User:Madhero88/Parkinson's disease

Signs and symptoms
Parkinson disease affects movement (motor symptoms). Other typical symptoms include disorders of mood, behavior, thinking, and sensation (non-motor symptoms). Patients' individual symptoms may be quite dissimilar and progression of the disease is also distinctly individual.

Motor symptoms
The cardinal symptoms are:
 * Tremor: normally 4–6 Hz tremor, maximal when the limb is at rest, and decreased with voluntary movement. It is typically unilateral at onset.  This is the most apparent and well-known symptom, though an estimated 30% of patients have little perceptible tremor; these are classified as akinetic-rigid.
 * Rigidity: stiffness; increased muscle tone. In combination with a resting tremor, this produces a ratchety, "cogwheel" rigidity when the limb is passively moved.
 * Akinesia/bradykinesia: absence of movement and slowness, respectively.  Rapid, repetitive movements produce a dysrhythmic and decremental loss of amplitude.
 * Postural instability: failure of postural reflexes, which leads to impaired balance and falls.

Other motor symptoms include:
 * Gait and posture disturbances:
 * Shuffling: gait is characterized by short steps, with feet barely leaving the ground, producing an audible shuffling noise. Small obstacles tend to cause the patient to trip.
 * Decreased arm-swing.
 * Turning "en bloc": rather than the usual twisting of the neck and trunk and pivoting on the toes, PD patients keep their neck and trunk rigid, requiring multiple small steps to accomplish a turn.
 * Stooped, forward-flexed posture. In severe forms, the head and upper shoulders may be bent at a right angle relative to the trunk (camptocormia).
 * Festination: a combination of stooped posture, imbalance, and short steps. It leads to a gait that gets progressively faster and faster, often ending in a fall.
 * Gait freezing: "freezing" is a manifestation of akinesia (an inability to move). Gait freezing is characterized by an inability to move the feet which may worsen in tight, cluttered spaces or when attempting to initiate gait.
 * Dystonia (in about 20% of cases): abnormal, sustained, painful twisting muscle contractions, often affecting the foot and ankle (mainly toe flexion and foot inversion) which often interferes with gait.
 * Speech and swallowing disturbances.
 * Hypophonia: soft speech. Speech quality tends to be soft, hoarse, and monotonous. Some people with Parkinson's disease claim that their tongue is "heavy" or have cluttered speech.
 * Monotonic speech.
 * Festinating speech: excessively rapid, soft, poorly-intelligible speech.
 * Drooling: most likely caused by a weak, infrequent swallow and stooped posture.
 * Dysphagia: impaired ability to swallow. Can lead to aspiration pneumonia.
 * Other motor symptoms:
 * Fatigue (up to 50% of cases);
 * Masked faces (a mask-like face also known as hypomimia), with infrequent blinking;
 * Difficulty rolling in bed or rising from a seated position;
 * Micrographia (small, cramped handwriting);
 * Impaired fine motor dexterity and motor coordination;
 * Impaired gross motor coordination;
 * Akathisia, the inability to sit still.

Neuropsychiatric
PD causes cognitive and mood disturbances, being in many cases related.

Estimated prevalence rates of depression vary widely according to the population sampled and methodology used. Reviews of depression estimate its occurrence in anywhere from 20–80% of cases. Estimates from community samples tend to find lower rates than from specialist centres. Most studies use self-report questionnaires such as the Beck Depression Inventory, which may overinflate scores due to physical symptoms. Studies using diagnostic interviews by trained psychiatrists also report lower rates of depression. More generally, there is an increased risk for any individual with depression to go on to develop Parkinson's disease at a later date. Seventy percent of individuals with Parkinson's disease diagnosed with pre-existing depression go on to develop anxiety. Ninety percent of Parkinson's disease patients with pre-existing anxiety subsequently develop depression; apathy or abulia.

Cognitive disturbances include:
 * Slowed reaction time; both voluntary and involuntary motor responses are significantly slowed.
 * Executive dysfunction, characterized by difficulties in: differential allocation of attention, impulse control, set shifting, prioritizing, evaluating the salience of ambient data, interpreting social cues, and subjective time awareness. This complex is present to some degree in most Parkinson's patients; it may progress to:
 * Dementia: a later development in approximately 20-40% of all patients, typically starting with slowing of thought and progressing to difficulties with abstract thought, memory, and behavioral regulation. Hallucinations, delusions and paranoia may develop.
 * Short term memory loss; procedural memory is more impaired than declarative memory. Prompting elicits improved recall.
 * Non-motor causes of speech/language disturbance in both expressive and receptive language: these include decreased verbal fluency and cognitive disturbance especially related to comprehension of emotional content of speech and of facial expression.
 * Difficulty deceiving others that links to prefrontal hypometabolism.
 * Medication effects: some of the above cognitive disturbances are improved by dopaminergic medications, while others are actually worsened.

Sleep

 * Excessive daytime somnolence
 * Initial, intermediate, and terminal insomnia
 * Disturbances in REM sleep: disturbingly vivid dreams, and REM Sleep Disorder, characterized by acting out of dream content—can occur years prior to diagnosis

Perception

 * Impaired visual contrast sensitivity, spatial reasoning, color discrimination, convergence insufficiency (characterized by double vision) and oculomotor control
 * Dizziness and fainting; usually attributable orthostatic hypotension, a failure of the autonomic nervous system to adjust blood pressure in response to changes in body position
 * Impaired proprioception (the awareness of bodily position in three-dimensional space)
 * Reduction or loss of sense of smell (hyposmia or anosmia) - can occur years prior to diagnosis
 * pain: neuropathic, muscle, joints, and tendons, attributable to tension, dystonia, rigidity, joint stiffness, and injuries associated with attempts at accommodation

Autonomic

 * Oily skin and seborrheic dermatitis
 * Urinary incontinence, typically in later disease progression
 * Nocturia (getting up in the night to pass urine)—up to 60% of cases
 * Constipation and gastric dysmotility that is severe enough to endanger comfort and even health
 * Altered sexual function: characterized by profound impairment of sexual arousal, behavior, orgasm, and drive is found in mid and late Parkinson disease. Current data addresses male sexual function almost exclusively.
 * Weight loss, which is significant over a period of ten years.

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Rewrite
Parkinson disease has many symptoms that is known to affects movement (motor symptoms). Other typical symptoms include disorders of mood, behavior, cognition, thinking, and sensation (non-motor symptoms). Patients' individual symptoms may be quite dissimilar and progression of the disease is also distinctly individual. That is why symptoms of Parkinson's disease are divided into motor symptoms, non-motor symptoms, and neuropsychiatric symptoms.

Motor symptoms
There are four cardinal features of PD that are considered carectiristic for the disease are, tremor at rest, rigidity, akinesia (or bradykinesia) and postural instability. In addition, flexed posture and freezing (motor blocks) have been included among classic features of parkinsonism, with PD as the most common form.

The most disabling motor feature of PD is bradykinesia, bradykinesia refers to slowness of movement and is the most characteristic clinical feature of PD, although it may also be seen in other disorders, including depression. Bradykinesia is a hallmark of basal ganglia disorders, and it encompasses difficulties with planning, initiating and executing movement and with performing sequential and simultaneous tasks. Fine motor control is also impaired, as evidenced by decreased manual dexterity and micrographia. Soft speech (hypophonia) and sialorrhea are other troubling manifestations of (bulbar) bradykinesia. Rest tremor, at a frequency of 4–6 Hz, typically appears unilaterally, first distally, involving the digits and wrist, where it may have a "pill-rolling" character. Tremor usually spreads proximally and occasionally to the ipsilateral leg before appearing on the other side after a year or more. It may appear later in the lips, tongue, and jaw but spares the head and neck. Rigidity is felt as a uniform resistance to passive movement about a joint throughout the full range of motion, accompanied by a characteristic "plastic" quality to the movement. Brief, regular interruptions of resistance during passive movement, due to subclinical tremor, may give rise to a "cogwheeling" sensation. Dystonia involving the distal arm or leg may occur early in the disease, unrelated to treatment, especially in younger patients. It can also be provoked by antiparkinsonian drug therapy.

Gait disturbance with shuffling short steps and a tendency to turn en bloc is a prominent feature of PD. Festinating gait, a classic sign of parkinsonism, results from the combination of flexed posture and loss of postural reflexes, which cause the patient to accelerate in an effort to "catch up" with the body's center of gravity. Freezing of gait, a feature of more advanced PD, occurs commonly at the onset of locomotion (start hesitation), when attempting to change direction or turn around, and upon entering a crowded room or narrow space such as a doorway.

Abnormalities of balance and posture tend to increase as the disease progresses. Flexion of the head, stooping and tilting of the upper trunk, and a tendency to hold the arm in a flexed posture while walking are common, as are changes in the posture of the fingers, hand, and arm. Postural instability is one of the most disabling features of advanced PD, contributing to falls and injuries and leading to major morbidity and mortality. It can be tested in the office with the "pull test" (Fig. 366-1). The development of postural instability and falls in the first years of the illness, however, strongly suggest a diagnosis of atypical PD. Patients are also at risk for hip fractures, which are associated with osteoporosis and vitamin D deficiency.

Non-motor features
Non-motor aspects of PD include depression and anxiety, cognitive impairment, sleep disturbances, sensory abnormalities and pain, loss of smell (anosmia), and disturbances of autonomic function. Together these may contribute as much to the burden of the disease as the more obvious motor abnormalities. Some of these non-motor disturbances may be present long before the onset of motor signs. The physiologic basis of the non-motor signs and symptoms are explained in part by widespread involvement of brainstem, olfactory, thalamic, and cortical structures, as discussed below.

Sensory symptoms often manifest as a distressing sensation of inner restlessness presumed to be a form of akathisia. Aching pain and discomfort in the extremities can be a prominent presenting symptom or develop when antiparkinsonian medications are wearing off. Some patients may develop a subjective shortness of breath in the absence of any underlying cardiorespiratory pathology.

Sleep disorders and impaired daytime alertness are common in PD. Factors that disrupt sleep include nighttime reemergence of bradykinesia and rigidity, with difficulty turning in bed, as well as tremor and involuntary movements (e.g., myoclonic jerks or periodic leg movements). Restless legs and rapid eye movement behavioral disorder often precede the onset of motor signs of PD. Vivid dreams and hallucinations related to dopaminomimetic therapy may also contribute to sleep disruption. Finally, sleep apnea and other sleep disturbances can also occur. Correction of these sleep disorders may improve daytime functioning, but often alertness remains impaired, pointing to a separate disorder of arousal or to drug-induced sedation.

Autonomic dysfunction can produce diverse manifestations, including orthostatic hypotension, constipation, urinary urgency and frequency, excessive sweating, and seborrhea. Orthostatic hypotension is present in many patients resulting from impaired vasomotor reflexes, sympathetic denervation of the heart, or as a side effect of dopaminomimetic therapy. This rarely leads to syncope unless the patient has developed true autonomic failure or has an unrelated cardiac problem. Paroxysms of drenching sweats may occur in advanced PD, often related to the wearing off of antiparkinsonian medications.

Neuropsychiatric symptoms
Changes in mood, cognition, and behavior are common accompaniments of PD, especially in its later stages, and may be the direct result of PD or its comorbid pathologies [e.g., Alzheimer's disease (AD), cortical dementia with Lewy bodies (DLB)] or may occur as a side effect of antiparkinsonian or concomitant therapy.

Depression affects approximately half of patients with PD and can occur at any phase of the illness. It is often difficult to diagnose due to the overlap between the somatic and vegetative symptoms of PD and depression. As a result, depression may go unrecognized and untreated. There is compelling evidence that depression in PD is an intrinsic part of the illness and not simply a reaction to disability. Recognizing even mild depression is particularly important since it can account for otherwise unexplained albeit reversible worsening of parkinsonian motor symptoms, new somatic symptoms, and sleep disruption. Depression can also be induced or aggravated iatrogenically by antiparkinsonian and psychotropic agents used to treat other symptoms. Finally, other causes for depressive symptoms and refractory depression should always be considered, including hypothyroidism, hypogonadism, and vitamin B12 deficiency.

Anxiety disorders in PD can appear in isolation or as an accompaniment of depression or progressive cognitive impairment. They can also be due to an akathisia equivalent provoked in part by undertreatment of motor symptoms. The development of drug-induced motor fluctuations can compound the problem by precipitating anxiety during the off periods that, in severe cases, may mimic panic attacks.

Mild or moderate cognitive abnormalities affect many patients with PD. These occur in the later stages of the illness and present as frontal lobe dysfunction. Difficulties with complex tasks, long-term planning, and memorizing or retrieving new information are common. Although some of these symptoms represent bradyphrenia (the cognitive equivalent of bradykinesia), it is now clear that the dysfunction also includes working memory, executive function, attention, mental flexibility, visuospatial function, and word fluency. In contrast, language and simple mathematical skills are relatively spared, unlike in patients with AD. Iatrogenic contributors to cognitive decline in vulnerable patients include the use of anticholinergics, amantadine, psychotropics, and even dopaminomimetic medications. Depression and intercurrent medical illnesses, especially infections (of the urinary tract or elsewhere) and dehydration, are important reversible causes of an acute change in cognitive function in PD.

The incidence of significant dementia in PD may be as high as six times that in age-matched controls and, in subspecialty clinics, can be as high as 70% or greater with long-term observation ( 8 years). In late stages the presence of substantial cognitive impairment may limit therapeutic options and contribute more to overall disability than the motor symptoms in PD. Predictors of dementia include late age of onset, akinetic-rigid phenotype, presence of severe depression, persistent hallucinations, and advanced stages of disease. In most instances, accumulating amyloid and -synuclein pathologies in the frontal lobes, basal forebrain, hippocampus, and amygdala account for the progression of these symptoms (see "Pathology," below).

Psychotic symptoms affect up to 40% of patients with PD, depending on the age, disease duration, and prevalence of dementia in the population surveyed. Early symptoms include visual illusions (e.g., shadows of the edge of the visual field) and formed visual hallucinations (usually people and animals), both with retained insight. Although depression and dementia are the most important risk factors for psychotic symptoms in PD, the symptoms are often triggered by drug therapy. Dopaminomimetics (especially dopamine agonists), anticholinergics, amantadine, and psychotropics are the chief drug offenders. Delusions are more disturbing than hallucinations because they place an even heavier burden on the family and caregivers. The prodrome to these psychotic symptoms includes sleep disturbances and subtle erratic behaviors with temperamental and sometimes unreasonable outbursts.

In recent years there has been increased recognition of insidious behavioral disturbances in a subset of patients with PD, referred to collectively as impulse control disorders (ICDs); these include pathologic gambling, hypersexuality, compulsive shopping, and compulsive eating and are associated primarily with the use of dopaminergic agents. A related disorder, termed punding, consists of stereotypical motor behavior in which there is an intense fascination with repetitive handling and examining of mechanical objects, such as picking at oneself, taking apart watches and radios, or sorting and arranging common objects. Current therapeutic approaches to these disorders include reduction or discontinuation of dopamine agonist therapy, psychosocial interventions, and in some cases consideration of deep brain stimulation with a goal of reducing the requirement for drugs.

Alt
Parkinson disease has many symptoms that is known to affects movement (motor symptoms). Other typical symptoms include disorders of mood, behavior, cognition, thinking, and sensation (non-motor symptoms). Patients' individual symptoms may be quite dissimilar and progression of the disease is also distinctly individual. That is why symptoms of Parkinson's disease are divided into motor symptoms, non-motor symptoms, and neuropsychiatric symptoms.

Motor symptoms
Bradykinesia refers to slowness of movement and is the most characteristic clinical feature of PD, although it may also be seen in other disorders, including depression. Bradykinesia is a hallmark of basal ganglia disorders, and it encompasses difficulties with planning, initiating and executing movement and with performing sequential and simultaneous tasks. The initial manifestation is often slowness in performing activities of daily living and slow movement and reaction times. This may include difficulties with tasks requiring fine motor control (eg, buttoning, using utensils). Other manifestations of bradykinesia include loss of spontaneous movements and gesturing, drooling because of impaired swallowing, monotonic and hypophonic dysarthria, loss of facial expression (hypomimia) and decreased blinking, and reduced arm swing while walking. Given that bradykinesia is one of the most easily recognisable symptoms of PD, it may become apparent before any formal neurological examination. Assessment of bradykinesia usually includes having patients perform rapid, repetitive, alternating movements of the hand (finger taps, hand grips, hand pronation–supination) and heel taps and observing not only slowness but also decrementing amplitude.

In common with other parkinsonian symptoms, bradykinesia is dependent on the emotional state of the patient. For example, immobile patients who become excited may be able to make quick movements such as catching a ball (or may be able to suddenly run if someone screams "fire"). This phenomenon (kinesia paradoxica) suggests that patients with PD have intact motor programmes but have difficulties accessing them without an external trigger, such as a loud noise, marching music or a visual cue requiring them to step over an obstacle.

Although the pathophysiology of bradykinesia has not been well delineated, it is the cardinal PD feature that appears to correlate best with degree of dopamine deficiency. This is supported by the observation of decreased neuronal density in the substantia nigra in elderly patients with parkinsonism regardless of PD diagnosis. In addition, positron emission tomography (PET) in patients with PD has demonstrated that the decreased 18F-fluorodopa uptake in the striatum and accumbens–caudate complex is proportional to the degree of bradykinesia.

It is hypothesised that bradykinesia is the result of a disruption in normal motor cortex activity mediated by reduced dopaminergic function. Anatomically, the deficit appears to be localised in the putamen and globus pallidus, resulting in a reduction in the muscle force produced at the initiation of movement. Analysis of electromyographic recordings showed that patients with bradykinesia are unable to energise the appropriate muscles to provide enough force to initiate and maintain large fast movements. Because patients with PD have decreased electromyographic activity, they need a series of multiple agonist bursts to accomplish larger movements.

Rest tremor is the most common and easily recognised symptom of Parkinson's disease. Tremors are unilateral, occur at a frequency between 4 and 6 Hz, and almost always are prominent in the distal part of an extremity. Hand tremors are described as supination–pronation ("pill-rolling") tremors that spread from one hand to the other. Rest tremor in patients with PD can also involve the lips, chin, jaw and legs but, unlike essential tremor, rarely involves the neck/head or voice. Thus a patient who presents with head tremor most likely has essential tremor, cervical dystonia, or both, rather than Parkinson's disease. Characteristically, rest tremor disappears with action and during sleep. Some patients also report an "internal" shaking that is not associated with a visible tremor. The tremor of Parkinson's disease is differentiated from that of essential tremor by a number of features. Some patients with PD have a history of postural tremor, phenomenologically identical to essential tremor, for many years or decades before the onset of parkinsonian tremor or other PD related features. We and others have provided a growing body of evidence that indicates that essential tremor is a risk factor for PD.

In addition to rest tremor, many patients with PD also have postural tremor that is more prominent and disabling than rest tremor and may be the first manifestation of the disease. Parkinson’s related postural tremor ("re-emergent tremor") is differentiated from essential tremor in that the appearance of tremor is often delayed after the patient assumes an outstretched horizontal position. Because re-emergent tremor occurs at the same frequency as classical rest tremor and is responsive to dopaminergic therapy, it is likely that it represents a variant of the more typical rest tremor. There are several clues to the diagnosis of existent essential tremor when it coexists with PD, including longstanding history of action tremor, family history of tremor, head and voice tremor, and no latency when arms are outstretched in a horizontal position in front of the body, although some patients may also have a re-emergent tremor related to their PD, tremulous handwriting and spiral, and improvement of the tremor with alcohol and beta-blockers.

Rigidity is characterised by increased resistance, usually accompanied by the "cogwheel" phenomenon, particularly when associated with an underlying tremor, present throughout the range of passive movement of a limb (flexion, extension or rotation about a joint). It may occur proximally (eg, neck, shoulders, hips) and distally (eg, wrists, ankles). Reinforcing manoeuvres (eg, voluntary movements of the contralateral limb), known as the Froment’s manoeuvre,39 usually increase rigidity and are particularly useful in detecting mild cases of rigidity.

Rigidity may be associated with pain, and painful shoulder is one of the most frequent initial manifestations of PD although it is commonly misdiagnosed as arthritis, bursitis or rotator cuff injury.40 41 A prospective study of 6038 persons (mean age 68.5 years) with no evidence of dementia or parkinsonism at baseline found that the presence of stiffness, tremor and imbalance were each associated with increased risk for PD (hazard ratios 2.11, 2.09 and 3.47, respectively).42 Among this cohort, 56 new cases of PD were identified over a mean follow-up of 5.8 years.

Postural deformities In addition, rigidity of the neck and trunk (axial rigidity) may occur, resulting in abnormal axial postures (eg, anterocollis, scoliosis). Postural deformities resulting in flexed neck and trunk posture and flexed elbows and knees are often associated with rigidity. However, flexed posture generally occurs late in the disease. Striatal limb deformities (eg, striatal hand, striatal toe) may also develop in some patients. Striatal hand is characterised by ulnar deviation of the hands, flexion of the metacarpophalangeal joints and extension of the proximal and flexion of the distal interphalangeal joints (fig 1A); striatal foot is characterised by extension or flexion (fig 1B) of the toes.43 44 In one study, striatal toe (extension of the big toe) was reported in 21% of patients with clinically diagnosed PD.45 Patients with striatal deformities tend to be younger and to experience earlier onset of initial parkinsonian symptoms.44

Other skeletal abnormalities include extreme neck flexion ("dropped head" or "bent spine"), truncal flexion (camptocormia) and scoliosis.44 46–48 Camptocormia is characterised by extreme flexion of the thoracolumbar spine. The condition is exacerbated by walking and is relieved by sitting, lying in the supine position or by volitionally extending the trunk when the patient leans against a wall or a high walker or a table (fig 2A–C).48 In addition to PD, other causes of camptocormia include dystonia and extensor truncal myopathy.49 50 Another truncal deformity is the Pisa syndrome, which is characterised by a tilting of the trunk, particularly when sitting or standing.51

Postural instability Postural instability due to loss of postural reflexes is generally a manifestation of the late stages of PD and usually occurs after the onset of other clinical features. The pull test, in which the patient is quickly pulled backward or forward by the shoulders, is used to assess the degree of retropulsion or propulsion, respectively. Taking more than two steps backwards or the absence of any postural response indicates an abnormal postural response. Postural instability (along with freezing of gait) is the most common cause of falls and contributes significantly to the risk of hip fractures.52 The long latency to the onset of falls differentiates PD from other neurodegenerative disorders, such as progressive supranuclear palsy (PSP) and multiple systems atrophy (MSA).53 In one study, the average time from onset of symptoms to the first fall was 108 months in patients with PD compared with 16.8 and 42 months, respectively, in patients with PSP and MSA.52

Several other factors also influence the occurrence of postural instability in patients with PD. These include other parkinsonian symptoms, orthostatic hypotension, age related sensory changes and the ability to integrate visual, vestibular and proprioceptive sensory input (kinesthesia).54 55 The fear of falling can further impair balance control in patients with PD.56 In one study, 38% of those evaluated experienced falls, and 13% fell more than once a week.57 As expected, the frequency of falls correlated with the severity of disease.57 Treatment (dopaminergic therapy, pallidotomy, deep brain stimulation) can improve some axial signs58 but usually does not robustly improve postural instability, measured by platform tilt and visual tilt.59 Targeting other nuclei for deep brain stimulation in addition to the subthalamic nucleus and globus pallidus, such as the zona incerta and pedunculopontine nucleus, is being explored as a potential surgical treatment of gait difficulties and postural stability.60

Freezing Freezing, also referred to as motor blocks, is a form of akinesia (loss of movement) and is one of the most disabling symptoms of PD.61 Although freezing is a characteristic feature of PD, it does not occur universally.62 Based on responses by 6620 patients to a questionnaire sent to 12 000 members of the German Parkinson Association, 47% of patients reported freezing; it occurs more frequently in men than in women and less frequently in patients whose main symptom is tremor.63 Freezing most commonly affects the legs during walking, but the arms and eyelids can also be involved.64 It typically manifests as a sudden and transient (usually <10 s) inability to move. This may include hesitation when beginning to walk (start hesitation) or a sudden inability to move the feet during specific situations (eg, turning or walking through a narrow passage, crossing busy streets, approaching a destination). Freezing is associated with substantial social and clinical consequences for patients. In particular, it is a common cause of falls.62

Five subtypes of freezing have been described: start hesitation, turn hesitation, hesitation in tight quarters, destination hesitation and open space hesitation.65 Episodes are more severe in the OFF state and are mitigated by levodopa therapy. In addition, patients often develop tricks to overcome freezing attacks. This includes marching to command, stepping over objects (eg, a walking stick, cracks in the floor), walking to music or a beat, and shifting body weight.66–68

Risk factors for the development of freezing include the presence of rigidity, bradykinesia, postural instability and longer disease duration.61 In contrast, tremor at disease onset is associated with a decreased risk of freezing. As freezing typically occurs later in the course of the disease or is not the predominant symptom, alternative diagnoses should be considered when these presentations occur. Freezing, particularly when it occurs during the ON period, does not usually respond to dopaminergic therapy, but patients treated with selegiline have been found to be at lower risk.69 Botulinum toxin injections, although effective for a variety of parkinsonian symptoms such as tremors, dystonia and sialorrhoea, have not been found consistently effective in the treatment of freezing.70

Other motor abnormalities Patients with PD may exhibit a number of secondary motor symptoms that may impact on their functioning at home, at work and while driving.71 Because of a breakdown of the frontal lobe inhibitory mechanisms, some patients display a re-emergence of primitive reflexes.72 73 One study that included 41 patients with PD found that the primitive glabellar reflex was present in 80.5% of patients.74 This symptom was a moderately sensitive (83.3%) indicator of a parkinsonian disorder but was not specific (47.5%) for PD. Patients with PD in this study also experienced an increased frequency (34.1%) of the palmomental reflex. This symptom was not sensitive (33.3%) but was more specific (90%) than the glabellar reflex. In addition, these primitive reflexes cannot differentiate among the three most common parkinsonian disorders (PD, PSP, MSA).74 Similarly, the "applause sign", initially thought to be specific for PSP, is frequently present in other parkinsonian disorders, particularly corticobasal degeneration.75 In some cases, unintended movements accompany voluntary activity in homologous muscles on the opposite side of the body. These so-called mirror movements may be observed in early asymmetric PD.76

Bulbar dysfunction manifested by dysarthria, hypophonia, dysphagia and sialorrhoea, frequently observed in patients with PD, can be equally or even more disabling than the cardinal features. These symptoms are thought to be related to orofacial–laryngeal bradykinesia and rigidity.77 Speech disorders in patients with PD are characterised by monotonous, soft and breathy speech with variable rate and frequent word finding difficulties, referred to as "tip-of-the-tongue phenomenon."78 79 Speech therapy, such as the Lee Silverman Voice Treatment,80 that emphasises efforts to improve the volume and quality of the speech, may ameliorate the symptoms of dysarthria. Dysphagia is usually caused by an inability to initiate the swallowing reflex or by a prolongation of laryngeal or oesophageal movement. Dysphagia is often subclinical, particularly in the early course of the disease.81 PD related drooling may result from a decrease in swallowing.25

A number of neuro-ophthalmological abnormalities may be seen in patients with PD. These include decreased blink rate, ocular surface irritation, altered tear film, visual hallucinations, blepharospasm and decreased convergence.82 The degree of abnormality in ocular pursuit and saccades as well as antisaccades83 is related to the degree of disease progression.84 Dopaminergic therapy generally improves these changes, but one study found no difference in smooth ocular pursuit between ON and OFF periods in patients with PD.85 Other neuro-ophthalmological abnormalities associated with PD include apraxia of eyelid opening, limitation of upward gaze and oculogyric crises.86 87

Respiratory disturbances in patients with PD can be restrictive or obstructive.88 These complications are associated with substantial morbidity and mortality; pneumonia is an independent predictor of mortality in nursing home patients with PD.89 The obstructive pattern may be related to rigidity, cervical arthrosis or restricted range of motion in the neck, and the restrictive pattern may be related to chest wall rigidity.90 Respiration may also be compromised by levodopa related respiratory dyskinesia in patients with PD.91

Non-motor features Non-motor symptoms are a common and under appreciated feature of PD.92 These include autonomic dysfunction, cognitive/neurobehavioral disorders, and sensory and sleep abnormalities.

Autonomic dysfunction Autonomic failure may be the presenting feature of PD, although it is more typically associated with MSA. Features include orthostatic hypotension, sweating dysfunction,93 sphincter dysfunction and erectile dysfunction.94 95 A community based study found that 47% (42/89) of PD patients met the diagnostic criteria for orthostatic hypotension.96

Cognitive and neurobehavioural abnormalities Neuropsychiatric disturbances can be as disabling as motor symptoms. The Sydney Multicenter Study of PD found that 84% of patients evaluated showed cognitive decline and that 48% met the diagnostic criteria for dementia after 15 years of follow-up.97 Another community based prospective study found that patients with PD are at almost sixfold increased risk for dementia.98 PD related dementia is also associated with a number of other neuropsychiatric comorbidities. Among 537 such patients, depression (58%), apathy (54%), anxiety (49%) and hallucinations (44%) were frequently reported.99 In a study of 114 patients with PD, 27.6% screened positive for depression during the average 14.6 months of follow-up; 40% were neither treated with antidepressants nor referred for further psychiatric evaluation.100 In addition to cognitive and affective disorders, many patients with PD exhibit features of obsessive–compulsive and impulsive behaviour, such as craving (especially for sweets),101 binge eating, compulsive foraging, hypersexuality, pathological gambling, compulsive shopping and punding, characterised by intense fascination with repetitive handling, examining, sorting and arranging of objects.102 These behavioural symptoms, sometimes referred to as "hedonistic homeostatic dysregulation", have been attributed to dopamine dysregulation syndrome associated with the use of dopaminergic drugs, particularly dopamine agonists, but the mechanism of these aberrant behaviours is not well understood.103 Cognitive and behavioural dysfunction in PD is not well understood, and its discussion is beyond the scope of this article; the reader is referred to some recent reviews of this topic.104

Sleep disorders Although sleep disturbances (eg, excessive sleepiness, sleep attacks) were once largely attributed to the pharmacological therapy for PD,105 some clinicians now believe that these features are an integral part of the disease.106 This is supported by the observation that rapid eye movement sleep behaviour disorder, which occurs in approximately one-third of patients with PD, is a substantial risk factor for the development of PD.107–110 Rapid eye movement sleep behaviour disorder, now considered a pre-parkinsonian state, is characterised by an increase in violent dream content110 accompanied by talking, yelling, swearing, grabbing, punching, kicking, jumping and other dramatic, violent and potentially injurious motor activity which may also involve the bed partner. Insomnia, particularly sleep fragmentation, is also frequent (>50% prevalence), but the occurrence is highly variable among patients.111 112 The sleep abnormalities observed in patients with PD may possibly be related to a 50% loss of hypocretin (orexin) neurons.113 114 Although excessive daytime sleepiness may contribute to fatigue, this common symptom is also seen independently of sleepiness.115

Sensory abnormalities Sensory symptoms such as olfactory dysfunction, pain, paresthesia, akathisia, oral pain and genital pain are frequent but are often not recognised as parkinsonian symptoms.41 116–121 One study found that olfactory dysfunction (hyposmia) may be an early marker of PD; it correlated with a 10% increased risk for the disease 2 years later compared with other asymptomatic relatives.122 A study involving 62 pairs of twins discordant for PD found that smell identification was reduced in twins affected with PD than in those who were asymptomatic.123 It has been postulated that olfactory dysfunction is related to either neuronal loss in the corticomedial amygdala124 or to decreased dopaminergic neurons in the olfactory bulb.