INTRODUCTION
Parkinson’s disease (PD) is a prevalent and progressive neurodegenerative condition, primarily recognized as a movement disorder. Affecting approximately 1% of individuals over the age of 65, PD is characterized by a combination of bradykinesia, rigidity, and tremor. However, the clinical presentation of PD is highly variable, encompassing a spectrum of non-motor symptoms such as cognitive impairment and sleep disturbances. Diagnosis remains clinical, relying on the identification of these cardinal features and the exclusion of other conditions that can manifest as parkinsonism. This article provides an in-depth guide on recognizing the core motor and non-motor symptoms of PD, distinguishing them from atypical signs that suggest alternative diagnoses. We will outline the essential differential diagnoses, categorized into neurodegenerative, secondary, genetic, and tremor disorders, as well as non-neurological conditions that may mimic PD.
Clinical Diagnostic Criteria for Parkinson’s Disease: Movement Disorder Society Guidelines
DIAGNOSING IDIOPATHIC PARKINSON’S DISEASE
The cornerstone of PD diagnosis is establishing the presence of “parkinsonism,” a clinical syndrome defined by bradykinesia combined with at least one of the following: tremor or rigidity. Bradykinesia, or slowness of movement, is mandatory for a parkinsonism diagnosis. PD typically presents asymmetrically, with symptoms more pronounced on one side of the body, particularly in the early stages, potentially manifesting as purely unilateral parkinsonism. Classical depictions of parkinsonism, such as those by William Gowers, highlight these key features.
Parkinson’s Disease Presentation: As Described by William Gowers
Once parkinsonism is confirmed, the critical next step in diagnosing PD is to rule out other potential causes. This involves a thorough evaluation of the patient’s history and physical examination to identify any atypical features. Beyond parkinsonism, several additional factors support a clinical diagnosis of PD. Non-motor symptoms, often appearing even in the early stages, play a significant role. Treatment response and the longitudinal evolution of the clinical syndrome are also crucial diagnostic elements. These aspects are detailed below and are integrated into the Movement Disorder Society’s clinical diagnostic criteria as exclusion criteria, supportive criteria, and “red flags.”
Bradykinesia: Slowness of Movement
Bradykinesia manifests as slowness and a reduction in spontaneous movements. Patients may report difficulties with fine motor skills, such as buttoning clothes, or notice changes in speech, such as a quieter, monotonous voice (hypophonia). Increased salivation due to infrequent swallowing can also be a sign. Bradykinesia can be observed even before a formal examination through a lack of typical gestures, reduced fidgeting, decreased facial expression (hypomimia), and less frequent blinking. Gait observation as the patient enters the clinic can reveal reduced arm swing, short, shuffling steps, and a stooped posture.
Specific examination techniques to elicit bradykinesia include repetitive hand movements like finger tapping or pronation/supination, and foot tapping for lower limbs. Parkinsonian bradykinesia is characterized not only by slowness but also by a progressive decrease in speed and amplitude during these repetitive movements. Handwriting changes, such as micrographia (small, cramped handwriting that gets progressively smaller) and sentences trailing off the line, are further indicators of bradykinesia.
It’s important to differentiate true parkinsonian bradykinesia from other conditions causing slow movements, such as psychomotor retardation in depression, pain from arthritis, cerebellar ataxia, or dyspraxia. In ambiguous cases, considering other examination findings and assessing for global bradykinesia is crucial.
Tremor: Parkinsonian Rest Tremor
Parkinsonian tremor is classically described as a “pill-rolling” tremor (pronation/supination) with a low frequency (4–6 Hz). It typically starts unilaterally and may become bilateral, but usually remains asymmetric. The tremor is most evident in the distal parts of limbs, such as the hand. Characteristically, it occurs at rest and diminishes or disappears during voluntary movement. In early PD, tremor may be intermittent, often noticed during relaxation, such as while watching television, making observation throughout the consultation important. The tremor can also become more pronounced when the patient is engaged in another task, like counting backward or walking. A re-emergence phenomenon, where the tremor disappears after movement and then reappears after a short delay, is also characteristic. While commonly associated with PD, tremor is not a necessary diagnostic criterion; a significant proportion of PD patients never develop tremor. Studies indicate that approximately 69% of patients present with rest tremor at disease onset, and about 75% will experience tremor at some point during their disease course.
Rigidity: Muscle Stiffness
Patients often report unilateral pain or stiffness, particularly in the shoulder, which can be an early symptom of PD. This can lead to initial misdiagnosis as frozen shoulder or referrals to rheumatologists or orthopedic surgeons.
Rigidity is assessed through passive joint movements (flexion, extension, and rotation) with the patient relaxed. It is often most palpable at the wrist and may only become apparent in early stages with reinforcement maneuvers, such as asking the patient to perform movements on the contralateral side (e.g., raising the arm). While slight tone increase with reinforcement can be normal, in PD, the rigidity is independent of velocity and is described as “lead-pipe” resistance, sometimes accompanied by a “cogwheel” phenomenon due to superimposed tremor.
Non-Motor Features: Beyond Movement
Non-motor symptoms significantly contribute to the diagnostic certainty of PD. A pre-motor phase, potentially representing the onset of neurodegeneration, is increasingly recognized. Years before motor symptoms manifest, individuals who later develop PD commonly experience depression, constipation, anosmia, and REM sleep behavior disorder. While these symptoms are non-specific and common in older adults, their presence adds weight to a PD diagnosis and should be specifically inquired about during consultation.
Other non-motor features can emerge at any point during the disease progression. Subtle cognitive deficits, often affecting attention, executive functions, visuospatial abilities, and memory, can be present even at diagnosis. Neuropsychiatric symptoms, including depression, anxiety, apathy, and psychosis, are also frequent. Psychosis in PD can range from minor illusions to formed hallucinations and delusions, sometimes leading to paranoid behavior. Autonomic dysfunction can manifest as urinary frequency or urgency, constipation, orthostatic hypotension, drooling, erectile dysfunction, or abnormal sweating.
These non-motor symptoms often develop insidiously and are not always volunteered by patients, who may not associate them with PD. Importantly, they are typically not addressed by dopaminergic therapies primarily prescribed for motor symptoms. Active screening for these non-motor features, such as checking blood pressure and inquiring about sleep, is essential, as they can significantly impact quality of life. Effective treatments are available for many non-motor symptoms, similar to motor symptoms.
Disease Progression: A Hallmark of Parkinson’s
Progression is a crucial diagnostic feature of PD. Patients typically present to clinics with a history of worsening symptoms that prompted them to seek medical advice. Monitoring disease progression at subsequent reviews is vital. Lack of progression or unusually rapid progression may indicate an alternative diagnosis. However, the rate of progression varies widely in PD. About 20% of patients remain well and experience few disease-related complications ten years post-diagnosis, while approximately 40% may develop dementia. Patients responding well to medication may experience extended periods of symptom stability, sometimes misinterpreted as a “cure.”
As PD progresses, other motor features become evident. Gait impairment becomes more pronounced, with patients adopting a stooped posture and reduced arm swing. Arm posture may become abnormally flexed during walking. Classic features include a flexed neck and camptocormia (truncal flexion at the thoracolumbar spine). Shuffling steps can progress to festination, characterized by increasingly shorter steps. Postural instability develops, significantly impacting quality of life and increasing fall risk. Freezing of gait, a disabling symptom with high fall risk, may also emerge, where patients are unable to initiate or continue walking, feeling as if their feet are stuck. This often occurs during turns, in narrow spaces, or when starting to walk.
A positive clinical response to levodopa, particularly in bradykinesia and rigidity, supports PD diagnosis. Levodopa’s effect on tremor is more variable. The development of dyskinesias or choreiform involuntary movements with dopaminergic therapy also supports the diagnosis, typically emerging as the disease progresses and with longer medication duration.
OTHER NEURODEGENERATIVE CAUSES OF PARKINSONISM
Several neurodegenerative conditions can mimic idiopathic PD, and differentiating them can be challenging, sometimes only becoming clear over time. Recognizing key historical and examination features is essential for accurate differential diagnosis.
Dementia with Lewy Bodies (DLB)
Dementia with Lewy bodies (DLB) is the second most common cause of dementia after Alzheimer’s disease. DLB is characterized by progressive cognitive decline accompanied by fluctuating attention, visual hallucinations, REM sleep behavior disorder, and parkinsonism. Both PD and DLB share Lewy body pathology, primarily composed of α-synuclein, indicating a significant clinical and pathological overlap. Diagnostic criteria distinguish DLB from Parkinson’s disease dementia (PDD) based on the timing of cognitive symptoms: if cognitive impairment precedes or develops within a year of parkinsonism onset, the diagnosis is DLB; if cognitive impairment develops in established PD, it’s PDD.
Cognitive impairment in DLB predominantly affects attentional-executive and visuospatial functions. Patients typically perform poorly on tasks like the Stroop test, trail-making tests, and drawing tasks, such as clock-drawing or interlocking pentagons. Fluctuating attention can manifest as inconsistent performance and periods of “zoning out.” Major fluctuations in cognitive state are a highly suggestive diagnostic feature of DLB. Visual hallucinations, occurring in approximately 80% of DLB patients, are often complex and involve humans or animals, with varying levels of patient insight.
DLB Cognitive Impairment: Interlocking Pentagon Task Difficulty
Supportive features for DLB include neuroleptic sensitivity, postural instability and falls, autonomic dysfunction, and neuropsychiatric symptoms like depression, apathy, anxiety, delusions, and hallucinations in other modalities. Management is multidisciplinary. Parkinsonism in DLB is often less responsive to dopaminergic therapies, which can worsen cognition and behavior. Cholinesterase inhibitors and low-dose quetiapine may be used to manage neuropsychiatric symptoms. When cognitive or behavioral issues arise, reversible causes like infection or subdural hematoma should always be considered.
Multiple System Atrophy (MSA)
Multiple system atrophy (MSA) is another α-synucleinopathy, rarer than PD. MSA involves a constellation of clinical features, including parkinsonism, cerebellar ataxia, autonomic failure, urogenital dysfunction, and corticospinal involvement, with relatively preserved cognition. MSA is categorized into MSA with predominant parkinsonism (MSA-P) and MSA with predominant cerebellar ataxia (MSA-C).
Parkinsonism in MSA is typically rapidly progressive and poorly responsive to levodopa. Bradykinesia and rigidity are usually prominent, while classic pill-rolling tremor is uncommon. Early MSA can be difficult to differentiate from PD, as symptoms are often asymmetric, and up to 30% of MSA patients show an initial response to levodopa. Dyskinesias can occur in MSA patients treated with levodopa, but they are often atypical, presenting as prolonged facial dystonia or torticollis.
Autonomic failure is almost always present at MSA presentation, whereas it typically occurs later in PD. This includes orthostatic hypotension, urinary incontinence, and erectile dysfunction. Features pointing towards MSA, not typically seen in PD, include stridor, Babinski sign, and cerebellar ataxia (gait or limb ataxia, dysarthria, oculomotor dysfunction). Myoclonus, particularly “poly-mini-myoclonus” (stretch-sensitive finger jerks), is also more characteristic of MSA than PD.
MRI can aid in differentiating PD from MSA by revealing brainstem and basal ganglia changes suggestive of MSA, including the “hot cross bun” sign. However, this sign is often only recognized by radiologists familiar with these syndromes. The key differentiator between MSA and PD is poor levodopa response and early involvement of systems outside the striatum, leading to prominent gait and autonomic problems early in the disease course.
Progressive Supranuclear Palsy (PSP)
Progressive supranuclear palsy (PSP) is a tauopathy that typically presents differently from PD. Onset is usually in the 60s, with walking difficulties, unsteadiness, falls, and visual symptoms like dry eyes and blurred vision. Parkinsonism in PSP is generally symmetrical, predominantly axial, and poorly responsive to levodopa. Axial rigidity in PSP results in a posture distinct from the stooped posture of PD patients; PSP patients tend to be upright, sometimes with retrocollis. Postural instability is early and pronounced in PSP, leading to frequent falls, often backwards, especially during turns, assessed clinically by the pull test. Freezing of gait can also be prominent and levodopa-resistant.
Eye movement abnormalities are characteristic of PSP. Early on, these may be subtle, such as square wave jerks or slowed vertical saccades. As PSP progresses, restriction of vertical eye movements develops, which can be overcome with vestibulo-ocular reflex activation. However, mild upgaze limitation can be normal in older adults.
PSP is associated with behavioral and cognitive syndromes, often present at initial presentation. Apathy is common (around 80% of patients), as is impulsivity. Cognitive deficits primarily involve executive functions and verbal fluency.
Neuroimaging, particularly MRI, can be helpful in PSP diagnosis, revealing midbrain atrophy and the “hummingbird sign” (sagittal midbrain atrophy resembling a hummingbird’s head and beak). Key differentiators between PSP and PD are poor levodopa response, early falls, eye movement abnormalities, and rapid progression.
Corticobasal Syndrome (CBS)
Corticobasal syndrome (CBS) is another tauopathy with clinical and pathological heterogeneity. Besides classical CBS presentation, other phenotypes linked to corticobasal degeneration pathology include frontal behavioral-spatial syndrome, non-fluent primary progressive aphasia, and a PSP-like syndrome.
CBS diagnosis is primarily clinical, based on motor features. It causes asymmetric limb rigidity or akinesia, potentially resembling PD parkinsonism. However, CBS often involves dystonia and myoclonus, and the parkinsonism is typically levodopa-resistant and may affect axial muscles. Tremor can occur, but it’s not the typical rest tremor of PD.
Higher cortical features are crucial for distinguishing CBS from PD. These include apraxia, cortical sensory loss, progressive non-fluent aphasia, and alien limb phenomenon (the limb feels foreign, has its own will, or performs unintentional complex actions). Cognitive impairment in CBS is varied, affecting executive function, episodic memory, visuospatial function, and cognitive flexibility. Behavioral changes, such as apathy, irritability, antisocial behavior, personality changes, and hypersexuality, can be prominent.
Imaging, particularly MRI, may show asymmetric atrophy primarily affecting frontal and parietal cortices, but it is not diagnostically conclusive.
SECONDARY CAUSES OF PARKINSONISM
Several secondary causes of parkinsonism must be considered before diagnosing idiopathic PD.
Drug-Induced Parkinsonism
Drugs acting on dopamine receptors in the central nervous system can induce parkinsonism and other movement disorders like tardive dyskinesia, akathisia, and dystonia. Antipsychotics are the most common cause, especially older “typical antipsychotics” like haloperidol and chlorpromazine, although these are now less frequently used. Atypical antipsychotics, such as risperidone and olanzapine, can also cause extrapyramidal side effects, including parkinsonism.
Other drugs inducing parkinsonism include antiemetics (metoclopramide, domperidone), calcium channel blockers (flunarizine, cinnarizine), antiepileptics (sodium valproate, phenytoin), dopamine-depleting drugs (tetrabenazine), and selective serotonin reuptake inhibitor antidepressants.
Drug-induced parkinsonism typically presents with symmetrical parkinsonism, prominent bradykinesia, and rigidity, but can closely mimic idiopathic PD. Symptoms usually resolve within weeks to months after discontinuing the offending drug. However, in some cases, the drug may unmask underlying early PD, in which case parkinsonism progresses despite drug cessation. DaTSCAN is useful in differentiating, as it is normal in drug-induced parkinsonism.
Toxins
The link between toxins and parkinsonism was first identified in the 1980s with intravenous drug users developing acute parkinsonism from MPTP, a contaminant in a pethidine analog. This led to MPTP use in creating animal models of PD.
Epidemiological studies have linked environmental toxin exposure to increased PD risk, including pesticides (rotenone, paraquat, organophosphates), solvents, and limited evidence for metals (lead, manganese, mercury). Environmental exposure appears to be one of several etiological factors in these cases. MRI brain scans in toxin-induced parkinsonism often show basal ganglia signal changes.
Acute carbon monoxide poisoning can cause parkinsonism, typically within a month of exposure. Clinical features include bradykinesia, rigidity, hypomimia, and gait disturbance, often alongside encephalopathy and frontal lobe signs like grasp reflex. Prognosis is generally good, with most patients fully recovering spontaneously.
Vascular Parkinsonism
Vascular parkinsonism, caused by cerebrovascular disease, is an important differential, especially in older adults, accounting for approximately 3–6% of parkinsonism cases. It has a different prognosis and treatment response compared to PD. Risk factors include increasing age, hypertension, prior TIAs, and diabetes mellitus. Vascular parkinsonism results from lesions affecting the substantia nigra or its projections, including subcortical white matter disease or lacunar infarcts.
Vascular parkinsonism has a distinct clinical presentation. It tends to be bilateral, symmetrical, and affects the lower limbs predominantly, causing a gait disorder. Gait is typically upright with a broad base, short steps, and normal arm swing, contrasting with the stooped posture, narrow base, and reduced arm swing of PD. Upper limbs are often spared, tremor is rare, and increased tone is a combination of spasticity and rigidity, with gegenhalten paratonia. Examination findings are often less pronounced when the patient is supine compared to when mobilizing. Progression is usually stepwise and rapid. Supporting features include extensor plantar response, brisk reflexes, pseudobulbar palsy, and cognitive impairment.
Both PD and cerebrovascular disease are common in older adults, leading to potential overlap and diagnostic challenges. Vascular disease findings on brain imaging are supportive but not conclusive, as similar changes can be seen in PD. DaTSCAN is usually normal in vascular parkinsonism, although basal ganglia infarcts can cause abnormal results. While vascular parkinsonism is generally considered levodopa-unresponsive, some patients may experience benefit. Levodopa trial is recommended in suspected vascular parkinsonism. Management focuses on rehabilitation and vascular risk factor control.
Normal-Pressure Hydrocephalus (NPH)
Normal-pressure hydrocephalus (NPH) is diagnosed by the classic triad of gait disorder, incontinence, and cognitive impairment or dementia, along with enlarged ventricles on imaging. NPH is also associated with parkinsonism in approximately 70% of cases. Bradykinesia is the most common parkinsonian feature, but rigidity and postural instability are also frequent. NPH, like PD, is a slowly progressive disorder of older adults.
The gait disorder in NPH can be very parkinsonian, with small, shuffling steps, turning difficulty, and falls. Urinary symptoms, part of NPH diagnostic criteria, are also common in PD. Cognitive impairment in NPH is similar to PD, with psychomotor slowing, daytime somnolence, and apathy.
Structural brain imaging is crucial if NPH is suspected as the cause of parkinsonism, especially because it’s a treatable condition. Approximately 80% of NPH patients improve after CSF shunt surgery. Differentiating NPH from brain atrophy on CT or MRI can be challenging, and neurosurgical consultation and CSF infusion studies may be needed if diagnosis is uncertain.
GENETIC CAUSES OF PARKINSONISM
Genetic testing should be considered in patients with young-onset parkinsonism (under 40) and a family history of PD. Atypical features can also suggest genetic etiologies.
Familial PD
Mutations in several genes are linked to familial PD. While phenotypes can vary, some are clinically indistinguishable from idiopathic PD, such as LRRK2 mutations. Well-documented genes include:
- SNCA gene: Mutations are associated with autosomal dominant early-onset parkinsonism. Clinical spectrum ranges from typical PD to aggressive syndromes with cognitive impairment and autonomic instability mimicking MSA. Myoclonus and hypoventilation can also occur. SNCA triplications often lead to severe phenotypes, while duplications are more common and tend to present as typical PD.
- LRRK2 gene: Mutations are a more common cause of autosomal dominant PD, often presenting as typical PD with variable onset age and less severe phenotype. LRRK2 mutations are frequent in people of South European, North African, or Ashkenazi Jewish descent.
- parkin, PINK1, and DJ-1 genes: Mutations are associated with early-onset parkinsonism with autosomal recessive inheritance. These typically have a slow progression, clinical features typical of PD, and good levodopa response. parkin mutations are most common, suggested by early onset, leg-dominant features, and slow progression over decades.
Wilson’s Disease
Wilson’s disease is a rare autosomal recessive disorder caused by ATPB7 gene mutations, leading to toxic copper accumulation. It typically presents in early adulthood but can manifest up to the sixth decade. It has hepatic, psychiatric, and neurological manifestations. Neurological presentation is primary in up to 68% of cases, involving dysarthria, tremor, dystonia, and parkinsonism. Progression can lead to choreoathetosis, ataxia, myoclonus, seizures, and eye movement abnormalities.
Parkinsonism in Wilson’s disease can closely mimic idiopathic PD, with asymmetric bradykinesia and rigidity. Rest tremor is less common but possible. Parkinsonian features rarely occur in isolation without other neurological signs. Hepatic and psychiatric involvement, with subclinical liver disease, are common in neurological presentations. Diagnostic tests include copper studies, slit-lamp examination for Kayser-Fleischer rings (usually present in neurological presentations), and genetic testing. Early diagnosis is crucial due to available effective treatments.
Huntington’s Disease
Huntington’s disease is a trinucleotide repeat disorder with autosomal dominant inheritance, typically presenting in middle age with chorea, cognitive, and behavioral features. However, parkinsonism is also recognized, particularly in juvenile Huntington’s disease (Westphal variant), associated with longer triplet repeats and younger onset. Juvenile Huntington’s presents with a parkinsonian hypokinetic rigid syndrome before age 20, often with cognitive and behavioral problems unlike typical PD.
Spinocerebellar Ataxia (SCA)
Spinocerebellar ataxias (SCAs) are progressive disorders primarily causing cerebellar degeneration, leading to ataxia. Many subtypes exist with heterogeneous clinical syndromes. Parkinsonism has been reported in SCA2, SCA3, and SCA17, sometimes mimicking MSA. These are autosomal dominant trinucleotide repeat disorders. SCA2 is most commonly associated with parkinsonism, which can be the presenting feature and mimic PD, including levodopa responsiveness. However, classical SCA2 presents with cerebellar ataxia and peripheral neuropathy, and ataxia tends to develop within a few years even in parkinsonian presentations.
SCA3 has subtypes, with type IV causing predominant, levodopa-responsive parkinsonism. Other types involve cerebellar ataxia and pyramidal signs with extrapyramidal rigidity, dystonia, or peripheral neuropathy. SCA3 type IV patients often have additional features atypical for PD, such as eye movement abnormalities and peripheral neuropathy.
SCA17 can also present with predominant parkinsonism in a subgroup of patients, clinically typical and levodopa-responsive PD. Other SCA17 features include cerebellar ataxia, epilepsy, dementia, psychosis, chorea, and dystonia.
Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder characterized by cerebellar ataxia and intention tremor, caused by a premutation CGG repeat expansion in the FMR1 gene. The premutation (55–200 repeats) typically presents in middle age with normal intelligence and characteristic imaging findings like increased T2 signal in the middle cerebellar peduncle. Besides cerebellar ataxia, FXTAS can also present with parkinsonism, including bradykinesia, postural instability, and rest tremor. Due to cerebellar features, FXTAS is often mistaken for MSA rather than PD.
Frontotemporal Dementia with Parkinsonism (FTDP)
Parkinsonism in frontotemporal dementia (FTD) is more common in the behavioral variant FTD and can precede or coincide with classic FTD syndrome. It can mimic idiopathic PD or resemble PSP or CBS. FTDP is associated with tau, TDP-43, or FUS pathology, and mutations in MAPT, PGRN, C9ORF72, FUS, and TARDBP genes. Rigidity and bradykinesia are usually more prominent parkinsonian features, with rest tremor being rare. Levodopa responsiveness is variable.
Neurodegeneration with Brain Iron Accumulation (NBIA)
Neurodegeneration with brain iron accumulation (NBIA) syndromes involve progressive extrapyramidal syndromes with iron deposition in basal ganglia. Pantothenate kinase-associated neurodegeneration (PKAN), caused by PANK2 gene mutations, is the most common NBIA. Classic PKAN presents in early childhood with pyramidal (spasticity, hyperreflexia) and extrapyramidal features (dystonia, parkinsonism). Rare adult-onset PKAN also exists. MRI typically shows the “eye-of-the-tiger” sign in the globus pallidus (central hyperintensity with surrounding low signal on T2 images).
PLA2G6-associated neurodegeneration (PLAN) is another main NBIA type. Infantile-onset PLAN causes progressive motor and mental retardation, cerebellar ataxia, seizures, and pyramidal signs. Later-onset PLAN can mimic PD, with rest tremor, rigidity, bradykinesia, and good levodopa response, but often with additional features like eye movement abnormalities and pyramidal signs.
Mitochondrial Disorders
Mutations in the POLG gene have been linked to early-onset parkinsonism. POLG is involved in mitochondrial DNA synthesis and repair, and its mutations are associated with various phenotypes, including progressive external ophthalmoplegia, ataxia, and peripheral neuropathy. Parkinsonism with bradykinesia and rigidity can also occur. This parkinsonism is often atypical for idiopathic PD, with symmetrical distribution, postural (not rest) tremor, and poor levodopa response.
Idiopathic Basal Ganglia Calcification (IBGC)
Idiopathic basal ganglia calcification (IBGC) is a heterogeneous disease with mineral deposition in basal ganglia and other brain structures. It often has a familial component, with SCL20A2 and PDGFRB gene mutations identified. IBGC commonly presents with movement disorders, including parkinsonian features of akinesia and rigidity with variable levodopa response. Other features include cognitive impairment, gait disorder, pyramidal signs, and psychiatric presentations. Imaging, particularly CT, is crucial for diagnosis to identify calcification areas.
TREMOR DISORDERS
Tremor is the most recognized symptom of PD, although not all PD patients develop tremor. Differentiating parkinsonian rest tremor from other tremor types is important.
Essential Tremor (ET)
Essential tremor (ET) is common, with increasing incidence with age, but can start at any age. It usually progresses slowly. The neuropathological basis is unknown, but there is a strong familial component. Patients often seek medical attention when concerned about PD or if tremor is disabling.
ET typically affects both upper limbs and occurs during action, either postural or kinetic. Tremor is often noticed during activities like writing or holding a cup. Alcohol may improve ET, and anxiety, illness, and tiredness worsen it. Tremor can also involve lower limbs, head, and voice. Diagnosis requires at least a 3-year history and absence of other neurological signs. ET is considered a heterogeneous syndrome, with some patients having subtle neurological signs, but consensus on including these in diagnosis is lacking.
ET is usually easily differentiated from PD rest tremor. However, some PD patients also have postural-action tremor. Cogwheeling rigidity can occur in any tremor syndrome, including ET. Re-emergent tremor, seen in PD, occurs several seconds after maintaining a posture. DaTSCAN can be helpful in differentiating ET from PD, especially in tremor-dominant, slowly progressive cases, as DaTSCAN is normal in ET.
Dystonic Tremor
Dystonic tremor is another common cause of tremor seen in neurology clinics. It occurs in body parts affected by dystonia. Assessing for abnormal posture, which may be subtle, is key. Dystonic tremor is caused by rhythmic muscle contractions, often inconsistent and “jerky.” It worsens with attempts to maintain normal posture. Cervical dystonia commonly causes dystonic head tremor, potentially with upper limb involvement. A “geste antagoniste,” a voluntary movement that corrects dystonic posture, is a diagnostic clue.
DaTSCAN is normal in dystonic tremor. Treatment of choice is typically local Botox injections.
NON-NEUROLOGICAL DIFFERENTIALS OF PARKINSON’S DISEASE
PD’s heterogeneous presentation, including non-motor symptoms, means it can present to specialties beyond neurology, such as rheumatology and psychiatry.
Arthritis
Pain is a common presenting non-motor symptom in PD, often leading to initial referrals to rheumatologists or orthopedic surgeons. Pain is usually related to the affected motor side and, with rigidity, can mimic a stiff joint. Frozen shoulder, degenerative spinal disease, and osteoarthritis are common initial misdiagnoses later revised to PD. Misdiagnosis can lead to unnecessary procedures like steroid injections and spinal surgery.
Rheumatological diseases can also resemble PD. Polyarthropathy joint stiffness can mimic PD rigidity, making it difficult to differentiate from bradykinesia clinically. Looking for decrement during bradykinesia examination, which is specific to PD, and exploring other supportive features and disease progression history are crucial. It’s also important to remember that PD patients can develop musculoskeletal disorders secondary to parkinsonian bradykinesia and rigidity.
Depression
Depression is common in PD, affecting up to 40% of patients, and can precede motor symptoms. Depression and PD commonly coexist and can be mistaken for each other. Psychomotor slowing in depression can mimic PD bradykinesia, and vice versa. Lack of facial expression and flat affect in depression can be confused with hypomimia in PD. Both conditions share comorbid features like sleep disturbance, anxiety, fatigue, apathy, and poor concentration.
Obsessional Slowness
Obsessional slowness is a rare motor presentation of obsessive-compulsive disorder (OCD) that can mimic PD. Motor slowness in obsessional slowness is separate from OCD obsessions and compulsions, though it occurs in patients with typical OCD features. Patients exhibit slow movement, poor speech, and difficulty initiating voluntary actions. However, motor slowness lacks the decrement seen in PD during repetitive actions, and DaTSCAN is normal. Motor speed may be normal for reflexive actions or during stress.
Psychogenic Parkinsonism (PP)
Psychogenic parkinsonism (PP), like other psychogenic movement disorders, is presumed to be a conversion or somatoform disorder, without conscious awareness or control. It can occur with other psychological or psychiatric disorders, and stress often plays a role.
PP diagnosis is based on identifying clinical features. Slowness in PP is effortful, without decrement, and improves with distraction. Rigidity is felt as active resistance and also improves with distraction. Tremor in PP has variable frequency, direction, and distribution, starts abruptly, and improves with distraction, unlike typical PD tremor. Postural stability testing may show bizarre or exaggerated responses without falls. Other functional neurological disorder signs, like “give-way” weakness, positive Hoover’s sign, or non-anatomical sensory loss, may be present.
CONCLUSION
Parkinson’s disease diagnosis is clinical, relying heavily on detailed history and thorough examination. Diagnostic certainty increases with positive treatment response and observed symptomatic decline over time. The differential diagnosis of PD is broad, encompassing many rare parkinsonism causes. While extensive investigation of all PD cases is not always necessary, maintaining an open mind regarding atypical features is crucial to consider alternative diagnoses.
Acknowledgment: R.A.Barker is supported by the Wellcome-MRC Cambridge Stem Cell Institute and an NIHR Senior Investigator. Both authors are supported by the NIHR Cambridge Biomedical Research Centre (Cambridge University Hospitals NHS Trust/University of Cambridge). The funding bodies had no role in the writing of this manuscript.
Conflict of interest: The authors declare no potential conflicts of interest with respect to research, authorship and/or publication of this article.
Copyright and permission statement: To the best of our knowledge, the materials included in this chapter do not violate copyright laws. All original sources have been appropriately acknowledged and/or referenced. Where relevant, appropriate permissions have been obtained from the original copyright holder(s).
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Doi: http://dx.doi.org/10.15586/codonpublications.parkinsonsdisease.2018.ch6
