Case Vignettes in Neurology

PATIENT CASE STUDIES

Case 27 3/9/99 Alzheimer’s disease
Case discussion Mr Y is a 76 year old retired salesman who comes to your office accompanied by his wife. She is concerned about his declining mental and physical functioning. She notes that 2 years ago he had coronary artery bypass surgery, and ever since that time he has not been himself. He was previously quite active and socially engaged, but now spends considerable time sitting in his chair and staring out the window or watching TV. He has lost interest in virtually everything. He is able to dress himself, but does so very slowly and requires assistance. He eats well but sloppily, and she is embarrased to go out with him. He is able to go out for walks, but walks very slowly and has fallen on a number of occasions. In addition to these physical concerns, Mrs. Y reports that her husband’s mental functioning has been deteriorating. He frequently forgets to do things she asks him to, and needs frequent reminders to bathe and groom himself appropriately. He can no longer pay the bills or prepare simple meals, and he is unable to fix things around the house when they break. He forgets things that he is told. One one occasion recently, he awoke in the middle of the night and urinated in the wastebasket. When asked about his problem, Mr. Y says "yes, I guess I have been slowing down a bit", but cannot provide any further information. Mr. Y has a long history of hypertension and hypercholesterolemia. He is currently on verapamil, lipitor, and one aspirin a day. He has never had a stroke that he or she knows of, and has no surgical history other than his CABG 2 years ago. He smoked one pack per day of cigarettes until 2 years ago, and used to have a glass of wine or beer occasionally but no longer drinks at all. His mother died at age 67 of "some sort of cancer", and his father died at age 72 of a "heart attack". On examination, Mr. Y had a blood pressure of 160/90, a pulse of 82, and appearred disheveled and slow. His general physical examination revealed a left carotid bruit and a systolic ejection murmur. On neurological examination, he responded to questions very slowly. He did not know where he was, saying that he was "where his wife brought me". He gave the date as July, 1968 and could not name the President. He gave the prior president as Nixon. When asked to name several common objects (a watch and a pencil) he took a very long time to answer but gave the correct responses. He was able to recall 1 out of 4 words after 5 minutes. The cranial nerves revealed an unexpressive face with diminished eyeblinks. His extraocular motions were intact and his pupils and fundi were normal. The face was symmetric, the tongue and uvula midline, and hearing was intact. On motor exam, the tone was diffusely increased with a mild degree of cogwheeling. There was no obvious weakness. Deep tendon reflexes were increased at the right biceps, triceps, brachioradialis, and knee, 3+ as opposed to 2+ on the left. There was a clear right Babinski sign. There was no clear sensory findings, but it was difficult to get him to respond to questions promptly. The gait was shuffling, with a tendency to circumduct the right leg.
Summarize the Case in 1-2 sentences. Pt is a 76 yo male with progressive history of loss of cognitive function over 2 yrs. On examination, he showed poor recall and naming of objects and thought the current president was Nixon. Motor function showed incr tone, incr DTRs, sensory was normal. PMH is positive for HTN, hi chol and CABG 2 yrs ago. note patient has carotid bruit, is disoriented, with poor memory, long latency in answering questions, increased tone with cogwheeling, masked facies, hyperreflexia and right extensor plantar refledx. Discuss lesion localization on the basis of the physical examination. Motor: incr tone, incr DTRs, R Babinski -- UMN cogwheeling -- basal ganglia shuffling gait -- cortex, BG, SC, cerebellum, muscle. Sensory: nl Cognitive: forgets things -- cortex, hippocampus Can't name president, says Nixon president-- hippocampus, other cortex: Recall 1/4 objects at 5 min -- hippocampus, other campus Naming of objects very slow -- cortex, Wernickes area PMH: HTN & Hi Chol. CABG 2 yrs ago. Smoked 1 pk/d till 2 yrs ago. Based on the above information, the patient's symptoms seem to involve diffuse areas of the cortex. In particular the association cortex (temporal, parietel, frontal) and other parts of the brain such as the hippocampus. ok; several of the findings also suggest subcortical involvement: parkinsonism, long latency, focal findings Discuss underlying pathogenesis on the basis of clinical course. This patients disorder is slowly progressive (over 2 yrs) which suggests a degenerative (metabolic) process. ok Indicate one likely clinical diagnosis. List (or classify) alternative diagnoses. Alzheimers Disease comment: AD may cause many of the findings, though not all (parkinsonism, focal findings) Alternative Diagnoses: Multi-infarct dementia Binswagers Disease Brain Neoplasm an alternative diagnosis is Lewy body dementia; Vascular dementia is also important here Indicate 2 ancillary tests that would assist in confirming or refuting the clinical diagnosis. Indicate the test results that would confirm the clinical diagnosis. MRI: a scan might show atrophy of cortex. It can rule of neoplasms or infarcts. Blood test: Can rule out a hormone or electrolyte imbalance causing the dementia. rather than rule out a hormonal or electrolyte imbalance, testing for these things and finding an abnormality is going to perhaps refute your primary diagnosis i.e. Alzheimer's disease Indicate complications of the disease and ancillary tests that would help evaluate them. Gradual worsening of cognitive function: pt's cognitive function can be tested with MMSE Depression: Can be watched for by family members and/or careful follow up. good; also additional neurological dysfunction secondary to the underlying disease eg. apraxia, aphasias, incontinence etc,; falls and injury; behavioural problems; difficulty with self care Discuss how the underlying pathophysiology is relevant in the management of this patient. Alzheimer's disease is a progessive disorder for which there is no definitive treatment and no cure. It's cause is multifactorial with no specific gene locus or cortical area alone involved. The most important risk factors are old age and a positive family history. The areas most severely affected are the hippocampus, temporal cortex, and nucleus basalis. In these areas the important microscopic findings are neuritic "senile" plaques and neurofibrillary tangles (NFTs). The neuritic plaques contain a central core that includes A amyloid, proteoglycans, Apo E, 1 antichymotrypsin, and other proteins. A amyloid is a protein that is derived proteolytically from a larger protein (amyloid precursor protein, APP). Accumulation of plaques in the extracellular space may disrupt intra-cortical connections causing impairment of ability to commit new things to memory. The NFTs are twisted neurofilaments in neuronal cytoplasm that represent abnormally phosphorylated tau () protein. Accumulation of NFTs in the neuron may disrupt function and eventually kill the neuron. 10% of AD has a genetic component and there is a strong association with Downs syndrome (chromosome 21) and also the Apo E gene on chromosome 19. There is also evidence that cholinergic neurons from the frontal cortex to other area may be destroyed in the disease. Frontal cortex: connection to temporal, parietal, occipital so it has access to present sonsory feeling as well as past experience. Also recipricol connection with Amygdaloid body in temporal lobe & MD thalamic nucleas forming a system that determines affextive reactions to current situations based on prior experience. Premotor area: apraxia (impairment of learned movements in absence of paralysis) Cholinergic neurons in basal forebrain: connections to al parts of the cortex including the hippocampus. Inability to form new memories may be due to loss of these neurons. But also due to degenerative changes in the entorhinal cortex contribute. Temporal lobe: lesions here cause docility & lack of emottional responses. Posterior parts causes loss of ability to recognize things that are seen good discussion: the pathophysiology issues I would be looking for with a patient of Alzheimer's disease are: 1) role of APP and loss of synapses 2) role for neurofibrillary tangles and loss of neuronal function in areas where they tend to be selectively found 3) role for degeneration of specific pathways especially though not only the cholinergic forebrain system. I wonder should I have included the motor signs in Q1 - they are not the most pertinent findings in Alzheimers (except late stage)? you are right, the patient likely does not have Alzheimer's disease. consequently including the motor signs is important; (just because a case is associated with a particular session or lecture does not necessarily mean it represents that disease) Another Version:
Summarize the Case in 1-2 sentences. This is a 76 year-old male 2 years post-CABG with history of hypertension, hypercholesterolemia, and smoking brought in by his wife who gives history of progressive decline since the operation, with anhedonia, bradykinesia, deteriorating memory, and decreasing ability to perform ADLs. On exam he has a left carotid bruit, decreased memory and orientation, mild cogwheeling, right hyperreflexia and right extensor response, and shuffling gait with circumduction of right leg. good, on the long side Discuss lesion localization on the basis of the physical examination. memory and dementia: hippocampus, limbic system, cortex bradykinesia, shuffling gait: basal ganglia left carotid bruit, hypertension, hypercholesterolemia, smoking: vasculature right UMN signs: left corticospinal tract, cortex, or white matter good Discuss underlying pathogenesis on the basis of clinical course. Chronic, progressive course over 2 years indicates a degenerative pathogenesis. good; note course is not very clear from hx patient and wife give you. Indicate one likely clinical diagnosis. List (or classify) alternative diagnoses. Binswanger’s disease Differential diagnosis: vascular (multi-infarct) dementia, lacunar state, stroke Degenerative dementia: Alzheimer’s, Pick’s disease, Lewy Body Dementia in Parkinson’s, normal-pressure hydrocephalus * Trauma: chronic subdural hematoma * Metabolic: hypothyroidism * Psychiatric: depression comment: good 5. Ancillary tests good Indicate 2 ancillary tests that would assist in confirming or refuting the clinical diagnosis. Indicate the test results that would confirm the clinical diagnosis. * MRI: areas of white matter lesions * trial of L-dopa: to differentiate from Parkinsonism good Indicate complications of the disease and ancillary tests that would help evaluate them. * stroke: blood pressure should be monitored, should be tested for diabetes, anticoagulation * loss of autonomy due to disability and declining mental function: should be followed closely, mental function should be assessed with Folstein Mini-mental state exam, or Blessed Dementia Scale * medical complications: dehydration, anorexia, pulmonary and urinary infections--requires follow-up care and supportive treatment * caregiver burden on wife: evaluate support network, give options for caring for husband if mental state declines further good Discuss how the underlying pathophysiology is relevant in the management of this patient. Binswanger’s disease is a chronic, diffuse disease of white matter with loss of white matter myelination, lacunar infarcts in basal ganglia, thalamus, pons, and white matter, and hydrocephalus. The pathophysiology is thought to include abnormalities in small penetrating arteries and arterioles caused by chronic hypertension (microangiopathy), leading to chronic ischemia of white matter combined with repeated, small white matter infarcts (leukoaraiosis). Another important component of the pathophysiology of this disease are thought to be high fibrinogen levels in serum, leading to increased viscosity of blood, which alters flow in cerebral microvasculature. Treatment should thus have several aims: blood pressure should be reduced, his hyperlipidemia should be addressed, and the patient should be tested for diabetes to prevent further damage to cerebral vessels. Anticoagulation should be considered to prevent stroke. His carotid bruit should be evaluated with ultrasound and possibly treated with endarterectomy if the degree of occlusion contributes to cerebral ischemia. Finally, phlebotomy to reduce hematocrit and thus blood viscosity and using plasmapheresis to reduce fibrinogen levels are being studied for their efficacy in reducing the progression and complications of Binswanger’s disease. (Source: Caplan, LR “Binswanger’s disease--revisited”, Neurology 1995; 45: 626-633) good

Case 27 3/9/99 Alzheimer’s disease

Case discussion

Mr Y is a 76 year old retired salesman who comes to your office accompanied by his wife. She is concerned about his declining mental and physical functioning. She notes that 2 years ago he had coronary artery bypass surgery, and ever since that time he has not been himself. He was previously quite active and socially engaged, but now spends considerable time sitting in his chair and staring out the window or watching TV. He has lost interest in virtually everything. He is able to dress himself, but does so very slowly and requires assistance. He eats well but sloppily, and she is embarrased to go out with him. He is able to go out for walks, but walks very slowly and has fallen on a number of occasions.

In addition to these physical concerns, Mrs. Y reports that her husband’s mental functioning has been deteriorating. He frequently forgets to do things she asks him to, and needs frequent reminders to bathe and groom himself appropriately. He can no longer pay the bills or prepare simple meals, and he is unable to fix things around the house when they break. He forgets things that he is told. One one occasion recently, he awoke in the middle of the night and urinated in the wastebasket.

When asked about his problem, Mr. Y says "yes, I guess I have been slowing down a bit", but cannot provide any further information.

Mr. Y has a long history of hypertension and hypercholesterolemia. He is currently on verapamil, lipitor, and one aspirin a day. He has never had a stroke that he or she knows of, and has no surgical history other than his CABG 2 years ago. He smoked one pack per day of cigarettes until 2 years ago, and used to have a glass of wine or beer occasionally but no longer drinks at all. His mother died at age 67 of "some sort of cancer", and his father died at age 72 of a "heart attack".

On examination, Mr. Y had a blood pressure of 160/90, a pulse of 82, and appearred disheveled and slow. His general physical examination revealed a left carotid bruit and a systolic ejection murmur. On neurological examination, he responded to questions very slowly. He did not know where he was, saying that he was "where his wife brought me". He gave the date as July, 1968 and could not name the President. He gave the prior president as Nixon. When asked to name several common objects (a watch and a pencil) he took a very long time to answer but gave the correct responses. He was able to recall 1 out of 4 words after 5 minutes.

The cranial nerves revealed an unexpressive face with diminished eyeblinks. His extraocular motions were intact and his pupils and fundi were normal. The face was symmetric, the tongue and uvula midline, and hearing was intact.

On motor exam, the tone was diffusely increased with a mild degree of cogwheeling. There was no obvious weakness. Deep tendon reflexes were increased at the right biceps, triceps, brachioradialis, and knee, 3+ as opposed to 2+ on the left. There was a clear right Babinski sign. There was no clear sensory findings, but it was difficult to get him to respond to questions promptly. The gait was shuffling, with a tendency to circumduct the right leg.

Summarize the Case in 1-2 sentences.

Pt is a 76 yo male with progressive history of loss of cognitive function over 2 yrs. On examination, he showed poor recall and naming of objects and thought the current president was Nixon. Motor function showed incr tone, incr DTRs, sensory was normal. PMH is positive for HTN, hi chol and CABG 2 yrs ago.

note patient has carotid bruit, is disoriented, with poor memory, long latency in answering questions, increased tone with cogwheeling, masked facies, hyperreflexia and right extensor plantar refledx.

Discuss lesion localization on the basis of the physical examination.

Motor:
incr tone, incr DTRs, R Babinski -- UMN cogwheeling -- basal ganglia shuffling gait -- cortex, BG, SC, cerebellum, muscle.

Sensory:
nl

Cognitive:
forgets things -- cortex, hippocampus Can't name president, says Nixon president-- hippocampus, other

cortex:
Recall 1/4 objects at 5 min -- hippocampus, other campus Naming of objects very slow -- cortex, Wernickes area

PMH: HTN & Hi Chol. CABG 2 yrs ago. Smoked 1 pk/d till 2 yrs ago.

Based on the above information, the patient's symptoms seem to involve diffuse areas of the cortex. In particular the association cortex (temporal, parietel, frontal) and other parts of the brain such as the hippocampus.

ok; several of the findings also suggest subcortical involvement: parkinsonism, long latency, focal findings

Discuss underlying pathogenesis on the basis of clinical course.

This patients disorder is slowly progressive (over 2 yrs) which suggests a degenerative (metabolic) process.

Indicate one likely clinical diagnosis. List (or classify) alternative diagnoses.

Alzheimers Disease comment: AD may cause many of the findings, though not all (parkinsonism, focal findings)

Alternative Diagnoses:
Multi-infarct dementia
Binswagers Disease
Brain Neoplasm

an alternative diagnosis is Lewy body dementia; Vascular dementia is also important here

Indicate 2 ancillary tests that would assist in confirming or refuting the clinical diagnosis. Indicate the test results that would confirm the clinical diagnosis.

MRI: a scan might show atrophy of cortex. It can rule of neoplasms or infarcts.

Blood test: Can rule out a hormone or electrolyte imbalance causing the dementia.

rather than rule out a hormonal or electrolyte imbalance, testing for these things and finding an abnormality is going to perhaps refute your primary diagnosis i.e. Alzheimer's disease

Indicate complications of the disease and ancillary tests that would help evaluate them.

Gradual worsening of cognitive function: pt's cognitive function can be tested with MMSE Depression: Can be watched for by family members and/or careful follow up.

good; also additional neurological dysfunction secondary to the underlying disease eg. apraxia, aphasias, incontinence etc,; falls and injury; behavioural problems; difficulty with self care

Discuss how the underlying pathophysiology is relevant in the management of this patient.

Alzheimer's disease is a progessive disorder for which there is no definitive treatment and no cure. It's cause is multifactorial with no specific gene locus or cortical area alone involved. The most important risk factors are old age and a positive family history.

The areas most severely affected are the hippocampus, temporal cortex, and nucleus basalis. In these areas the important microscopic findings are neuritic "senile" plaques and neurofibrillary tangles (NFTs). The neuritic plaques contain a central core that includes A amyloid, proteoglycans, Apo E, 1 antichymotrypsin, and other proteins. A amyloid is a protein that is derived proteolytically from a larger protein (amyloid precursor protein, APP). Accumulation of plaques in the extracellular space may disrupt intra-cortical connections causing impairment of ability to commit new things to memory.

The NFTs are twisted neurofilaments in neuronal cytoplasm that represent abnormally phosphorylated tau () protein. Accumulation of NFTs in the neuron may disrupt function and eventually kill the neuron. 10% of AD has a genetic component and there is a strong association with Downs syndrome (chromosome 21) and also the Apo E gene on chromosome 19. There is also evidence that cholinergic neurons from the frontal cortex to other area may be destroyed in the disease.

Frontal cortex: connection to temporal, parietal, occipital so it has access to present sonsory feeling as well as past experience. Also recipricol connection with Amygdaloid body in temporal lobe & MD thalamic nucleas forming a system that determines affextive reactions to current situations based on prior experience.

Premotor area: apraxia (impairment of learned movements in absence of paralysis)

Cholinergic neurons in basal forebrain: connections to al parts of the cortex including the hippocampus. Inability to form new memories may be due to loss of these neurons. But also due to degenerative changes in the entorhinal cortex contribute.

Temporal lobe: lesions here cause docility & lack of emottional responses. Posterior parts causes loss of ability to recognize things that are seen

good discussion: the pathophysiology issues I would be looking for with a patient of Alzheimer's disease are:
1) role of APP and loss of synapses
2) role for neurofibrillary tangles and loss of neuronal function in areas where they tend to be selectively found
3) role for degeneration of specific pathways especially though not only the cholinergic forebrain system.

I wonder should I have included the motor signs in Q1 - they are not the most pertinent findings in Alzheimers (except late stage)?

you are right, the patient likely does not have Alzheimer's disease. consequently including the motor signs is important; (just because a case is associated with a particular session or lecture does not necessarily mean it represents that disease)

Another Version:

Summarize the Case in 1-2 sentences.

This is a 76 year-old male 2 years post-CABG with history of hypertension, hypercholesterolemia, and smoking brought in by his wife who gives history of progressive decline since the operation, with anhedonia, bradykinesia, deteriorating memory, and decreasing ability to perform ADLs. On exam he has a left carotid bruit, decreased memory and orientation, mild cogwheeling, right hyperreflexia and right extensor response, and shuffling gait with circumduction of right leg.

good, on the long side

Discuss lesion localization on the basis of the physical examination.

memory and dementia: hippocampus, limbic system, cortex bradykinesia, shuffling gait: basal ganglia left carotid bruit, hypertension, hypercholesterolemia, smoking: vasculature right UMN signs: left corticospinal tract, cortex, or white matter

good

Discuss underlying pathogenesis on the basis of clinical course.

Chronic, progressive course over 2 years indicates a degenerative pathogenesis.

good; note course is not very clear from hx patient and wife give you.

Indicate one likely clinical diagnosis. List (or classify) alternative diagnoses.

Binswanger’s disease

Differential diagnosis:
*vascular (multi-infarct) dementia, lacunar state, stroke
* Degenerative dementia: Alzheimer’s, Pick’s disease, Lewy Body Dementia in Parkinson’s, normal-pressure hydrocephalus
* Trauma: chronic subdural hematoma
* Metabolic: hypothyroidism
* Psychiatric: depression
comment: good 5. Ancillary tests

good

Indicate 2 ancillary tests that would assist in confirming or refuting the clinical diagnosis. Indicate the test results that would confirm the clinical diagnosis.

* MRI: areas of white matter lesions
* trial of L-dopa: to differentiate from Parkinsonism

good

Indicate complications of the disease and ancillary tests that would help evaluate them.

* stroke: blood pressure should be monitored, should be tested for diabetes, anticoagulation
* loss of autonomy due to disability and declining mental function: should be followed closely, mental function should be assessed with Folstein Mini-mental state exam, or Blessed Dementia Scale
* medical complications: dehydration, anorexia, pulmonary and urinary infections--requires follow-up care and supportive treatment
* caregiver burden on wife: evaluate support network, give options for caring for husband if mental state declines further

good

Discuss how the underlying pathophysiology is relevant in the management of this patient.

Binswanger’s disease is a chronic, diffuse disease of white matter with loss of white matter myelination, lacunar infarcts in basal ganglia, thalamus, pons, and white matter, and hydrocephalus. The pathophysiology is thought to include abnormalities in small penetrating arteries and arterioles caused by chronic hypertension (microangiopathy), leading to chronic ischemia of white matter combined with repeated, small white matter infarcts (leukoaraiosis). Another important component of the pathophysiology of this disease are thought to be high fibrinogen levels in serum, leading to increased viscosity of blood, which alters flow in cerebral microvasculature. Treatment should thus have several aims: blood pressure should be reduced, his hyperlipidemia should be addressed, and the patient should be tested for diabetes to prevent further damage to cerebral vessels. Anticoagulation should be considered to prevent stroke. His carotid bruit should be evaluated with ultrasound and possibly treated with endarterectomy if the degree of occlusion contributes to cerebral ischemia. Finally, phlebotomy to reduce hematocrit and thus blood viscosity and using plasmapheresis to reduce fibrinogen levels are being studied for their efficacy in reducing the progression and complications of Binswanger’s disease. (Source: Caplan, LR “Binswanger’s disease--revisited”, Neurology 1995; 45: 626-633)

good