommon pustular drug eruption characterised by superficial pustules coalescing to form pustular lakes on an erythematous base. There is superficial epidermal detachment in areas where the pustules have become confluent. The time interval between drug ingestion and onset is short (23 days). Occasionally it may be localised to limited areas of skin such as the face (acute localised exanthematous pustulosis) Over 90% cases of AGEP are provoked by medications, most often beta-lactam antibiotics (eg, penicillins, cephalosporins). Other medications include tetracyclines, sulfonamides, oral antifungals, hydroxychloroquine, carbamazepine, calcium-channel blockers and more. Viral infections such as EBV, CMV, Hepatitis B, adenovirus and enterovirus are also common triggers of AGEP in children.

A 25-year old female presented with rapid swelling, mottling and pain on both palms when exposed to water for a brief time (3-5 minutes). The symptoms resolve within 30 minutes after the hands are dried.

Aquagenic wrinkling of the palms. It is a rare dermatosis that usually presents in the 2nd decade of life with equal sex incidence. It is an exaggeration of the normal finger wrinkling that occurs when fingers are soaked in water for a prolonged period. The exact pathology is unknown, however it is likely due to salt imbalance in the skin cells, resulting in increased water retention and transepidermal water loss. Aquagenic wrinkling of the palms has a strong association with cystic fibrosis (CF), affecting up to 84% of patients with CF and 35% of carriers. It can be the first presenting sign of CF carrier status in otherwise healthy individuals or non-classical CF. It can also be drug related (aspirin and COX inhibitors).

A 4-month old infant presented with severe exacerbation of eczema and poor feeding.

Eczema herpeticum is also known as Kaposi varicelliform eruption. It is a skin infection caused by Herpes simplex virus (HSV) type I and II. It most commonly develops in individuals who already have atopic dermatitis/eczema. Eczema herpeticum can cause an acute exacerbation of eczema. It is usually very painful and young children can be unwell with fever and swollen lymph nodes. Eczema herpeticum can become infected with bacteria, commonly Staphylococcus or Streptococcus. Secondary bacterial infection can lead to impetigo or cellulitis. It can cause herpetic keratitis if the eyes are infected by HSV from the surrounding lesions, which if left untreated, can lead to blindness. Eczema herpeticum is considered as one of the few dermatological emergencies. Prompt treatment with antiviral medication (eg, aciclovir, valaciclovir) should eliminate the need for hospital admission.

This 3-month old infant presented with a rapidly growing lesion on the back of her ear. The plaque is bright red, non-pulsatile, and non-tender.  She also has another similar lesion on her anterior abdomen.

Infantile haemangiomas (IH) are the most common benign vascular skin tumour in children. They are caused by proliferating vascular endothelial cells. They usually appear shortly after birth (rarely at birth), and grow rapidly in the first 6 months. Most IH stop growing by 6-9 months. They involute over years. Most IH do not require treatment as they usually involute with time. Depending on the location, size, and presence of ulceration, some require treatment. Treatment with beta blockers (oral propranolol) has now replaced oral corticosteroids as the gold standard treatment for complicated or ulcerated IH. The earlier treatment is commenced, the more effective it is likely to be in preventing further growth. Other treatment options include:

A newborn presents with an unusual birthmark confined to one leg.

A linear epidermal naevus. It is an overgrowth of the epidermis and usually presents at birth or during early childhood. It is mostly flat and hyperpigmented, but there is slight thickening and scale around the ankle. Epidermal naevi present as streaks and swirls of thickened (verrucous, hyperkeratotic, or velvety) skin along the lines of Blaschko, usually with hyperpigmentation and sometimes with adnexal involvement.They are usually unilateral, and only rarely generalised, when they may be associated with skeletal abnormalities (epidermal naevus syndrome). In infancy, epidermal naevi can present as flat tan or brown marks, but as the child ages, they become thickened and verrucous. Most epidermal naevi do not require treatment. Topical calcipotriolmay reduce the thickness of the verrucous lesions. Verrucous epidermal naevi can be treated with an ablative laserwith good long-term aesthetic results.

A 12-day-old neonate presents with a large thickened area of skin discoloration on the back.

Subcutaneous fat necrosis of the newborn. This is an uncommon panniculitis of neonates. It usually occurs in the first days of life. There has often been fetal distress in labour and it may be associated with therapeutic hypothermia for hypoxic ischaemic encephalopathy. It can be painful. It usually, ultimately, self-resolves. It is associated with symptomatic hypercalcemia (irritability, constipation, poor weight gain, and arrhythmia) as frequently as in 50% of cases. A baby with subcutaneous fat necrosis should have their blood calcium checked periodically for the first few months of life. Hypercalcaemia can be treated with low calcium milk feeds, increasing fluid intake, frusemide, or bisphosphonates. Sclerema neonatorum is an extremely rare disorder which was described in premature or debilitated children who developed a diffuse board-like stiffness due to generalized fat necrosis. This condition usually appears in the first days after birth and is usually fatal. Read more on subcutaneous fat necrosis of the newborn.

A 12-year-old boy with a history of atopic dermatitis presents with bilateral, itchy, swollen, and painful nipples.

This is nipple eczema. It is a localised dermatitis involving the nipple and areola. This is frequently bilateral and fluctuates in severity. Lichenification due to scratching can be conspicuous, as can hyperpigmentation, particularly in skin of colour. It improves in response to topical steroids and can deteriorate rapidly when irritated by scratching, soaps, shower gels, and detergents. Nipple eczema is a common local manifestation of atopic dermatitis but can occur in isolation. Patients should avoid any precipitating irritants and allergens. Regular emollients and topical corticosteroids are the mainstay of treatment. Moderate potency topical steroids are usually very effective, followed by low potency topical steroids as maintenance therapy if necessary.Topical coal tar preparations are an effective old fashioned remedy. Sometimes, use of a potent topical steroid with hydrocolloid dressing occlusion for a few days will break the itch-scratch cycle that perpetuates the problem.

This forty-six year old lady has had a pink weeping lesion under her chin for the last eight months.

This is a granuloma resulting from a dental sinus. They arise when there is longstanding dental abscess or necrosis of a tooth. When a dental sinus connects with the skin rather than the intraoral mucosa, they characteristically occur along the border of the mandible, but may also arise around the maxilla. The tethering of the skin around the sinus opening is a feature and may be appreciated either visually or on palpation. The teeth adjacent to the sinus should be inspected for signs of previous fillings, caries, and local tenderness on tapping. Radiology is the most important investigation and will show bone loss around the root tip of the affected tooth. MRI or CT may be required. Occasionally insertion of a radio-opaque probe into the sinus may be needed to identify the affected tooth. Removal of the affected tooth, retained root or necrotic material is required and the sinus should heal readily thereafter.

This 80-year-old man has had large crusted lesions over his bald anterior scalp for some months. A large scab has been removed revealing the appearance seen in the photograph.

There are superficial erosions over the scalp surmounted with thick pus. There are also several actinic keratoses. The picture is typical of erosive pustular dermatosis of the scalp. It is seen mostly in older bald men with sun damaged scalps. It has also been reported on the lower leg, a heavily sun exposed site particularly in women. Removing the overlying crusts and using a potent topical steroid and antibiotic combination cream can be very gratifying. Areas that do not heal should be re-evaluated and possibly biopsied to exclude squamous cell carcinoma.

This 18-year-old man has had a rash on his abdomen for 8 months. Mycology has been negative on 3 occasions and it has not responded to oral itraconazole.

There is a slightly scaly net-like (reticulate) eruption on the abdomen. The features are typical of confluent and reticulated papillomatosis. It is frequently misdiagnosed as pityriasis versicolor, but mycology is negative and oral azoles are not as effective as tetracycline antibiotics. Recent evidence suggests it is due to infection with a Gram-positive actinomycete called Dietzia papillomatosis. It usually responds to a course of tetracyclines. For more information, see the topic page on confluent and reticulated papillomatosis.

This 69-year-old woman has noticed a rash over her upper chest in the last 2 years. It is non-itchy.

There is striking telangiectasia over the light-exposed area of her upper chest. The likely cause is amlodipine-induced phototelangiectasia. Telangiectasia in light-exposed areas has been reported with nifedipine and diltiazem, although it has had a more common association with amlodipine. In some cases, its resolution has been noted after substitution of the calcium channel antagonist with a different class of antihypertensive.

This 33-year-old man presented in the summer with a streaky rash over his trunk of 2 days duration. In some areas, it is starting to blister. He denies any drug ingestion.

This is typical of a phytophotodermatitis, a rash that results from a phototoxic plant sap coming into contact with the skin, and subsequent light exposure. It results in redness and sometimes blistering of the exposed skin. He has used a strimmer, or string weeder, and has been working with his top off! The strimmer has spattered phototoxic sap over his trunk. His face was unaffected because he had correctly used a face mask as personal protection. With photoprotection, the rash will heal, but will leave marked post-inflammatory pigmentation which may last for several months.

This 35-year-old woman has had three episodes of redness and blistering affecting the same area on only one foot in the last four years.

The recurrent development of redness and blistering in exactly the same place on the skin is very suggestive of a fixed eruption, most commonly caused by drugs. Occasionally they can be caused by foodstuffs, preservatives and other food and beverage additives. Lesions may be solitary or multiple. Uncommon sites to develop fixed eruptions are the lids, lips, palms, soles, and genitalia. They frequently arise within minutes or hours after exposure to the offending agent, once sensitisation has occurred. When they resolve, they commonly leave areas of hyperpigmentation. The likely cause in this case is the antibiotic used to treat her urinary tract infections. Avoiding the offending drug, and similar potentially cross reacting drugs, is the most important aspect of treatment. If there is a blister, then this can be aspirated leaving the roof intact as a biological dressing. A potent topical steroidcan then be applied until the inflammation resolves.

This elderly man is undergoing terminal care – he is receiving opiates for pain relief. He has developed constipation and overflow incontinence. In the last few days, he has developed this florid rash on his posterior thighs.

He has streaked erythema where there has been accidental skin exposure to his faeces. Sadly, his opiates have constipated him, and this has been treated with co-danthrusate (dantron and docusate), an anthralin-like agent that acts as a stimulant laxative. It is metabolised in the gut to anthralin, and when there is accidental contact with faeces and the skin, it produces an irritant dermatitis. It may oxidise to a purple-brown colour just as anthralin (dithranol) does in the treatment of psoriasis. The co-danthrusate should be stopped and substituted with a different aperient; the erythema can be treated with a short course of a potent topical steroid.

This 80-year-old lady has atrial fibrillation and has been on warfarin for 2 years. Her anticoagulation control has been erratic in the last months.

These acute haemorrhagic lesions are the early stages of coumarin necrosis. Shortly after initiation of a coumarin, there may be a temporary state of thrombophilia, as coumarin reduces the effect of both natural anticoagulants and coagulants. The former (Proteins C and S) have shorter half-lives than the coagulants, hence the early temporary thrombophilic state before anticoagulation is effected. The same situation may occur with longstanding coumarin use if control has been erratic. It is more likely to develop if heparin is not used in the early initiation of coumarins, or if the coumarin loading dose is too high. Lesions tend to occur on the fatter areas of the body such as the thighs and breasts. The coumarins should be stopped and heparin initiated. The condition does not occur with newer oral anticoagulants. Ulceration is likely to happen; surgical debridement may be required.

This 20-year-old woman has noticed that the skin under both eyes has changed over the last few years.

These are typical syringomas (syringomata)in the most frequently encountered location. They occasionally develop in the bathing trunk area and on the upper trunk. They are benign tumours of the sweat duct; they may be familial. Unlike xanthelasma, which tend to produce plaques, syringomas remain as discrete papules. There are no easy treatments. Light electrocautery can help as may laser, but all modalities may scar, and recurrent lesions are common.

This 55-year-old woman has a 3-month history of an unusual eruption over her trunk and limbs. She is otherwise well.

The eruption shows the classical wood graining with redness and scale of erythema gyratum repens. The erythema slowly spreads in a gyrate fashion, leaving scale on the trailing edge of the advancing edge. The term repens probably best translates as creeping. 80% of cases are associated with an underlying malignancy; often affecting the lung, oesophagus, breast, and stomach. Full clinical investigation and meticulous history taking should be performed. This includes probing for symptoms of an underlying cancer, tumour markers, mammography, and PET CT scanning.

This 6-year-old boy has problems with both feet — they are dry and split producing painful fissures.

The forefoot is dry, red and fissured; the typical features of juvenile plantar dermatosis. It occurs more commonly in boys with an average age of onset of 8. It is more common in atopic children. It is thought to be due to impervious occlusive footwear, and exacerbated by friction. In a small proportion of children, it is due to an allergic footwear dermatitis, identified by patch testing. Avoiding synthetic socks, and wearing two pairs of cotton or wool socks may help. Emollients or humectantssuch as urea cream may help. Applying steroid impregnated tape over fissures or using paste bandages accelerates healing. Topical steroidointments are sometimes useful.

This 60-year-old man has noticed a change in the appearance of one thumbnail. The rest of his nails are normal and there is no history of skin disease.

There is wrinkling and rippling of the central portion of the nail plate, also there is loss of the cuticle at the proximal nail fold. This is a habit-tic nail deformity. It is caused by frequent subconscious picking of the proximal nail fold either from the adjacent or the contralateral index finger. The repetitive pushing back of the cuticle results in minor trauma to the nail matrix; secondary rippled central dystrophy subsequently develops. The affected patient is often unaware of the habit but is often appreciated by spouses or other family members. Applying a hydrocolloid dressingaround the nail including the proximal nail fold can break the habit, allowing the nail to regrow normally.

This seven-day-old girl has developed a rash distributed only on the left forearm in the last few days. There are some vesicles and pustules, and a biopsy of one of these has shown an epidermal vesicle full of eosinophils.

This is the early vesicular phase of incontinentia pigmenti, an inherited condition which affects the skin, eyes, teeth, and central nervous system. It is inherited as a sex-linked dominant condition on the X chromosome. It is usually incompatible with life in utero in males, and therefore manifests only in females. Early in life, the rash is vesicular with eosinophil-filled vesicles. Later, lesions become warty (verrucous phase), before becoming hyperpigmented. In all phases, the rash follows the lines of Blaschko. Read more on Incontinentia pigmenti

This 40-year-old lady has developed an itchy eruption over her neck and upper back.  It has not improved with the use of emollients and topical steroids.

There is a rippled hyperpigmented maculopapular eruption on the neck. These features are typical of macular amyloidosis, a reaction that is thought to result from perpetual scratching of the affected areas. It is common in both men and women of Asian heritage. Histopathologically, amyloid deposits are seen within a skin biopsy; furthermore, macular amyloid is not associated with systemic disease as opposed to systemic AL amyloid that is associated with plasma cell dyscrasias.

Fingernail groove with sticky discharge

The groove has been caused by pressure from a myxoid cyst (digital mucous cyst) which overlies the nail matrix. Pressure applied to the nail matrix from any cause will result in either a line or groove in the nail plate distally. The discharge of clear, sticky, mucoid material is typical of intermittent rupture of the false cyst. The diagnosis is usually made clinically, but the presence of a pseudocyst can be confirmed by high resolution MRI scanning of the affected digit. Treatment is difficult and is frequently advocated by recurrence. Under a digital block, the proximal nail fold can be reflected back, the cyst identified, and its communication with the synovium ligated. More proximal digital myxoid cysts can be treated by repetitive puncture and expression of the contents, injection of sclerosants, or surgery.

Changes to all nails on hands and feet

There is roughness of the nail plates (trachyonychia) affecting all finger and toenails. With repeatedly negative mycology, and absent skin problems elsewhere, the likely diagnosis is twenty-nail dystrophy. This may be associated with previous, concurrent, or the ultimate development of alopecia areata or lichen planus. Evidence of these conditions should be sought in the scalp, mouth, and elsewhere on the skin. Less convincing associations are with psoriasis and eczema. The condition is difficult to treat, but may undergo spontaneous resolution. For more information, see twenty-nail dystrophy.

Unusual facial rash of 3 months

The eruption has a violaceous hue, and the area covered by his hat and shirt (below the collar line) is spared. These features together suggest a photolichenoid eruption. Biopsy will show epidermal hyperkeratosis, hypergranulosis, basal cell liquefactive degeneration, and a dense upper dermal band-like lymphocytic infiltrate. For more information see lichenoid drug eruption pathology. Photolichenoid eruptions are usually due to medication, and quinine is a well-known cause. Some HIV medications, thiazide diuretics, and docetaxel are other incriminated drugs. Stop suspect medicines (eg, quinine) and use a sunscreen with a good UVA spectrum of protection, as well as other general sun protection measures. A potent topical steroid will need to be used for a short period of time to suppress the lichenoid reaction.

58-year-old with red tight skin on upper back

This is scleroedema (U.S. scleredema), not to be confused with scleroderma. It occurs as a result of the accumulation of mucin in the dermis. It may be associated with a paraprotein, diabetes, and can occur acutely after a respiratory infection. Less robust associations include Sjogren syndrome, rheumatoid arthritis, hyperparathyroidism, and HIV infection. Testing for associated biochemical abnormalities (paraprotein, immunoglobulins, HbA1c) should be conducted. Skin biopsy will show accumulation of dermal mucin.

This patient, now in her early 60s, is concerned about the appearance of her nails. Over the years she has found that they grow much more slowly than when she was younger.

The nail plates are yellow in colour, and have excessive transverse and longitudinal curvature. These features are typical of yellow nail syndrome, and patients usually describe the need to only infrequently cut their nails as the nail growth rate is substantially slower than normal. It is most commonly associated with lymphoedema, pleural effusions, and bronchiectasis. The cause is unknown; there is limited evidence that it may improve with oral or topical vitamin E supplements, and the antifungal agents. Oral itraconazole and fluconazole are oral antifungal agents. It has been noted that they appear to speed up the rate of growth of nails, which may be of benefit in yellow nail syndrome even though it is not caused by fungal infection.

Papulosquamous rash over trunk and chest

A papulosquamous eruption with lesions on the palms and soles should always raise suspicion of secondary syphilis. This should initiate questioning regarding sexual contacts, and recent history of genital, oral, or perianal primary syphilis lesions (chancres). There may be scars at the site of a recent chancre, and mucosal lesions of secondary syphilis (snail track ulcers and condylomata lata). Other sexually transmitted disease lesions should be sought eg, warts, mollusca. The VDRL test will always be positive in secondary syphilis unless there is co-infection with HIV. Treponema pallidum PCR testing may be positive from mucosal lesions. Referral to STD services is mandatory to both contact trace and identify co-infection with other sexually transmitted diseases. The syphilis infection will be treated with intramuscular penicillinaccording to local guidelines.

This 8-year-old boy has returned from a hiking holiday with his parents in rural England. He has developed a slowly spreading red ring over his chest. He does not recall any bites. He is otherwise well.

The subtle but slowly spreading red ring is characteristic of erythema migrans, the early cutaneous manifestation of Lyme disease. Inoculation occurs after a bitefrom an infected tick. The rash often starts days after inoculation of the skin with a causative bacterium, Borrelia burgdorferi, and slowly spreads over a number of weeks. It is usually the case that the tick needs to feed from the human victim for at least 24-hours in order for infection to occur. A significant proportion of those infected have no recollection of the tick attachment. Early associated symptoms include fever, chills, muscle and joint aches, swollen lymph nodes, and erythema migrans (in about 80%). Late symptoms include arthritis, carditis and arrhythmias, neuritis, and encephalitis. Late skin manifestations include acrodermatitis chronica atrophicans and lymphocytoma cutis. Children under the age of nine should be treated with amoxicillinor azithromycinif they have non-focal symptoms. The presence of carditis or central nervous system disease would require intravenous treatment.

This 20-year-old woman has sore red spots around both eyes; her only other problem is allergic rhinitis for which she uses a steroid nasal spray.

This is periocular dermatitis; it often coexists with perioral dermatitis. It produces small red papules and occasionally pustules firstly at the lower lateral lid, then may spread around the entire periocular skin. It is often sore rather than itchy. It is quite distinct from other causes of periocular eczema, such as atopic, seborrhoeic, or contact eczema. Many cases of perioral and periocular dermatitis (periorificial dermatitis) are due to either intentional or inadvertent topical steroid exposure to the affected sites. Back spray from the nasal steroid aerosol onto the periocular skin has caused this young womans problem. Treatment involves improvement of spray technique to prevent accidental exposure or withdrawal of topical steroids. Oral tetracyclines are very effective and may be needed for a few months; repeat courses may be given should it recur. Other oral antibiotics such as macrolides and metronidazole are effective. Topical therapies such as metronidazole, clindamycin, and calcineurin antagonists have been used but are often not tolerated.

26-year-old with spots on her back

The image shows monomorphic papules over the interscapular area. There are no comedones, and there is no variety in the size and shape of lesions as one sees in acne. These features all suggest Malassezia (pityrosporum) folliculitis. The condition results from the overgrowth of pityrosporum yeasts within the hair follicles. Humidity, heat, seborrhoea, immunosuppression, and HIV contribute to the overgrowth of the yeasts. The back is the most frequently affected area; it can also occur on the chest. It is often associated with seborrhoeic dermatitis in other sites. Routine bacteriology from affected follicles is negative as the causative yeasts require very specialised culture media to grow them. They are most easily visualised on biopsy. Topical antifungals such as selenium sulfide shampoo, or azoles such as econazole lotion or ketoconazole shampoo, can be helpful both in initial treatment and recurrence prevention. Oral fluconazole or itraconazole are sometimes more convenient to use.

A 67-year-old man gives a six-week history of a progressive, itchy, and blistering eruption affecting his limbs. There has been no involvement of his mucous membranes. He has a 10-year history of Crohn disease.

Linear IgA bullous dermatosis. There are blisters arranged in a ring the so-called string of pearls sign, which is most often seen in this condition. Perilesional immunofluorescence will show a linear band of IgA at the dermoepidermal junction, in contrast to the granular deposits of IgA seen in dermatitis herpetiformis. The blisters are sub-epidermal. As opposed to dermatitis herpetiformis, linear IgA disease is not associated with gluten enteropathy. Linear IgA disease may be associated with solid cancers and lymphomas, inflammatory bowel disease, and rheumatoid disease. Several drugs have been implicated in initiating this condition. Treatment of this condition involves the use of potent topical steroids, but oral steroids combined with oral dapsone are usually required.

3-year history of scalp lesions with discharge

This is dissecting cellulitis of the scalp, also known as perifolliculitis capitis abscedens et suffodiens and Hoffman disease. It produces nodules, cysts, and discharging scalp lesions with eventual patchy scarring hair loss (alopecia). It may be associated with severe acne(including acne conglobata) and hidradenitis suppurativa, collectively called the follicular occlusion triad. More recently, pilonidal sinus diseasehas been added to this list (follicular occlusion tetrad). Therapy is difficult. It involves considering the following:

Female with slow spreading plaque on forehead

There is a well-circumscribed plaque on a sun exposed area. Centrally, there is some atrophy. There is some scaling and follicular plugging. The lesion is red. Coupled with the pathology, the features suggest discoid lupus erythematosus (DLE). The patient requires routine haematology, lupus serology, and urinalysis. If she is a smoker, this should be strongly discouraged. Treatment strategies include:

This 18-year-old girl has noted a scaly and slightly tender lesion on her chin; she has had a similar lesion on her scalp which has resulted in a patch of hair loss.

The photograph shows a well circumscribed scaly patch of erythema as well as early atrophy. Coupled with history of the patch of alopecia, discoid lupus erythematosus is the most likely diagnosis. Skin biopsy is required for diagnostic confirmation; it can be expected to show hyperkeratosis and follicular plugging. There may be epidermal atrophy, and patchy basal cell keratinocyte degeneration. PAS stainingmay show thickening of the basement membrane. In the dermis, there will be dense perivascular and periadnexal chronic lymphocytic inflammation. Topical treatments will include photo protection with sunscreens. Super potent topical steroids, which are usually avoided on the face, can be accurately applied to the lesions. Additional benefit is sometimes shown by combining the use of topical steroids with topical tacrolimus. Intralesional steroids may be useful for recalcitrant disease. Antimalarials, such as mepacrine (quinacrine) or hydroxychloroquine are indicated. If the condition is progressive despite the above, immunosuppression with either methotrexate or azathioprine may be offered as progressive disease will result in permanent scarring and hair loss.

This 46-year-old man has itchy lesions symmetrically on his elbows and knees, sacrum, scalp, and beard area. The lesions started six months ago and topical steroids have been of little help in reducing the itch. There is a family history of atopic eczema, although he has never had any atopic symptoms.

This man has dermatitis herpetiformis. This is an immunobullous disorder associated with gluten sensitivity. The vesicles and blisters that arise in this condition are small (2 to 4 mm) and because the condition is so itchy, they are often excoriated so that intact blisters are seen only infrequently. The clue to the diagnosis is often from the rash distribution. It affects symmetrically the elbows and knees, sacrum, interscapular area, scalp, and beard area. Itch is usually severe. It is slightly more common in atopic individuals. The diagnostic test is direct immunofluorescence from a perilesional skin biopsy. Granular IgA deposits are seen at the dermo-epidermal junction. It is positive in 80% of sufferers on the first biopsy, 95% with the second biopsy, and close to 100% on the third biopsy so repeat investigation may be needed if clinical suspicion persists. Coeliac serology may be positive. Gluten-sensitive enteropathy is always present but may be asymptomatic and may be unassociated with biochemical evidence of malabsorption. However, ironor folic acid deficiency may be identified. There is a known association with haemochromatosis. Treatment requires a rigorous gluten-free diet; this may take two years to be fully effective. It can reduce the incidence of small-bowel lymphoma that can complicate the enteropathy. Oral dapsone usually results in the welcome and rapid relief of itch. The dose can be reduced to the lowest that maintains symptom relief.