html xmlns=”http://www.w3.org/1999/xhtml” xmlns:mml=”http://www.w3.org/1998/Math/MathML” xmlns:epub=”http://www.idpf.org/2007/ops”>
Tremor
Tremors are the most common movement disorder and occur as a result of dysfunction of the basal ganglia, cerebellum, or the brainstem connections between these systems. Tremors are defined as involuntary, rhythmic, oscillatory movements that can affect any part of the body. Furthermore, they are categorized based upon the type of activity that maximizes the tremor.
Action tremors appear when holding a certain posture (e.g., arms outstretched) or during deliberate targeted movement (e.g., writing, holding a fork) and disappear when the affected body part is relaxed or at rest. A rest tremor is observed when the affected body part is supported and completely at rest; for example, when the hands are supported in one’s lap or hanging at the side. Voluntary action typically suppresses this tremor temporarily, but it may reemerge with a sustained posture. The primary question that a geriatrician will likely face regarding tremor is to differentiate between the tremor of Parkinson’s disease or essential tremor (see Table 17.1). In general, a rest tremor is a parkinsonian tremor until proven otherwise. Rarely, a parkinsonian tremor can occur as a result of cerebellar or brainstem lesions. The characteristics of the parkinsonian tremor will be discussed in detail in the subsequent section on parkinsonism. Dopaminergic agents such as levodopa and anticholinergic agents such as trihexyphenidyl are often highly effective for this type of tremor.
Essential tremor (ET) is the prototypical action tremor, and the most common adult-onset movement disorder with a prevalence of 0.9% in persons over the age of 65.[1] The term “benign” refers to the fact that the majority of persons with ET have mild, minimally progressive symptoms at onset and do not seek medical attention for years. However, the condition has a tendency to progress with age and can lead to significant disability. Because of the hereditary nature of the condition, a family history of similar tremor may be present. ET most commonly affects the arms and hands, but may also involve the head or voice, either in combination or in isolation. The chief complaints of patients with ET are difficulties writing, holding utensils, or drinks. Tremulous handwriting can be demonstrated in the office and used to document responses to therapy. When the head and neck are involved, the tremor can result in horizontal (“no-no”) or vertical (“yes-yes”) bobbing.
The main indicators for treatment are social, occupational, or functional disability. Beta blockers (e.g., propanolol and atenolol) and primidone are considered first-line agents for the treatment of ET (see Table 17.2).[2] Both agents decrease tremor amplitude, but generally do not abolish the tremor. Second-line agents such as topiramate, gabapentin, benzodiazepines, and phenobarbital should be tried in individuals who are intolerant of or refractory to first-line agents. Occasionally, medications may be more effective in combination, but the authors caution against polypharmacy in this population.
Both stereotactic thalamotomy and high frequency thalamic deep brain stimulation (DBS) can be dramatically effective for medically refractory ET.[3] The obvious limitations of the procedure are the invasive nature of a brain procedure, with a very low rate of serious complications (<1%–5%). The primary advantage of stimulation compared to thalamotomy is the ability to reverse and optimize response by adjusting electrical stimulation.[4]
An intention tremor is a specific type of action tremor in which the amplitude increases as the affected limb approaches a goal. A true intention tremor results from dysfunction of the tracts exiting the cerebellum, leading to the term “cerebellar outflow tremor.” The term “rubral tremor” may also be used to describe an intention tremor and implies dysfunction of the midbrain red (rubral) nucleus, although intention tremors may arise from lesions outside the midbrain. Multiple sclerosis, head trauma, stroke, and degenerative diseases of the brainstem and cerebellum may produce a rubral tremor.[5] The full spectrum of a rubral tremor may include a rest component, titubation (head and trunk oscillation when the trunk is unsupported), gait ataxia, and a coarse “flapping” quality due to involvement of proximal muscle groups. Rubral tremors are very disabling as they can severely impair basic activities such as feeding, dressing, and hygiene. They are notoriously difficult to treat, and surgical therapies have been attempted with limited success.
Obtaining a thorough medication history in the geriatric population is imperative since polypharmacy is common and drug-induced tremors are often reversible and avoidable. The diagnosis of drug-induced tremor is made by exclusion of other causes of tremor, establishing a temporal relation with exposure to a tremorigenic drug, and a identifying a dose-response relationship. Table 17.3 provides a list of medications commonly associated with tremor. Antipsychotics and other psychotropic medications are often culprits, but other drugs associated with tremor include albuterol, amiodarone, prednisone, and theophylline. Chronic treatment with lithium carbonate causes a fine postural or kinetic tremor. In overdose or toxicity, lithium can also be associated with a cerebellar or parkinsonian syndrome.[6, 7] Withdrawal from benzodiazepines, alcohol, or other central nervous system depressants often results in tremor. If the causative medication cannot be discontinued, treatment with propranolol or primidone can be considered.
Parkinsonism and Parkinson’s disease
General concepts
“Parkinsonism” is a general term used to describe a clinical syndrome characterized by rest tremor, bradykinesia, rigidity, and postural instability. Although most cases of parkinsonism are sporadic, idiopathic, and neurodegenerative, parkinsonism may also occur as a result of a structural lesion, drugs, or toxin affecting basal ganglia function. Common secondary causes of parkinsonism include vascular parkinsonism, drug-induced parkinsonism, and normal pressure hydrocephalus (NPH) and will be discussed individually in the following section.
The most common neurodegenerative form of parkinsonism is Parkinson’s disease (PD). The prevalence of PD is estimated between 100 and 300 per 100,000.[8] Although PD can occur on a familial basis, the vast majority of cases are sporadic suggesting an unknown environmental risk factor. The hallmark of the condition is the selective degeneration of midbrain dopaminergic neurons, which leads to the cardinal features of the disorder and the characteristic response to levodopa.
Finally, several related degenerative disorders known as Parkinson’s plus or atypical parkinsonian syndromes are a part of the larger complex of parkinsonism and may be mistaken for Parkinson’s disease. Features common to this group of disorders include poor response to levodopa, more rapid progression to severe disability compared to idiopathic PD, and additional neurological features that make them atypical for PD.
Clinical features of parkinsonism
“Bradykinesia,” the hallmark of Parkinson’s disease, refers to slowing of movements, hesitancy, arrests, decreased amplitude, or poverty of movements. Passively manipulating joints such as the wrist, elbow, or knee will reveal either a constant increase in tone (lead-pipe rigidity) or a ratchety increase in tone (cogwheel rigidity).
Tremor is the most recognizable aspect of parkinsonism, but may not be present in up to 40% of patients with parkinsonism. The typical parkinsonian tremor presents unilaterally at rest, may affect the hands, legs, jaw, or tongue, and remains asymmetric throughout the course of the disease. Mental concentration (e.g., counting backwards) and walking enhance a parkinsonian tremor. Furthermore, lifting the arms to sustain a posture will dampen the tremor temporarily, but the original amplitude and frequency will return after a delay of two to three seconds. This so-called re-emergent tremor is a pathognomonic clue to a parkinsonian tremor.
In early disease, the examination may reveal a subtle unilateral tremor, decreased arm swing or dragging of one leg. Patients often report that walking feels unnatural. Impaired finger dexterity, loss of facial expression (hypomimia), and small handwriting (micrographia) are often the earliest signs of bradykinesia and parkinsonism. The voice can be hypophonic and monotone with a loss of diction. The combination of rigidity and bradykinesia leads to difficulty with ordinary tasks such as turning in bed, rising from a chair, or getting in and out of a car. Because of the loss of dexterity and range of motion, dressing and routine hygiene can become laborious.
A characteristic stooped posture develops with forward flexion of the trunk, neck, elbows, shoulders, and knees. Stride height and length are reduced leading to a shuffling gait. The stooped posture and shift in the center of gravity contributes to a tendency to fall forward (propulsion) and an inability to stop (festination). Turning occurs “en-bloc,” as the head, neck, torso, and extremities no longer rotate independently due to rigidity and bradykinesia. Start hesitation causes difficulty rising from a chair or initiating walking. Patients may describe freezing as though the feet are transiently stuck or “glued” to the ground. The phenomenon typically occurs in doorways, narrow hallways, or near obstacles. Patients often find that visual cues such as floor or sidewalk markings will release them from freezing. Freezing of gait (FOG) is one of the more debilitating symptoms encountered in parkinsonian states and often leads to falls and subsequent injury. Unfortunately, freezing can be refractory to dopaminergic therapy.
Postural stability is tested using the pull test in which the examiner firmly tugs the patient from behind and assesses the ability to maintain an upright stance. Retropulsion or toppling backward occurs when the ability to adjust or maintain the center of gravity is lost. Due to the combination of flexed posture and postural instability, forward falls are typical of moderate to advanced stages of PD.
Secondary or nonmotor features of parkinsonism include dysphagia, excess saliva or drooling (sialorrhea), constipation, overactive bladder, erectile dysfunction, seborrheic dermatitis, orthostatic hypotension, pain, paresthesias, and sleep disturbances including REM sleep behavior disorder (RBD), periodic limb movements of sleep (PLMS), restless legs syndrome (RLS), insomnia, and obstructive sleep apnea. Numbness, tingling, aching pains, fatigue, and weakness are common complaints of PD that may be dismissed early in the diagnosis or mistaken for other neurological or medical conditions.
Neuropsychiatric symptoms that may occur in a parkinsonian disorder include subcortical dementia, depression, apathy, anxiety, hallucinations, or delusions (see Table 17.4).
| Cognitive and intellectual impairment and dementia |
| Visual hallucinations |
| Delusions |
| Depression, anhedonia, dysphoria |
| Anxiety |
| Akathisia |
| Apathy or amotivation |
| Sleep disorders such as insomnia, sleep fragmentation, excessive daytime somnolence, sleep attacks, REM behavior disorder, periodic leg movements of sleep |
| Impulse control behaviors |
Differential diagnosis
The diagnosis of PD or an atypical parkinsonian disorder is made by a clinical exam. When all cardinal symptoms are present, the diagnosis is fairly obvious. Diagnostic difficulty usually arises in early stages of the disease when the predominant symptoms are subtle secondary symptoms. In the hands of experienced neurologists, up to 20% of patients have an alternate diagnosis at autopsy while cases with atypical features may prove to have PD.[9] Since 2011, the Dopamine Transporter SPECT scan (DaT)© has been available in the United States and can aid in the early diagnosis of Parkinsonism. The radiotracer ioflupane labels the dopamine transporter found in nigrostriatal neurons. Therefore, it can distinguish parkinsonism from essential tremor, but it does not distinguish between parkinsonian disorders.
The single most important feature distinguishing idiopathic PD from secondary and atypical forms of parkinsonism is the response to levodopa. Patients with idiopathic PD display a robust response to levodopa that lasts for many years because PD primarily affects midbrain dopaminergic neurons in the substantia nigra (SN). The lack of response characteristic of other forms of parkinsonism is due to degeneration of post-synaptic receptors and non-dopaminergic systems (see Table 17.5).
Red flags suggesting an atypical or secondary form of parkinsonism include ocular motor palsy, cerebellar signs, early, prominent falls, gait, cognitive, or cranial nerve dysfunction, autonomic failure, or pyramidal signs. These conditions tend to be more rapidly progressive than PD due to the lack of disease specific treatment options.
Progressive supranuclear palsy (PSP) refers to the characteristic eye movement abnormality associated with the condition. The hallmarks of the condition are an akinetic-rigid parkinsonism with early imbalance leading to falls. Postural instability leading to falls is often a later manifestation of PD and should alert the physician to alternate forms of parkinsonism. The characteristic vertical gaze palsy is not always a presenting feature, but invariably develops over time. Other characteristic features include a prominent stare with a worried or astonished facial expression and dysarthria. Patients with PSP often develop personality changes and cognitive impairment due to concomitant frontal lobe degeneration. The combination of cognitive impairment and lack of insight often leads to issues with medication compliance, social withdrawal, and falls. Microscopically, microtubule associated protein tau accumulates, forming neurofibrillary tangles, so that pathogically PSP may be more closely related to Alzheimer’s disease rather than PD.[10]
Dementia with Lewy bodies (DLB) is a relatively new diagnostic entity that is the second most common cause of dementia after Alzheimer’s disease.[11] DLB presents with prominent mental symptoms that often overshadow the movement disorder. Visual hallucinations (VH) develop insidiously and are very similar to the well-formed, complex medication-induced VH in PD. In contrast to PD, VH in DLB develop in the absence of dopaminergic medication exposure or with relatively low doses. Delusions revolving around spousal infidelity as well as neighbors, friends, or relatives stealing from them are also common. Striking cognitive fluctuations differentiate DLB from other causes of dementia. Patients may be relatively intact at one moment and minutes later become confused, disoriented, psychotic, or obtunded.
When present, several secondary features help to confirm the diagnosis. Repeated falls occur due to postural instability. Syncope and transient loss of consciousness may mimic seizures, stroke, transient ischemic attack, or a cardiac event and often prompt repeated evaluations or hospitalizations. DLB patients may be very sensitive to dopamine receptor blockers and can develop delirium or akinetic-rigid crises with neuroleptic treatment. For this reason, only antipsychotics such as quetiapine or clozapine should be considered when treating psychosis in DLB.
Both PD and DLB have in common the characteristic pathological inclusion called the Lewy body (LB), cytoplasmic inclusions containing the synaptic protein α-synuclein. In DLB, LB are present throughout the brainstem, limbic regions, and cortex, leading to the pathological term “diffuse Lewy body disease.”
Multiple system atrophy (MSA) is a clinical term used to refer to three formerly distinct parkinsonian conditions, Shy-Drager syndrome (SDS), olivopontocerebellar atrophy (OPCA), and striatonigral denegeration (SND). The currently accepted designations are MSA-A (autonomic form) for SDS, MSA-C (cerebellar form) for OPCA, and MSA-P (parkinsonian form) for SND. Autonomic features include orthostatic hypotension, bowel or bladder incontinence, and sexual dysfunction. Cerebellar features include dysarthria, gait ataxia, and limb incoordination. In practice, there is often overlap between the syndromes.[12]
Although the response to levodopa in MSA is generally limited, some patients with MSA may experience partial benefit and should be tried on levodopa at least once. At the same time, even if there is a response, side effects such as facial dystonia, orthostasis or nausea may limit treatment. Secondary features suggestive of the diagnosis include early sexual dysfunction which may precede the diagnosis of MSA by many years, stridor, REM behavior disorder and obstructive sleep apnea due to brainstem respiratory and sleep center dysfunction.
Pathologically, all three syndromes share a common pathological finding of cytoplasmic inclusions containing α-synuclein in glial cells. The clinical phenotype is largely determined by the location of pathology, autonomic centers in the brainstem, cervical and sacral spinal cords are affected primarily in MSA-A. In MSA-C, the medulla, pons, and cerebellum are primarily affected and in MSA-P, the substantia nigra and the striatum.
Corticobasal ganglionic degeneration (CBD) is a condition that may present with either parkinsonism or dementia. Pathologically, it resembles Alzheimer’s disease and frontotemporal dementia rather than Parkinson’s disease. The classic corticobasal syndrome consists of asymmetric parkinsonism with prominent limb rigidity, dystonic posturing, and a gait disorder. There may be myoclonic jerks, cognitive impairment involving frontal lobe function, memory systems, or visuospatial systems. One of the most distinctive features of the syndrome is limb apraxia, or inability to perform a voluntary movement that is not due to muscle weakness, sensory loss, or ataxia. With time, the so-called alien limb phenomenon may develop in which the limb may assume unusual postures, wander in space, or seem out of the control of the person. Over time, rigidity and dementia predominate.[13]
In clinical practice, the most common secondary forms of parkinsonism that one needs to consider are vascular parkinsonism, drug-induced parkinsonism, and normal pressure hydrocephalus (NPH).
Cerebrovascular disease is a relatively common cause of parkinsonism, occurring as a result of both strategically placed lacunar infarctions in the basal ganglia or diffuse white matter disease. Patients may present with abrupt onset of a gait disorder or “lower body” parkinsonism. A stepwise pattern of progression is often a clue to recurrent small vessel ischemic events. Levodopa is not typically effective, but should be attempted for both diagnostic and therapeutic purposes. Cerebrovascular risk factors, a history of stroke or transient neurological events, cognitive disturbance, or gait apraxia are often present.[14]
Parkinsonism due to chronic antipsychotic treatment is a potentially reversible syndrome that may be identical to idiopathic PD. The risk of parkinsonism due to antipsychotic medications is dose dependent and increases in the elderly. With the exception of clozapine, no antipsychotic is free of this risk. Other medications that potentially may induce parkinsonism include antiemetics such as metoclopramide or prochlorperazine due to their dopamine blocking capabilities, dopamine depleting agents such as reserpine or tetrabenazine, and lithium. MPTP (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine), a compound that causes selective nigrostriatal degeneration, was discovered after it led to acute parkinsonism in a group of college students experimenting with heroin.[15] In addition to MPTP, other toxins associated with parkinsonism include manganese[16] and carbon monoxide.[17]
Treatment of PD
Treatment overview
Symptomatic treatment is typically initiated when patients begin to experience social or functional disability. Factors to consider when deciding to initiate treatment include primary symptom complex, age, functional status, comorbid medical conditions, and cognitive status. A wide range of medications with proven symptomatic effects exist for PD, including monoamine oxidase inhibitors (MAOI), anticholinergic agents, amantadine, catechol-O-methyltransferase (COMT) inhibitors, dopamine agonists, and levodopa (see Table 17.6).
Both selegiline and rasagiline irreversibly inhibit MAO type B resulting in modest enhancement of striatal dopamine levels. Side effects may include insomnia and orthostatic hypotension. One of the first agents studied for its potential neuroprotective effects was Selegiline, an irreversible MAO-B inhibitor with antioxidant properties. In the landmark DATATOP (deprenyl and tocopherol antioxidative therapy of parkinsonism) study, selegiline treatment was found to delay disability and the need for levodopa therapy.[18] However, the effect was deemed to be at least partly symptomatic, and a clear neuroprotective benefit was never demonstrated.
Anticholinergic agents such as benztropine and trihexyphenidyl were among the first treatments for PD. They have moderate effects on tremor, rigidity, and dystonia; however, side effects such as urinary retention, cognitive impairment, delirium, dry mouth, and blurred vision limit their use in the elderly.[19]
Amantadine, originally developed for use against influenza, is a tricyclic amine with multiple putative mechanisms including enhancing dopamine release, inhibition of dopamine reuptake, antimuscarinic effects, and N-methyl D-aspartate (NMDA) receptor antagonism. In addition to its use in early PD, antidyskinetic properties make it useful for advanced patients with motor fluctuations. Amantadine is generally well tolerated, but lower extremity edema and hallucinations may complicate treatment. In patients with renal insufficiency, dose adjustments need to be made based on creatinine clearance since amantadine is renally excreted.
Dopamine agonists directly stimulate striatal dopamine receptors and are used both in early PD and as an adjunct in advanced patients with motor fluctuations. Ropinirole, pramipexole, rotigotine, and subcutaneous apomorphine are available in the United States. Subcutaneous apomorphine injections has been available in the United States for the treatment of refractory off periods. The various non-ergot agonists have similar efficacy and side effects common to the class include nausea, lightheadedness, pedal edema, hallucinations, and sedation. Most adverse effects are dose-related and can be avoided by slow titration of the drug. The ergot agonists (e.g., bromocriptine and pergolide) carry the additional risk of retroperitoneal fibrosis and Raynaud’s phenomenon. Furthermore, cardiac valvular abnormalities attributed to pergolide led to its withdrawal from the US market.[20] Long-term experience with the agonists, particularly pramipexole and ropinirole, has revealed that dopamine agonist use may be linked to compulsive behaviors such as gambling, binge eating, spending, and hypersexuality.[21]
The initial studies of ropinirole and pramipexole monotherapy compared to levodopa have both demonstrated reduced motor fluctuations and dyskinesias compared to levodopa therapy.[22, 23] However, a recent longitudinal study suggested that the development of motor fluctuations and dyskinesias are not associated with the duration of exposure to levodopa, but are associated with duration of disease and dose of levodopa.[24] Longitudinal experience with use of dopamine agonists either as monotherapy or adjunctive therapy has revealed that symptom control tends to be poorer with dopamine agonists and side effects are often more common on dopamine agonists.[25, 26]
Despite the recent advances in pharmacotherapy, levodopa remains the most time-honored and effective treatment for symptoms of PD. The majority of PD patients will attain significant, long-lasting benefit from levodopa superior to any of the previously mentioned agents. It is well tolerated and effective at a large dose range as long as it is administered with a peripheral decarboxylase inhibitor (e.g., carbidopa). Without such an inhibitor, large doses of levodopa would be required to provide a benefit that in turn would lead to intolerable peripheral side effects of dopamine such as orthostatic hypotension, nausea, and emesis. In the United States, carbidopa is combined with levodopa in various formulations (10/100, 25/100, 25/250) and marketed as Sinemet® allowing for flexible dosing. The half-life of Sinemet is approximately 90 minutes, so that multiple daily doses are necessary. We typically start with 1/2 of a 25/100 tablet three times daily, increasing over a few weeks to 1–2 tablets three times daily. Central nervous system side effects such as sedation, insomnia, visual hallucinations, confusion, or psychosis are more likely to occur in the elderly (>80 years of age) or in later stages of PD (see Table 17.7).
