According to the International Parkinson and Movement Disorder Society (MDS), full diagnostic certainties is impossible during life and between 75% and 95% of patients only have their diagnosis confirmed on autopsy.
PD has a prevalence of about 3% in the age group over 60, and becomes increasingly common with advancing age, particularly affecting men. The epidemiology of the condition is unknown in SA and limited in Africa, although it is thought to be commonest in people of Northern European origin, according to Carr et al.
Factors influencing diagnostic accuracy
Diagnostic accuracy is influenced by disease duration (lower on first visit than after longer follow-up), age, the expertise of the clinician, and evolution in the understanding of PD. As a result, diagnostic accuracy varies considerably.
Failure to recognise other pathologies causing neurodegenerative or secondary parkinsonism (e.g. multiple system atrophy, progressive supranuclear palsy, subcortical arteriosclerotic encephalopathy), or the absence of a true progressive parkinsonian disorder (e.g. essential tremor, dystonic tremor) contribute to diagnostic error, according to the MDS.
In an attempt to address some of the diagnostic challenges in PD, the MDS developed new criteria, which were designed to be broadly applicable without need for ancillary diagnostic testing. However, stressed the authors, in some instances, ancillary testing is required to resolve uncertain cases.
In future, diagnostic biochemical markers, anatomical neuroimaging, and methods to detect Alpha-synuclein deposition may become available to assist physicians in making more accurate diagnoses.
Clinical diagnostic criteria
The MDS criteria use a two-step PD diagnosis process. Firstly, parkinsonism is defined (as bradykinesia in combination with either rest tremor, rigidity, or both). Secondly, once a diagnosis is made, the criteria then define whether this parkinsonism is attributable to PD.
Criteria for parkinsonism
The prerequisite to apply the MDS-PD criteria is the diagnosis of parkinsonism, which is based on three cardinal motor manifestations. These are bradykinesia, in combination with either rest tremor, rigidity, or both. These features must be clearly demonstrable and not attributable to confounding factors.
Several studies have shown that mild parkinsonian syndromes are seen in up to 25% of elderly persons without PD. The authors pointed out that this mild nonspecific parkinsonism may be unrelated to synuclein deposition.
The aim of the parkinsonism criteria is to differentiate parkinsonism caused by clinical PD from these common mild parkinsonian syndromes. An additional aim is to create a threshold for identifying when a patient has evolved from prodromal PD to full clinical PD.
Definition of cardinal parkinsonism
Bradykinesia: Defined as slowness of movement and decrement in amplitude or speed (or progressive hesitations/halts) as movements continue. Bradykinesia can be evaluated by using finger tapping hand movements, pronationsupination movements, toe tapping and foot tapping. Bradykinesia can also occur in voice, face, and axial/gait domains. Limb bradykinesia must be documented to establish a diagnosis of PD.
Rigidity: Judged on ‘slow passive movement of major joints with the patient in a relaxed position and the examiner manipulating the limbs and neck’. Rigidity refers to ‘leadpipe’ resistance. That is, velocity-independent resistance to passive movement not solely reflecting failure to relax (e.g. distinct from spasticity or paratonia), explained the authors.
Cogwheel phenomenon is often present and may reflect tremor incidentally felt while assessing tone. Isolated ‘cogwheeling’ without ‘leadpipe’ rigidity does not fulfil minimum requirements for rigidity.
Rest Tremor: Refers to a 4- to 6-Hz tremor in the fully resting limb, which is suppressed during movement initiation. Rest tremor can be assessed during the interview and examination. However, kinetic and postural tremors alone do not qualify for parkinsonism criteria.
The authors noted that in parkinsonian rest tremor in the hand also can be observed with prolonged posture, but to meet the criteria, tremor also must be observed during rest.
Diagnostic criteria for PD
Having established that the patient has parkinsonism, the MDS-PD criteria can be used to determine whether the patient meets the requirements for PD as the cause of parkinsonism:
Diagnosis of clinically established PD requires:
- Absence of absolute exclusion criteria.
- At least two supportive criteria.
- No red flags.
Diagnosis of clinically probable PD can be made in:
- Absence of absolute exclusion criteria.
- Presence of red flags counterbalanced by supportive criteria. If one red flag is present there must also be at least one supportive criterion and if two are present, at least two supportive criteria are needed. If there are more than two red flags, clinically probable PD cannot be diagnosed, noted the authors.
- Clear and dramatic beneficial response to dopaminergic therapy. To meet this criterion, during initial treatment, patients should have returned to normal or near-normal level of function. In the absence of clear documentation of initial response (e.g. initial treatment with lower-efficacy agents or very low dose), a dramatic response also can be classified as: Marked improvement with dose increases or marked worsening with dose decreases. The authors stressed that mild changes with dose changes do not qualify. This can be documented either objectively (defined as >30% in unified PD rating scale III with change in treatment), or subjectively with a clear history of marked changes provided by a reliable patient or caregiver or as unequivocal and marked on/off fluctuations, which must have at some point included predictable end-of-dose wearing off.
- Presence of levodopa-induced dyskinesia.
- Rest tremor of a limb, documented on clinical examination (in the past, or on current examination).
- Positive results from at least one ancillary diagnostic test having specificity greater than 80% for differential diagnosis of PD from other parkinsonian conditions. Currently available tests that meet this criterion include: Olfactory loss and metaiodobenzylguanidine scintigraphy.
Absolute Exclusion Criteria
- For all absolute exclusion criteria and red flags, the criterion is assumed to not be met because of an alternate unrelated cause. For example, unilateral cerebellar abnormalities attributable to a cerebellar hemisphere stroke, or a wheelchair-bound state attributable to spinal cord injury would not necessarily be exclusion criteria.
- The presence of any of these features rules out PD:
- Unequivocal cerebellar abnormalities on examination, such as cerebellar gait, limb ataxia.
- Cerebellar oculomotor abnormalities (e.g. sustained gaze-evoked nystagmus, macro square wave jerks, and hypermetric saccades).
- Downward vertical supranuclear gaze palsy.
- Selective slowing of downward vertical saccades
- Diagnosis of probable behavioural variant frontotemporal dementia or primary progressive aphasia, defined according to consensus criteria within the first five years of disease.
- Parkinsonian features restricted to the lower limbs for more than three years.
- Treatment with a dopamine receptor blocker or a dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism.
- Absence of observable response to high-dose levodopa despite at least moderate severity of disease. To meet this criterion, patients must have received a sufficiently high dose of levodopa daily (>600 mg/d). For patients who are untreated, or who have received less than 600 mg levodopa, this criterion cannot be applied.
- Unequivocal cortical sensory loss (e.g. graphesthesia, stereognosis with intact primary sensory modalities), clear limb ideomotor apraxia, or progressive aphasia.
- Normal functional neuroimaging of the presynaptic dopaminergic system. This criterion does not imply that dopaminergic functional imaging is required for diagnosis. If no imagining has been done, this criterion does not apply.
- Documentation of an alternative condition known to produce parkinsonism and plausibly connected to the patient’s symptoms, or the expert evaluating physician, based on the full diagnostic assessment, believes that an alternative syndrome is more likely than PD. This criterion includes not only rare conditions that can mimic PD, but also can include the more common alternative parkinsonian syndromes. Dementia with Lewy Bodies is not considered an alternative parkinsonian syndrome according to this criterion.
- Rapid progression of gait impairment requiring regular use of wheelchair within five years of onset.
- A complete absence of progression of motor symptoms or signs over five or more years unless stability is related to treatment. This criterion is targeted at patients who may have been misdiagnosed with parkinsonism. This must be defined based on observation (e.g. historical information cannot suffice). The absence of progression must be continuous over a five a minimum of five years.
- Early bulbar dysfunction, defined as one of severe dysphonia, dysarthria (speech unintelligible most of the time), or severe dysphagia (requiring soft food, nasogastric tube or gastrostomy feeding) within the first five years of disease.
- Inspiratory respiratory dysfunction defined as either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs.
- Severe autonomic failure in the first five years of disease. This can include: Orthostatic hypotension (orthostatic decrease of blood pressure within three minutes of standing by at least 30mmHg systolic or 15mmHg diastolic, in the absence of dehydration, medication, or other diseases that could plausibly explain autonomic dysfunction) or severe urinary incontinence or urinary retention in the first five years of disease (excluding longstanding low-volume stress incontinence in women), which is not simply functional incontinence (e.g. inability to get to the bathroom in a reasonable time). In men, urinary retention must not be caused by prostate disease, and this must be associated with erectile dysfunction.
- Recurrent (>1/y) falls because of impaired balance within three years of onset.
- The presence of disproportionate anterocollis (dystonic in nature) or contractures of hand or feet within the first 10 years.
- Absence of any of the common nonmotor features of disease despite five years’ disease duration. These include: Sleep dysfunction, autonomic dysfunction, hyposmia and psychiatric dysfunction. This criterion is designed primarily to detect nonparkinsonian conditions mimicking PD (e.g. subjects without evidence of dopaminergic deficit, dystonic tremor, and essential tremor).
- Otherwise unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyperreflexia (excluding mild reflex asymmetry in the more affected limb, and isolated extensor plantar response).
- Bilateral symmetric parkinsonism throughout the disease course. The patient or caregiver reports bilateral symptom onset with no side predominance, and no side predominance is observed on objective examination.
SA treatment guideline
According to Carr et al, treatment of PD is predominantly symptomatic should be individualised according to the stage of the illness.
Recommended treatment for early PD
In this stage of the disease, severity if mild and patients have limited signs, which typically involve one side of the body. Tremors is the predominant dysfunction. In this stage of the disease, severity if mild and patients have limited signs, which typically involve one side of the body. Tremors are the predominant dysfunction.
Despite some controversy, dopamine agonists are recommended as treatment in the early phase because they are associated with a lower incidence of dyskinesias, an important complication in patients with advancing PD.
Apart from dopamine agonists, other recommended therapies include amantidine and anticholinergic agents. The authors pointed out that there are some concerns about cognitive impairment in patients on the latter. Monoamine oxidase (MAO) inhibitors have a part to play in the treatment of early PD. Rasagiline, an MAO inhibitor, improves parkinsonian symptoms, and its potential role in slowing the progression of the degenerative process is being investigated.
Recommended treatment for moderate PD
During this stage of the disease, a patient has more obvious disease that impaired function. Addition of levodopa to the treatment regimen is an appropriate step. Domperidone is a useful agent that limits side-effects arising from the peripheral action of levodopa. Catechol-O-methyl transferase (COMT) inhibitors retard the breakdown of levodopa, resulting in more sustained dopamine levels. The claim that this may prevent later motor complications needs to be further substantiated, but there may be a role for early introduction of COMT inhibitors with levodopa, according to Carr et al.
Recommended treatment for moderate to severe PD
Patients in this stage of the disease have more advanced symptoms, which are frequently associated with motor fluctuations and an increasing burden of non-motor manifestations. Critical problems may include the short half-life and the narrow therapeutic window of levodopa. Adding dopamine agonists, COMT inhibitors and MAO-B inhibitors help overcome this problem.
Specific categories of disability requiring intervention
- Dyskinesias: Amantadine, botulinum toxin, surgery.
- Autonomic dysfunction: Fludrocortisone, pyridostigmine, treatment of bladder dysfunction (urinary antispasmodics), treatment of constipation (bulk laxatives, osmotic laxatives). Psychosis: Modify regimen, atypical antipsychotics (quetiapine, clozapine).
- Depression: Selective serotonin reuptake inhibitors (SSRIs), mirtazapine, tricyclics, tetracyclic agents.
- Anxiety: SSRIs, benzodiazepines (include sublingual forms).
- Rapid eye movement sleep behaviour disorder: Benzodiazepines.
- Hypersalivation: Botulinum toxin, atropine drops.
Surgical intervention for PD
Suggested indications for surgical intervention:
- Severe fluctuations, with preservation of responsiveness to levodopa.
- Tremor resistant to medical treatment.
- Moderate to severe dyskinesias.
Exclusion criteria for surgical intervention:
- Severe non-motor symptoms.
- Severe gait disorder unresponsive to levodopa.
- Ongoing poorly controlled neuropsychiatric disturbance.
Postuma RB, Berg D, Stern M et al. MDS Clinical Diagnostic Criteria for Parkinson’s Disease. Movement Disorders, 2016.
Carr J, Kies B, Fine J et al. Guideline for the treatment of Parkinson’s disease. SAMJ, 2009.