Patient I


The following is adapted from a case presented in the New England Journal of Medicine.
New England Journal of Medicine (2010) "Case 22-2010-An 87-Year-Old Woman with Dementia and a Seizure" 363: 373-381

An 87-year old woman with a history of dementia was admitted to this hospital because of a seizure.

The patient had been in her usual state of health until 2 days before admission, when she appeared to be fatigued, sleeping later each morning than usual. One hour before admission, her husband heard her fall, and he found her on the floor. She was lying on her left side with her right arm shaking; there was no apparent head trauma. She was confused but able to speak.

A diagnosis of mild cognitive impairment had been made 5 years earlier when, on initial evaluation by a neurologist at this hospital, the patient made 6 errors on the Information-Memory-Concentration subscale of the Blessed Dementia Scale. During the next 4 years her memory gradually became more impaired. A diagnosis of possible Alzheimer’s disease was made 1 year after her initial evaluation.

This patient has progressing dementia based on her declining performance on cognitive tests. Why do you suppose her diagnosis is possible Alzheimer's disease?

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Is seizure activity a typical feature of Alzheimer's disease?

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On examination, the patient was unresponsive to sternal rub...and was unable to swallow secretions. The head was turned to the left, the face was symmetric, and the eyes were closed; when the eyes were open, the pupils were the size of pinpoints. She did not speak or move purposefully. The plantar responses were extensor. The trachea was intubated for airway protection and mechanical ventilation was begun.

"Sternal rub" is a test that is used to see if the patient is responsive. The sternum is rubbed vigorously to create pain. The seizure, the lack of response to sternal rub, and the other signs of motor dysfunction suggest that this patient is having an acute neurological crisis.

What do you think is meant by "plantar responses"?

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Is an "extensor response" normal?

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The patient had had a stroke in the past, with language abnormalities and a decrease in the visual field, which resolved. Sixteen months before admission, an episode of expressive aphasia and weakness occurred, which resolved spontaneously. At that time, magnetic resonance imaging (MRI) and computed tomography (CT) with angiography of the head and neck revealed nonspecific white matter abnormalities that were consistent with small-vessel ischemic changes.

What part of the brain would be affected to cause expressive aphasia?

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What is meant by the term ischemic changes?

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An MRI scan of the brain obtained 16 months before admission showed mild scattered periventricular white matter intensities…and a few chronic microhemorrhages. A scan obtained 12 days before admission showed more extensive white-matter changes. The MRI scan obtained on admission showed progression of the white-matter abnormalities, with development of white-matter edema…The MRI properties of these abnormal regions suggest that they represent areas of extracellular fluid accumulation or vasogenic edema.

The MRI findings, along with this patient’s history of stroke, seem to indicate that vascular problems may be contributing to her neurological disease. In particular, the MRI scan obtained when she was admitted to the hospital following her seizure shows vasogenic edema. Vasogenic edema is cerebral edema that occurs due to a breakdown in endothelial tight junctions that make up the blood-brain barrier. Cerebral edema can cause various symptoms such as nausea, vomiting, light-headedness, or in severe cases, seizures.

The patient's doctor comments:

My diagnosis of possible Alzheimer's disease in this patient was driven by her evident cerebrovascular disease.  She had had a stroke in the remote past...there were also clinically silent lesions:  hyperintensities around the cerebral ventricles, and several cortical-subcortical microbleeds detected by [the MRI technique that is] sensitive to iron.

With the high sensitivity of MRI for detecting small, clinically asymptomatic lesions, the question arises of how to interpret such lesions in patients with dementia. Do the lesions suggest the presence of other diseases? The answer is often yes. Cerebral microbleeds, in particular, occur in approximately 20% of patients with Alzheimer’s disease. The spatial distribution of cerebral microbleeds in patients with Alzheimer's disease closely resembles the spatial distribution of hemorrhages associated with cerebral amyloid angiopathy or CAA.  Since CAA frequently overlaps with Alzheimer’s disease, cortical-subcortical cerebral microbleeds seen in patients with dementia appear to be strongly suggestive of coexisting CAA.

Cerebral amyloid angiopathy (CAA) is a disorder in which there are amyloid protein deposits specifically associated with blood vessels. "Amyloid" is a term that refers to insoluble protein aggregates with a characteristic protein structure.  Different proteins may form amyloid in CAA, but the most common form of CAA results from deposition of amyloid formed from Aβ peptides. Thus the pathogenesis of CAA is related to Alzheimer's disease since both disorders result from an accumulation of Aβ.

CAA typically affects small blood vessels located in the cerebral cortex. Amyloid deposition destroys normal tissue in the walls of the blood vessels, causing them to weaken and increasing the chance for hemorrhages.

The doctor's comments continue:

The patient’s acute presentation with a seizure and rather dramatic MRI changes starkly altered my view of the importance of her vascular lesions. Seizures occur with increased incidence in dementia, but still affect fewer than 10% of patients. …The MRI properties of these abnormal regions—in particular, their high diffusivity—suggest that they represent areas of extracellular fluid accumulation or vasogenic edema.

The neuroimaging constellation of multiple strictly cortical-subcortical hemorrhagic lesions and extensive vasogenic edema is strongly suggestive of the inflammatory subtype of CAA.

The patient was admitted to the neurologic intensive care unit. Fosphenytoin was administered, and no further seizure activity occurred. While in the ICU, the patients was treated with a 5-day course of methylprednisolone, followed by a slow taper of oral prednisone. The patient became more alert, oriented, conversant and interactive. Repeat MRI scans on the eighth hospital day showed no evidence of acute infarct or new hemorrhage. She was discharged on the 17th day to a rehabilitation facility and then to home.

Methylprednisolone and prednisone belong to what class of drug?

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Inflammatory CAA is a subtype of CAA in which there is presumably an autoimmune response to β-amyloid deposits in blood vessels. Inflammatory CAA differs in that the patient presents with headaches or seizures and moderately rapid cognitive decline, as opposed to other forms of CAA in which there are typically small hemorrhagic strokes that may have mild or transient neurological symptoms.  The key finding was the MRI imaging indicating vasogenic edema, which occurs because inflammation associated with blood vessels leads to endothelial dysfunction, breakdown in tight junctions, and leakage of fluid into the extracellular space.

Because her doctor suspected inflammatory CAA, the patient was treated with anti-inflammatory medication (glucocorticoids).  This resulted in a normalization of her neurological symptoms, and a return to her pre-seizure level of cognitive function.

Unfortunately, shortly after her return home, the patient suffered a heart attack, was readmitted to the hospital, and eventually died. After her death, an autopsy examination of her brain showed amyloid deposits associated with cerebral blood vessels, confirming the diagnosis of cerebral amyloid angiography.