Parkinson Disease Case File
Eugene C. Toy, MD, Gabriel M. Aisenberg, MD
Case 39
A 50-year-old man comes into the office complaining of difficulty completing his daily duties due to increasing stiffness on the right side of his body. He states for the last 18 months, he has felt that he had to “command his right arm” to move and perform tasks. In fact, he started using his left arm more often. He denies any tremors. Otherwise, he is healthy. The patient is a former college football player and suffered multiple concussions without neurologic deficits. Both his parents have hypertension, and his older brother was recently diagnosed with Parkinson disease (PD). On examination, the patient appears comfortable sitting in the examination chair. His temperature is 99 °F, heart rate is 88 beats per minute (bpm), and blood pressure is 121/80 mm Hg. His heart and lung examinations are unremarkable. An abdominal examination reveals normal bowel sounds and no masses. On neurologic examination, the patient has decreased sense of smell to lemon and coffee beans. The strength of the four extremities is normal without atrophy or fasciculation. The patient has increased muscle tone (rigidity) throughout, and there is difficulty with repetitive movements of his right hand. While his equilibrium seems normal, he walks slightly bent forward at his waist, and his right arm does not swing. Sensation is intact. Laboratory tests, including cell count, metabolic panel, thyroid tests, rapid plasma reagin, and vitamin B12 levels are normal.
▶ What is the most likely diagnosis?
▶ What is your next diagnostic step?
▶ What is the next step in therapy?
ANSWERS TO CASE 39:
Parkinson Disease
Summary: A 50-year-old man presents with
- History of concussions
- Right-sided rigidity and difficult movements, especially repetitive movements
- Hyposmia
- Normal laboratory tests
Most likely diagnosis: Parkinson disease.
Next diagnostic step: Brain magnetic resonance imaging (MRI). Though it does not add to the diagnosis, it is important to rule out other possibilities in the differential diagnosis for this condition.
Next step in therapy: Consider initiation of therapy with amantadine. If no improvement is noted, consider carbidopa/levodopa.
ANALYSIS
Objectives
- Recognize the clinical features of PD. (EPA 1)
- Understand its pathophysiology and clinical course. (EPA 1, 12)
- Outline the differential diagnosis based on presentation. (EPA 2, 3)
- Describe the therapeutic options. (EPA 4)
Considerations
This is a 50-year-old man who has history of multiple brain concussions and complains of difficulty starting movements of the right arm. He also endorses a history of hyposmia (decreased sense of smell). On examination, there is increased rigidity of the muscle tone throughout. Parkinson disease is a clinical diagnosis and there are no lab biomarkers, or imaging findings that are diagnostic. The classic presentation is a patient aged 55 or older with slowly progressive resting tremor and bradykinesia or ridigity. This condition must be differentiated from essential tremor and multiple sclerosis. Also Wilson disease should be considered in patients below age 40. Because this patient is age 50, a careful history and physical examination should be performed to decide whether further tests should be performed to investigate for secondary causes of PD. While the symptoms and signs are consistent with PD, establishing whether this is primary or secondary is important, especially considering the different response to dopamine agonistic (DA) drugs.
APPROACH TO:
Parkinson Disease
DEFINITIONS
AKINESIA: Difficulty initiating movements.
BRADYKINESIA: Slowness of movements.
EXTRAPYRAMIDAL SYSTEM: The area of the brain including the substantia nigra, striatum (includes caudate and putamen), globus pallidus, subthalamic nucleus, and thalamus (often referred to collectively as the basal ganglia).
PARKINSON DISEASE (PD): A chronic, progressive, neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra pars compacta. It is clinically diagnosed by the presence of classic symptoms, including tremor, rigidity, bradykinesia/akinesia, and postural instability (TRAP).
POSTURAL INSTABILITY: Impairment of the central postural reflexes causing a sensation of imbalance and a tendency to fall.
PRIMARY PARKINSON DISEASE: cause of clinical findings without an identifiable cause and accounts for about 80-85% of cases.
SECONDARY PARKINSON: This is also called Parkinsonism and has an underlying etiology such as brain tumors, repeated head trauma, drugs or toxins, or other neurological disorders.
CLINICAL APPROACH
Epidemiology
The etiology of PD is currently unknown. PD is estimated to affect 6.1 million people worldwide (1 million in the United States) and is the fastest growing neurologic disorder causing disability, likely due to the increasing age of the general population. It is estimated that there are 8 to 18.6 people per 100,000 persons diagnosed each year. A family history of the disease and older age are the most commonly associated risk factors. Smoking, caffeine/coffee intake, exercise, ibuprofen, and statins have been shown to decrease overall risk. Depression is also often linked to PD, but it is unclear if depression is a risk factor or a prodromal symptom. For patients diagnosed prior to age 50, there is increasing evidence to suggest genetic causes of PD. One out of every four patients with PD reports at least one first-degree relative with the diagnosis.
Pathophysiology
Parkinson disease is caused by depletion of dopamine in the basal ganglia, leading to the development of parkinsonian symptoms. The first three manifestations of PD are tremor, bradykinesia, and rigidity. Postural instability is another salient feature that typically develops later in the disease course. The severity of the symptoms is an independent predictor of mortality in patients. The clinical diagnosis is made by having at least two of the classic symptoms of resting tremor, rigidity, bradykinesia, and postural instability with a benefit from dopaminergic therapy. Diseases that mimic PD include communicating hydrocephalus, lacunar infarcts, progressive supranuclear palsy, and diffuse Lewy body disease. However, these conditions do not respond to extended therapies of dopaminergic drugs.
Three major subtypes of PD exist: tremor dominant, akinetic/rigid dominant, and gait difficulty or postural instability. The postural instability subtype tends to be the most life altering and disabling. These patients tend to exhibit significant tremor and be wheelchair-bound with a slower progression of symptoms. Parkinson subtypes can change as the disease progresses, making the clinical usefulness of the classifications variable and limited.
Clinical Presentation
The most common presenting symptom of PD is the tremor, which typically begins unilaterally in the hand and spreads contralaterally several years later. The “pill rolling” or resting tremor of PD is 4 to 6 Hz, and is most notable when the patient is not engaged in activities, and tends to be intermittent in the early stages of disease. With purposeful movements, the tremor of PD lessens, distinguishing it from other common conditions, such as essential tremor or multiple sclerosis. As symptoms progress, the tremor may become difficult to distinguish between an action and resting tremor.
Bradykinesia or generalized slowing of movement is present at diagnosis in 80% of patients. Beginning distally, bradykinesia typically decreases manual dexterity, causing difficulty with simple activities of daily living in the upper extremities and difficulty walking in the lower extremities. Patients complain of a shuffling gait and feelings of unsteadiness. Evaluation of limb movements should include finger, heel, and toe tapping; hand gripping; and pronation/supination of the hands.
Increased resistance to passive motion, or rigidity, is due to increased tone. Approximately 90% of patients exhibit some form of rigidity throughout the disease course. Classically, cogwheel rigidity can be seen when the patient demonstrates a ratchety pattern of resistance as the limb is examined for range of motion. Additionally, patients can have “lead-pipe” rigidity with constant resistance throughout the entire range of motion.
As PD progresses, patients develop postural instability, in which the postural reflexes are impaired and lead to imbalance and falls. Clinicians should evaluate patients for postural instability by standing behind the patient and pulling back on the patient’s shoulders. This “pull” test is considered positive if the patient falls or has to take more than one step backward to maintain balance. Early falling and injuries should lead the clinician to consider different diseases than parkinsonian disease, such as supranuclear palsy or multiple-system atrophy (MSA).
In addition to the four cardinal symptoms of PD, there are numerous motor and nonmotor features of the disease. Patients often exhibit hypomimia (masked facial expressions), impaired eye movements, blurry vision, and a shuffling gait. Meyerson sign, or glabellar tap sign, is the inability to suppress eyelid blink in response to the examiner repeatedly tapping on the forehead. Nonmotor symptoms include psychiatric symptoms such as depression, hallucinations, cognitive decline, sleep disturbances, and olfactory dysfunction, which is called hyposmia. In a study of over 1000 patients with PD, 97% of patients reported nonmotor symptoms, averaging eight nonmotor symptoms. Cognitive dysfunction and dementia are independent predictors of mortality in PD.
Currently, there are no diagnostic biomarkers or imaging useful for recognizing PD. To rule out rare parkinsonian syndromes, MRI is typically obtained after PD is suspected. According to the Movement Disorder Society, the true “gold standard” for diagnosis is a postmortem examination of brain tissue, which would show discrete, intensely eosinophilic intracytoplasmic inclusion bodies surrounded by a pale halo, called Lewy bodies.
Treatment
PD has no cure. Compared to other neurodegenerative diseases, PD has more surgical and pharmacologic treatments. Nearly all the available treatments only provide symptom relief and do not appear to influence the progression of the disease. After the establishment of diagnosis, patients and medical professionals need to determine when to start pharmacologic therapy depending on the degree of symptoms and their impact on quality of life. There are four main drug classes used for the treatment of PD (Table 39–1).
Many patients develop levodopa-related complications, including motor fluctuations, after 5 to 10 years of treatment. These complications are most likely due to degenerative progression of the nigrostriatal dopamine terminals, which limits uptake of dopamine as opposed to the initiation of treatment. However, increasing evidence suggests that delaying treatment does not affect long-term outcomes for PD patients. Therefore, clinicians should initiate therapy with the lowest dose of dopaminergic medication that improves the patient’s symptoms.
Some patients with mild symptoms opt to avoid medication and its potential side effects in the early stages of disease when the symptoms are not interfering with everyday activities. If a patient with mild disease decides to pursue pharmacologic options, monotherapy with monoamine oxidase type B inhibitors (MAO-B) or amantadine is typically well tolerated and can effectively control symptoms.
When a patient’s quality of life begins to be affected by the motor symptoms of PD, treatment with DAs or levodopa should be considered. The choice of therapy is typically patient specific. Levodopa has been shown to control motor symptoms more effectively compared with DAs but can produce dyskinesia, especially in younger patients. Therefore, the risk and benefits of each therapy should be weighed when considering each patient’s symptoms and goals. PD symptoms are highly variable, and there are no signs or symptoms to gauge the future disease burden on the patient. It is estimated that 67% of individuals are disabled after 5 years post-diagnosis, increasing to 80% at 10 years following diagnosis.
Surgical options for PD include deep-brain stimulation (DBS). Since its initial approval in 1997, DBS has been considered when motor symptoms are not adequately controlled on medications. High-frequency electrical stimulation is accomplished by placing thin wires in the thalamus, subthalamus, or globus pallidus interna; an impulse generator battery is implanted under the collarbone or abdomen. DBS has shown improvement of the axial function without influencing behavioral, genitive, or speech symptoms.
CASE CORRELATION
- See also Case 36 (Transient Ischemic Attack) and Case 37 (Alzheimer disease/Dementia).
COMPREHENSION QUESTIONS
39.1 A 57-year-old man is evaluated in the clinic for an 8-month history of right-hand tremor. He has noticed that he has had difficulty signing his checks, but that the tremor is less intense when he brushes his teeth. He denies falls, urinary incontinence, or difficulty with memory. On physical examination, vital signs are normal. His voice is low in volume, and facial expressions are normal. A low-frequency right-hand tremor is noted. Repetitive movements of the right upper and lower extremities slow after 10 seconds. Finger-to-nose testing reveals a bilateral tremor. Muscle tone is increased bilaterally, and you have a difficult time moving the upper extremities passively. Gait is normal, but arm swing is decreased. A presumptive diagnosis of PD is made. What is the best next step to confirm the diagnosis?
A. Dopamine transporter scan
B. PARK1 genetic testing
C. MRI of the brain
D. No additional testing
39.2 A 59-year-old woman presents with 1 year of right-sided tremor. She reports numerous falls when standing up or turning. She reports urge incontinence and has a history of intermittent constipation. Her husband has begun sleeping on the couch because the patient has been acting out her dreams at night. On physical examination, blood pressure is 120/85 mm Hg and heart rate 66 bpm while sitting; blood pressure is 92/54 mm Hg and heart rate is 76 bpm while standing. She has scattered ecchymosis around her extremities due to numerous falls. A tremor is noted in her right hand with repetitive finger tapping, revealing bradykinetic movements. Mild dysmetria is present with ataxic gait. Pull test confirms postural instability. What is the most likely diagnosis?
A. Alcohol intoxication
B. Progressive supranuclear palsy
C. Parkinson disease
D. Multiple-system atrophy (MSA)
39.3 A 69-year-old man was diagnosed with PD 10 years ago. His symptoms were initially controlled on amantadine. After worsening motor symptoms 7 years ago, carbidopa-levodopa was added, but the patient notes worsening symptoms in the past 2 years. He has tried to increase the dose and has noticed visual hallucinations that frighten his wife. On physical examination, vital signs are within normal limits. He has masked facies and an asymmetric tremor at rest, with marked cogwheel rigidity. Reexamination 1 hour after medication administration shows improvements in his symptoms. Which of the following is the best next treatment option for this patient?
A. Deep-brain stimulation
B. Increased dose of levodopa
C. Addition of MAO-B inhibition
D. Discontinue amantadine
E. No additional interventions needed
39.4 A 45-year-old man is evaluated for depression and suicidal ideation. He reports feelings of general disinterests for the past 5 years that have acutely worsened with the loss of his job. He reports that his wife thinks he is more forgetful, and he walks with small, slow steps. The patient is a former professional football player and is upset that he lacks interests in playing sports with his kids. The patient denies medications. On physical examination, the blood pressure is 132/64 mm Hg. During neurologic examination, he is asked to perform rapid, alternating movements with his hands; and these maneuvers are abnormally slowed bilaterally. He also has a shuffling gait. The patient has a flat affect and appears to think a long time prior to answering a question. He has difficulty with delayed recall. What is the most likely diagnosis?
A. Parkinson disease
B. Lewy body dementia
C. Chronic traumatic encephalopathy
D. Alzheimer disease
ANSWERS
39.1 D. This is a 57 year old man who has a straightforward history suggestive of primary PD. There does not seem to be atypical features such as hallucinations, rapid disease progression, supranuclear gaze palsy, or urinary incontinence. Based on the classic symptoms of bradykinesia, rigidity, and resting tremor, this patient most likely has PD. Further testing is not needed in this patient’s situation (answers A, B, and C). While PD is a clinical diagnosis, a very careful history and physical exam is required to assess for other potential causes of the presenting symptoms. This can be especially difficult early in the disease course.
39.2 D. While this patient has many symptoms of classic PD (answer C), her early postural instability and history of recurrent falls are atypically early in the disease. However, she has ataxia, which is not common with PD. The combination of parkinsonian symptoms with cerebellar ataxic is most consistent with MSA or Shy-Drager syndrome. MSA has also been associated with orthostatic hypotension and dream acting (acting out their dreams), making it the likely diagnosis for this patient. Alcohol intoxication (answer A) should be diagnosed by history and would be associated with slurred speech and bilateral (not unilateral) symptoms. Progressive supranuclear palsy (answer B) is a degenerative disorder of unknown etiology associated with postural instability, falls, and ocular palsy. This patient has no eye findings; also, supranuclear palsy is not associated with acting out dreams.
39.3 A. Deep-brain stimulation is appropriate for this patient experiencing symptoms despite pharmacologic therapy. The patient has begun to experience medication-related complications but continues to have benefit until the medication wears off. DBS is likely to provide control of his motor symptoms with possible reduction in medications (not an increase, as in answers B and C), possibly improving the medication side effects. Answer D (amantidine) should be continued and not removed. Answer E (no additional intervention) is not indicated due the patient’s severe symptoms.
39.4 C. The most likely diagnosis for this patient is chronic traumatic encephalopathy related to repetitive mild head injuries. This disease is often seen in veterans and athletes with history of multiple concussions. This patient’s history of playing professional football increases his risk of developing neurologic symptoms. While this patient has features of PD (answer A), he lacks the cardinal symptoms of the disease, making it less likely the diagnosis. Both Lewy body dementia and Alzheimer disease (answers B and D) are associated with cognitive impairment and usually occur in older patients; because of the patient’s young age and history of concussions, these dementia conditions are less likely.
CLINICAL PEARLS
▶ Parkinson disease is a chronic, progressive, neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra pars compacta.
▶ The diagnosis of PD is clinical and requires no confirmatory testing.
▶ Mild disease is typically treated without medications, but MAO-B and amantadine monotherapies have been shown to decrease symptoms.
▶ For moderate-to-severe disease, DA and levodopa can improve symptoms. Potential side effects of the medication should be discussed with the patient.
▶ Deep-brain stimulation is a surgical option for patients who have had PD for more than 4 years and whose disease is not controlled on medications.
▶ All therapies for PD only impact symptoms and do not alter the disease progression.
REFERENCES
Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Mov Disord. 2015;30:80-89.
Jankovic J. Etiology and pathogenesis of Parkinson disease. Post TW, ed. UpToDate. Waltham, MA: UpToDate; 2019. https://www.uptodate.com/contents/etiology-and-pathogenesis-of-parkinson-disease. Accessed July 1, 2019.
Louis ED, Levy G, Côte LJ, et al. Clinical correlates of action tremor in Parkinson disease. Arch Neurol. 2001;58:1630-1634.
Nutt JG. Motor subtype in Parkinson’s disease: different disorders or different stages of disease? Mov Disord. 2016;31:957-961.
Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology. 2001;56(11 suppl 5):S1-S88.
Parkinson Study Group. Pramipexole versus levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA. 2000;284:1931-1938.
0 comments:
Post a Comment
Note: Only a member of this blog may post a comment.