33 Parkinson Disease

Clinical Vignette

This 54-year-old lady, a very dedicated high school art teacher, jammed her finger while playing basketball. Although the discomfort cleared rapidly, she continued to “favor” that hand. Her husband soon noted that her arm swing was absent on that side, telling her she carried the arm flexed “like Napoleon.” Soon she lost the normal range of motion of that limb; eventually this arm became stiff, and she had increasingly limited motion at the shoulder. This led to her seeking chiropractic help; here she received manipulation, acupuncture, and heat. About 2 years after onset, she began to drag her right foot while walking. Subsequently, her art work became more limited, taking increasingly more time to do simple things such as coloring a boat. Her handwriting became more difficult as her hand began to shake and the figures increasingly small the longer she tried to write.

Neurologic examination demonstrated moderate masking of her face, a positive Myerson’s sign, a mild 6-Hz rest tremor of her right hand, cogwheel rigidity of that wrist and elbow, diminished right arm swing, and a mild tendency to petit-pas gait. Extraocular muscle function was full, with no limitation of vertical gaze. Although a diagnosis of Parkinson disease (PD) was made here, initially she did not agree to take medication. Her tremor became much more pronounced at rest, particularly noticeable to her students. Activities of daily living were increasingly limited, such as getting dressed, going up and down stairs, and getting out of chairs. She had no problems with her left extremities.

Head computed tomographic (CT) scan was normal. No other investigations were indicated, as the diagnosis of PD is primarily a clinical one. Because of her moderately significant functional impairment, levodopa/carbidopa was initiated. Within 4 weeks, she demonstrated marked improvement. She was able to move faster, and her fine motor activities and tremor were significantly improved. This allowed her to return to a more vigorous approach to her celebrated teaching style. This excellent response made it most likely that idiopathic PD was the diagnosis.

In 1817, James Parkinson made the seminal observations on this disorder defining a specific neurodegenerative illness characterized by bradykinesia, resting tremor, cogwheel rigidity, and postural reflex impairment. Parkinson disease (PD) has a relatively stereotyped clinical presentation that now bears the name of this early 19th-century physician. PD is one of the most common neurologic disorders worldwide. It affects at least 1,500,000 persons within the United States. Its incidence typically peaks in the sixth decade; however, one can see classic clinical cases with onset as early as the fourth decade. On occasion, medication-induced Parkinson disease may also occur in early middle-aged individuals. In contrast, PD sometimes presents well into the late eighth or even the ninth decade. Usually the patient’s clinical status progresses from a relatively modest limitation at diagnosis to an ever-increasing disability over 10 to 20 years in many but not all patients. The primary neuropathologic features are loss of pigmented dopaminergic neurons mainly in the substantia nigra (SN) and the presence of Lewy bodies—eosinophilic, cytoplasmic inclusions found within the pigmented neurons (Fig. 33-1). These neurons’ primary projection is to the striatum, for example, the putamen and caudate. Dopamine is released primarily from these striatal cells. From here dopamine neurotransmission sequentially is directed through the globus pallidus, the subthalamic nucleus, to the thalamus per se, and then to the primary motor cortex (Figs. 33-2 and 33-3).

Figure 33-1 Neuropathology of Parkinson Disease.

Figure 33-2 Parkinson Disease—Anatomy with Biochemical Pathways.

Figure 33-3 Horizontal Brain Sections of Basal Ganglia.

Etiology

Despite intensive research, the precise etiology of PD remains elusive. One conceptualization is that an unknown environmental toxin acts on genetically susceptible individuals to cause PD. The principal link between PD and an environmental toxin is the chemical MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This chemical was initially used by drug abusers in hopes of mimicking in the laboratory a synthetic narcotic-like substance. When ingested by humans, this narcotic model serendipitously led to a clinical entity that directly mimicked PD. As MPTP interferes with the function of nerve cell mitochondria, investigators next conjectured that chemicals impairing mitochondrial DNA may be one major pathophysiologic mechanism underlying human PD. It is here that evidence exists for a disturbance in oxidative phosphorylation, particularly reduced activity of complex I of the mitochondrial electron transport chain. Additionally, there are increased levels of free iron that may enhance toxic free radical formation.

Fifteen percent of Parkinson patients have a family history of PD; a small percentage of these individuals have at least three affected generations. It is unknown whether the clinical picture results from a defective gene per se, a shared environmental insult, or both. Currently there are several causative genes identified that are specific to young-onset PD. Although these well-identified PD genes are pathogenic in only a very small minority of individuals, their biochemical signatures are providing extraordinary insight into the molecular pathology of this disease. The currently identified genes are listed in Table 33-1.

Table 33-1 Genetic Causes of Parkinson Disease

Genes for Parkinson Disease

Alpha-Synuclein

Alpha-synuclein (AS) is a ubiquitous neuronal protein of unknown function that may have a role in synaptic vesicle transport or recycling. Overexpression of AS in animal models leads to dose-dependent neurodegeneration, with dopaminergic cells in the substantia nigra being particularly susceptible. PARK 4 was identified as being a triplication of the normal AS gene, resulting in elevated protein levels and development of early-onset PD. In addition, AS promoter variants have been associated with increased risk for PD. Alpha-synuclein mutants are implicated for PD in several European families.

The discovery that mutant AS could cause PD quickly led to the discovery that AS also served as the principal component of Lewy bodies. These are proteinaceous cytoplasmic inclusions specifically found in the brains of PD patients; however, even today, the exact role of Lewy bodies is still unknown (see Fig. 33-1). The confirmation that triplication of the AS gene and the subsequent elevated protein levels (in the CSF) could cause PD has greatly strengthened the hypothesis that accumulation of protein is a fundamental event in the pathogenesis of PD.

Parkin

Parkin is an ubiquitin ligase, whose job is to add ubiquitins to proteins destined for degradation by the proteasome. Mutation of parkin impairs its ligation function, leading to protein accumulation within the cell. Homozygous mutation of parkin leads to early-onset PD, also called autosomal recessive juvenile PD (ARJP). Although classified as a recessive disorder, there is some evidence that haploinsufficiency may also occur, increasing susceptibility to disease in older patients. Parkin mutation is the single most common genetic cause of PD. In one European study, this was identified in 40% of individuals with PD onset before age 40 years.

Other Proteins

UCHL1 is another member of the ubiquitin proteasome system (UPS). Ubiquitin carboxyterminal hydrolase L1 is involved in the metabolism of ubiquitins. PINK1 is a recently identified mitochondrial protein kinase whose mutation may increase susceptibility to oxidative stress and apoptosis. DJ-1 is a protein of unknown function.

These various genetic findings suggest that a critical step in the pathogenesis of PD is dysfunction of the UPS. Supporting this conclusion is evidence that specific inhibitors of the UPS cause the neuropathologic and motor abnormalities of parkinsonism in animal models. The precise pathophysiologic dysfunction that leads to dopaminergic cell death is still not certain. Possible mechanisms include a toxic gain of function of accumulated protein, mitochondrial impairment, and increased oxidative stress. These three mechanisms may also, in the face of other insults, act independently or interdependently to provoke dopaminergic cell death.

Pathology/Pathophysiology

The pathologic sites responsible for the parkinsonian disorders reside in a group of brain gray matter structures known as the extrapyramidal system or basal ganglia (Fig. 33-2). These include striatum (caudate nucleus and putamen), globus pallidus interna and externa, subthalamic nucleus, substantia nigra pars reticulate and pars compacta, and the ventral nuclei of the thalamus.

Degeneration of the substantia nigra (SN) pars compacta is the pathologic hallmark of PD (Figs. 33-2 and 33-4). Neurons within the SN per se synthesize the neurotransmitter dopamine. These cells contain a dark pigment called neuromelanin. Parkinson symptoms develop when approximately 60% of these cells die. Concomitantly, direct inspection of the SN in PD demonstrates an abnormal pallor when compared with that characteristically seen with the normal hyperpigmented melanin-containing cells.

Figure 33-4 Parkinsonism—Hypothesized Role of Dopa.

Direct dopaminergic projections from the SN influence motor processing within the basal ganglia by facilitating movement execution and concomitantly helping to suppress certain unwanted motor activity. When intra-SN dopaminergic neuron cell death occurs within the SN, the number of specific dopamine nerve terminals in the striatum decreases. These findings are associated with the classic PD clinical findings of rigidity and akinesia. In addition, basal ganglia function appears to extend beyond simple motor control concepts. The cortico-striato-pallido-thalamo-cortical circuit comprises several distinct and segregated loops, each having a different motor agonistic function. Within each loop are parallel pathways having antagonistic effects on this circuit outflow. The loss of dopamine provokes a less active direct pathway and a more active indirect pathway. Disinhibition of the major output nuclei and increased inhibition of the thalamocortical system result in the classic pill rolling tremor.

The direct pathway arises from neurons that connect the striatum with the output nuclei, including the globus pallidum internum (Gpi) and substantia nigra pars reticularis (SNr). Direct pathway neurons contain GABA, the inhibitory neurotransmitter, and substance P (a neuropeptide that functions both as a neurotransmitter and neuromodulator), and express the excitatory D1 dopamine receptor. Direct pathway neurons receive glutamatergic projections from the cortex to the striatum. They also send GABAergic projections from SNr/Gpi to the ventral anterior and ventral lateral thalamic nuclei, completing the loop by sending glutamatergic fibers back to the cortex. The direct striatopallidal influence inhibits the Gpi neurons. These neurons inhibit the thalamic outflow to the cortex. The net effect of direct pathway activity is excitatory by stimulating cortical activity.

The indirect pathway includes intermediate synapses within the globus pallidum externum (Gpe) and subthalamic nucleus (STN). Neurons within this pathway contain enkephalins and express the inhibitory D₂ dopamine receptor. This pathway consists of three glutamatergic and three GABAergic-type neurons. Glutamatergic neurons in the cortex project to the striatum; striatal GABAergic neurons project to the Gpe. From Gpe, a second set of GABAergic neurons projects to a second set of glutamatergic neurons in the STN that project to the Gpi/SNr. The neurons from Gpi/SNr send GABAergic neurons to the thalamus. The final thalamocortical projection is glutamatergic. By contrast, increased indirect pathway activity excites the Gpi neurons, ultimately inhibiting cortical activity.

Decreased dopaminergic neurons in PD affects the direct pathway by reducing activity at Gpi and SNr leading to increased inhibitory output of Gpi and SNr. In the indirect pathway, dopamine deficiency in PD disinhibits striatopallidal neurons synapsing in Gpe, reducing activity in the inhibitory pallidosubthalamic neurons. Dopamine loss increases the striatal activity via the projections to GABAergic neurons that increase actions on the Gpe. Furthermore, dopamine loss causes a disinhibition of the STN through the indirect pathway.

Clinical Presentation

The four primary signs of PD are bradykinesia, tremor, rigidity, and gait disturbance (Fig. 33-5). The primary criteria for a diagnosis of PD require that the patient’s neurologic examination demonstrate at least two of these four features. There are certain additional features very suggestive of idiopathic PD. These include an asymmetric or unilateral onset and a clear response to levodopa treatment. Importantly from the point of differential diagnosis, neither of these features occurs in some of the atypical parkinsonism syndromes.

Figure 33-5 Clinical Signs of Parkinson Disease.

Bradykinesia, the most disabling PD symptom, is a decreased ability to initiate movement (akinesia is the extreme manifestation). This may affect multiple functions, particularly fine motor tasks such as buttoning a shirt or handwriting, the latter becoming micrographic. Other individuals may present with a masked facies nonemotional, bland, and expressionless, which later on becomes associated with decreased blink frequency, muted speech, and slowed swallowing. Typically, the gait is shuffling with decreased arm swing, stooped posture, and en bloc turning, The Myerson’s sign, or glabellar tap sign, is elicited by having the patient look straight ahead while the examiner gently taps with her or his index finger tip between the medial ends of the eyebrows. Normally the patient blinks for the first few taps and then such is inhibited. In contrast, the PD patient persistently blinks as long as the tapping is maintained and thus a positive test.

Rigidity is a resistance to passive movement throughout the entire range of motion occurring in flexor and extensor muscles. This contrasts with spasticity, wherein there is an initial marked resistance to passive movement and then a sudden release, for example, clasp-knife phenomena. The classic cogwheel quality (stop-and-go effect) is from a tremor superimposed on the altered muscle tone. Very early on, patients are often concerned about stiffness, “weakness,” or fatigue. Initially, the patient will just note a limitation in their daily activities or exercise capacity—unable to hike as long a distance, inability to get to the ball when playing tennis, or simply walking from the car to the store. When more pronounced, these bradykinetic symptoms may represent the combination of bradykinesia with rigidity.

Tremor occurs in 75% of patients. Typically, it is prominent at rest, having a frequency of 3–7 Hz. Although this tremor usually does not significantly interfere with activities of daily living (ADLs), such as eating or writing, the patient finds it very embarrassing. PD patients frequently sit in the physician’s office placing the affected hand out of sight down by their side or underneath a jacket. Sometimes they will actually hold the tremulous hand with the unaffected opposite hand. One should look for the tremor to be “uncovered” when asking the patient to walk; not only is the arm swing lost but a minor pill rolling tremor may become amplified as the hand comes away from the body and the patient is no longer able to cover it. Occasionally a PD tremor has a significant postural or action component complicating distinction from the more benign essential tremor.

Gait disturbance, postural instability, or both usually present at later stages of PD characterized by a change in the center of gravity typified by falling forward (propulsion) or backward (retropulsion) and a festinating (shuffling, slowly propulsive) petit pas (small steps) gait. When these symptoms are found early in PD, evaluation for other causes of parkinsonism, including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), is required.

Typically PD progresses in stages (Fig. 33-5). There are two commonly utilized rating scales to measure the degree of disability that these patients manifest: (1) UPDRS (Unified Parkinson Disease Rating Scale) and (2) Hoehn and Yahr (H&Y) scale (Box 33-1).

Box 33-1 Parkinson Disease Rating Scales