A young adult with progressive limb shaking and slownessRT Chakor1, GC Rajadhyaksha2
1 Department of Neurology, T. N. Medical College, B. Y. L. Nair Ch Hospital, Mumbai, Maharashtra, India
2 Department of Medicine, T. N. Medical College, B. Y. L. Nair Ch Hospital, Mumbai, Maharashtra, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.85221
Source of Support: None, Conflict of Interest: None
A 32-year old man presented with history of right-hand tremor for 9 months and slowness for 6 months. The tremors were more at rest and decreased on action. Three months later, he noticed rest tremors in the right leg and later in the left hand and leg. There was no history of use of antipsychotics or similar medications. There was no history of exposure to toxins such as organophosphorus compounds and carbon monoxide (CO). There was history of similar illness in his sibling with the onset of illness at the age of 30 years. There was no history of parental consanguinity.
What are the common causes of rest tremor?
Reply: Parkinson disease (PD) is the most important cause of rest tremor.  Other Parkinsonian disorders such as multiple system atrophy, progressive supranuclear palsy, diffuse Lewy body disease have rest tremor. Heredodegenerative disorders such as Wilson disease, Huntington disease, and Neuroacanthocytosis have rest tremor. Secondary Parkinsonism More Details due to toxins such as MPTP 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) CO, manganese (Mn), methanol and dopamine receptor blocking drugs such as neuroleptics, dopamine depleting drugs (reserpine, tetrabenazine), lithium, valproate have rest tremor. Severe essential tremor, midbrain (rubral) tremor also have tremor at rest. 
Could you summarize the history?
Reply: This is a young adult with progressive Parkinsonism syndrome without any obvious secondary cause with nonaffected parents and history of similar illness in sibling.
What is Parkinsonism?
Reply: Parkinsonism is a syndrome manifested by a combination of six cardinal features. See [Table 1] for the features of Parkinsonism.
A combination of these signs is used to clinically define definite, probable, and possible Parkinsonism. Parkinsonism is said to be definite when at least two of these features are present, one of them being rest tremor or rigidity, probable when any one of these two features is present alone and possible when at least two of features 3 to 6 is present. This patient has tremors at rest and slowness (bradykinesia) so he has definite Parkinsonism syndrome.
His general physical examination was normal. There was no Kayser-Fleischer (KF) ring. On CNS examination, his higher mental functions were normal. Cranial nerves were normal. He had atrophy of the right calf as a residue of old polio. There was cogwheel rigidity bilaterally in the limbs, more on the right side. Power was normal except in the right leg distally where it was 3/5. Deep tendon reflexes were normal except absent right ankle jerk. The sensory system was normal. There were no cerebellar signs. He had rest tremors of 5-6 Hz frequency more in the right hand and right leg. He had bilateral limb bradykinesia that was more on the right side. Gait was normal except for a mild flexed posture. There was no loss of postural reflexes.
What do you conclude from the history and examination findings?
Reply: Examination confirms the findings of history namely rest tremors that are bilateral, right more than left. He has bradykinesia that is also bilateral and right more than left. He also has asymmetric cogwheel rigidity that is more on the right side. He has mild flexed posture. There is no KF ring. He has distal right leg weakness due to old polio, which is not contributory to the present illness.
Considering the age of onset, temporal profile, and history of similar illness in sibling this patient has young onset Parkinson disease (YOPD) with autosomal recessive inheritance.
What are the clinical criteria to diagnose PD?
Reply: The commonly used clinical criteria for diagnosis of PD are the UK Parkinson's Disease Society Brain Banks clinical criteria for the diagnosis of probable Parkinson disease [Table 2].
What is YOPD?
Reply: PD with onset between 20 to 40 years is referred to as YOPD.  Early onset Parkinson disease (EOPD) is arbitrarily defined as onset of PD before the age of 45 years. 
What are the causes of YOPD?
Reply: For causes of YOPD [Table 3].
What are the causes of secondary young onset Parkinsonism?
Reply: Parkinsonism due to acquired causes is secondary Parkinsonism. Postencephalitic Parkinsonism can follow Japanese encephalitis. Here there is history of acute encephalitic illness (fever, headache, and seizures). A Parkinsonian syndrome with dystonia is seen during recovery. Magnetic resonance imaging (MRI) may show gliotic lesions in the substantia nigra and thalamus.
Drug-induced Parkinsonism is the most common form of secondary Parkinsonism. Parkinsonian symptoms often indistinguishable from those seen in patients with PD may be evident within the first few days of neuroleptic therapy and nearly all cases become evident within 3 months after initiation of treatment. Neuroleptic Parkinsonism is usually seen in the elderly and in women.
Exposure to toxins like CO can result in a delayed relapsing encephalopathy with slow shuffling gait, bradykinesia, but little or no tremor. This develops after a 3-week recovery period from the acute exposure. Parkinsonism with short stepping gait and stiff legs but without the classical rest tremor may be seen in hydrocephalus. Brain tumors or granulomas (e.g. tuberculoma) involving the basal ganglia may cause unilateral or bilateral rigidity and bradykinesia. Associated features may include focal neurologic deficits, seizures, headache, and vomiting depending on the size and location of the lesions.
Discuss heredodegenerative young onset Parkinsonism?
Reply: Parkinsonism as an associated feature or as a dominant feature is seen in some heredodegenerative disorders. Wilson disease needs to be excluded in all young patients presenting with akinetic rigid syndrome. Facial rigidity, dystonia, drooling of saliva, dysarthria along with cognitive decline and psychiatric manifestations are the other features of Wilson disease. In neurological Wilson disease, patients almost always have a corneal KF ring due to deposition of Copper in Descemet's membrane.
The Westphal variant of Huntington disease with onset before 20 years can present as a Parkinsonism syndrome with additional dystonia, chorea, pyramidal features, and eye movement abnormalities. Progressive behavioral change and cognitive decline evolves into severe mental impairment in these patients.
What are the differentiating features between dopa responsive dystonia and young onset Parkinsonism?
Reply: Dopa responsive dystonia (DRD) is usually characterized by childhood onset of leg dystonia, diurnal fluctuation of symptoms, and a dramatic response to L-dopa therapy. Later in the course of the disease, parkinsonian features occur frequently. Parkinsonism in DRD responds well to L-dopa therapy, however, unlike in idiopathic PD, patients usually do not develop motor fluctuations and dyskinesias. Dominantly inherited DRD is caused by mutations in the GTP cyclohydrolase I (GCHI) gene (DYT5a). 
One of the recessive PARK genes (parkin) has to be considered in the differential diagnosis of a young individual presenting with prominent leg dystonia that is responsive to L-dopa therapy. For example, Parkin mutations have been demonstrated to account for some cases of ''GCHI mutation-negative DRD.'' Mutations in the tyrosine hydroxylase (TH) gene cause the rare autosomal recessive form of DRD (DYT5b).
In X-linked recessive dystonia Parkinsonism of Lubag, dystonic symptoms usually start in adulthood as focal dystonia. Symptoms progress and generalize with Parkinsonism being a frequent concurrent feature. Parkinsonism may also precede the onset of dystonia.
Which is the commonest genetic cause of EOPD?
Reply: The recently described (PARK 2) parkin gene mutation related PD is considered to be the predominant cause of EOPD, particularly when the family history is compatible with autosomal recessive inheritance (clinically unaffected parents, similar illness in sib) as in this patient. It accounts for approximately half of the familial cases with disease onset before age 40 years as well as 18% of the early onset apparently sporadic cases. Around 75% of those with onset before 20 years (juvenile PD) are due to parkin gene mutation.  This patient has onset of PD before the age of 40 and history of similar illness in sib; hence, parkin gene mutation related PD is a strong possibility.
What are the usual clinical features of parkin gene mutation related PD and what are the differentiating features among the various genetic causes of Parkinsonism?
Reply: Mutations in the genes encoding Parkin/PARK2, PINK1/PARK6, and DJ-1/PARK7 are considered the classic examples of young-onset Parkinsonism.  Parkin is the most commonly mutated gene in patients with young onset PD. Parkin-linked PD has a broad range of clinical phenotypes. Some features are atypical, but generally an early-onset Parkinsonism very similar to typical PD, with a slow clinical course, excellent response to low doses of levodopa is seen. The clinical phenotype is dominated by L-dopa responsive Parkinsonism with a benign course and a correlation between onset age and evolution. Dystonia usually affecting the lower limbs is a presenting sign in 40%. Pyramidal features in the form of brisk reflexes occur in about half of the patients. Overall, no clear clinical signs distinguishing idiopathic PD from parkin-related Parkinsonism have been identified. However, neuropathologically, parkin is distinct from idiopathic PD where Lewy bodies are a hallmark feature. In parkin, Lewy bodes are absent or scarce, although this remains a matter of debate. ,
Mutations in the PINK1-gene are much less common than Parkin mutations, and probably account for only 1-2% of early-onset cases. Foot dystonia at onset, hyperreflexia, sleep benefit, urinary urgency, orthostatic hypotension, cognitive and psychiatric features may also be present, which is very similar to parkin-related Parkinsonism; and in fact, parkin and PINK1 are part of the same molecular pathway. 
Small numbers of cases of DJ-1-associated Parkinsonism have been reported. The phenotype of DJ-1-associated Parkinsonism (OMIM 602533, chromosome 1p) is again similar to Parkin, with young onset age, slow progression, response to L-dopa. Focal dystonia and psychiatric symptoms are also common. 
Synuclein, alpha (SNCA) gene mutations are rare, accounting for less than 1% of PD in the general population. PD patients carrying SNCA mutations have clinically typical PD, with levodopa responsiveness, although disease onset is earlier than in patients with idiopathic PD, and progression appears to be more rapid. Neuropathological findings are similar to those in idiopathic disease, with cell degeneration, Lewy bodies, and neurites. 
Recently adult-onset cases of gene-proven PLA2G6-related neurodegeneration have been reported. These patients present with subacute onset of dystonia-parkinsonism, pyramidal signs, eye movement abnormalities, cognitive decline, and psychiatric features with onset age of 10 to 26 years. ,,,,,,
Leucine-rich repeat kinase 2 (LRRK) gene-mutation-associated Parkinsonism closely resembles idiopathic PD with autosomal-dominant inheritance, but age of onset is not typically at a younger age.  Mutations in the glucocerebrosidase gene (GBA) are associated with increased incidence of Lewy body disorders. The mean age of onset of PD in these patients with mutant GBA is 48 years. Patients with Gauchers disease and family members have a higher propensity to develop PD. 
What investigations will you do in this patient?
Reply: There is no blood or cerebrospinal fluid test that can diagnose PD. Neuroimaging with MRI is helpful in differentiating PD from other Parkinsonian disorders. Here the clinical course is typical of PD; hence, no additional tests are required for diagnosis. Brain imaging is generally unnecessary in patients with typical Parkinson disease, especially if the patient has an asymmetric presentation, tremor, and a good response to medications.  One may do serum ceruloplasmin levels, but in the absence of KF ring Wilson disease is unlikely.
How would you confirm the diagnosis of parkin-gene mutation related PD ?
Reply: Parkinsonism and PD are clinical diagnosis. The definite diagnosis of PD requires the demonstration of Lewy-type synucleinopathy, a diagnostic autopsy feature that is not available in the clinical setting. Mutations in the parkin gene are considered to be the predominant cause of early-onset Parkinson disease (EOPD) particularly when the family history is compatible with autosomal recessive inheritance (history of similar illness in siblings, parental consanguinity, and unaffected parents). Molecular analysis of the parkin gene can be performed by denaturing high-performance liquid chromatography and sequencing and semiquantitative multiplex PCR to specify the mutation.  This may not be necessary in clinical practice.
Which patients of PD should be subjected to genetic testing and what are the possible implications of genetic testing?
Reply: There are no formal testing guidelines developed by movement disorder society or any other PD alliance group. Genetic testing might prove useful to minimize further patient work-up, to clarify treatment approaches and to assist with future family planning in cases of juvenile onset PD irrespective of family history, early onset PD with atypical features and/or a positive family history of PD and late onset PD with a strong family history of PD. An argument against genetic testing for PD is that the outcome of such testing does not affect patient management. This reasoning may not be valid since a genetic testing ends diagnostic uncertainty in early onset PD and can provide information on prognosis. The advent of neuroprotective or gene therapy will definitely change our views on genetic testing and benefit patients with PD. 
Can you briefly discuss the approach to treatment in this patient with mild (symptoms and signs interfering with activities) stage YOPD?
Reply: This patient has mild stage PD with symptoms and signs interfering with activities. Hence, symptomatic therapy is indicated. Dopamine precursor levodopa (combined with decarboxylase inhibitor carbidopa) is the most powerful drug available. If symptoms are not severe enough and the patient is younger than 60 like our patient dopa replacement is avoided. A dopa sparing strategy is followed since early use of levodopa causes motor complications of fluctuations (wearing off) and dyskinesias.
Dopamine agonists (ropinirole, pramipexole) are the most powerful antiparkinson medications after levodopa. These have to be initiated at a small dose (to avoid adverse effects) and are increased gradually till a satisfactory response is achieved. I will start pramipexole 0.125 mg for 3 days then increase to bid for next 3 days. The dose will be increased by 0.125 mg weekly till a dose of 1mg tid is reached. If the response is less satisfactory and levodopa is to be avoided I will add amantadine or an anticholinergic (trihexyphenidyl, procyclidine, benztropine).  Though anticholinergics are less effective antiparkinson agents addition of an anticholinergic agent may be beneficial and can sometimes lessen tremor severity. Parkin-gene-mutation-related YOPD may have dramatic response to anticholinergic therapy and this is considered as one of the distinguishing features of this mutation. 
Is there consensus on levodopa sparing in the treatment of mild-stage PD with symptoms and signs interfering with activities?
Reply: There is no evidence that levodopa itself causes either neurotoxicity or motor complications of dyskinesias and fluctuations. It is the severity of disease, which allows these complications to appear with levodopa. Whether motor complications seen with chronic levodopa therapy in patients with PD are actually caused by long-term levodopa therapy or simply reflect progression of disease is unknown and debated. Therefore, levodopa being the most effective drug could be used first to provide highest quality of life. 
Does levodopa have a beneficial effect in progression of PD?
Reply: The earlier versus later Levodopa therapy in Parkinson disease (ELLDOPA) study assessed the effect of levodopa on the rate of progression of PD. The results suggested that levodopa either slows the progression of Parkinson's disease or has a prolonged effect on the symptoms of the disease. In contrast, the dopamine transporter-binding ligand neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that the pharmacologic effects of levodopa modify the dopamine transporter. Therefore, the potential long-term effects of levodopa on Parkinson's disease remain uncertain. 
What is the treatment of early PD (with mild or no symptoms) in a patient who is functionally independent?
Reply: Since PD is a progressive disease and no medication prevents worsening, the goal in treating PD is to keep the patient functioning independently for as long as possible. The patient is encouraged to remain active and mobile. The treatment of PD has to be individualized. For early-stage PD with mild symptoms and no threat to activities, levodopa or dopamine agonists are not used. Whether dopamine agonists slow the rate of progression is not clear. Various neuroprotection strategies have been tried. Monoamine oxidase-B (MAO-B) inhibitors selegeline and rasagaline have mild symptomatic effect and there are reports suggesting potential neuroprotective effect. The antioxidants vitamin C and vitamin E are ineffective in slowing down the progression of PD. 
What is the treatment of moderate stage PD?
Reply: For moderate stage PD (when there is an inadequate response to non levodopa medications) levodopa with carbidopa is used. The rule of thumb is to utilize the lowest dosage that controls the symptoms. Treatment is initiated with a single tablet of levodopa/carbidopa 100/25 at bedtime. A target dose of 100/25 three times a day is reached over three weeks. A maximum dose of 2000 mg of levodopa can be used before concluding that levodopa is ineffective. 
What is the treatment of advanced PD?
Reply: In advanced PD there are motor complications like fluctuations to levodopa response namely wearing-off phenomenon, delayed "on," dose failure, on-off phenomenon, and early morning dystonia. Patients can have dyskinesias that can be peak-dose dyskinesias and diphasic dyskinesias.
In wearing off phenomenon, the clinical improvement from a dose of levodopa lasts only as long as the plasma concentration of levodopa is high. As the plasma level gradually falls there is a loss of clinical response. In patients with wearing off (and on-off) as the plasma concentration of levodopa falls there is rapid loss of anti-PD effect which parallels the falling plasma concentration. For wearing off phenomenon, addition of MAO-B inhibitors (Selegiline and rasagiline) may decrease the off time by 1 h per day. Catechol-O-methyl transferase (COMT) inhibitors (entacapone, tolcapone) increase the on time by about an hour per day. The dosing of levodopa/carbidopa can be made frequent, giving the doses closer together. The patient may require as many as six doses per day. Ultimately, most patients will develop progressively shorter duration of effectiveness from these doses as the disease progresses.
In patients with delayed "on" there is problem getting "on" with the first dose of levodopa. These patients may need a larger dosage of levodopa as their first dose of the day. Failure of the patient to respond to a dose of levodopa (dose failure) can be due to poor gastric emptying. For this liquefied levodopa (dissolved in carbonated water or soda) can be used for quick effect.
Early morning dystonia is the most common form of off period dystonia. It is the presence of sustained painful contraction in the feet. A controlled release levodopa or dopamine agonist at night is effective in preventing early morning dystonia. This also responds to levodopa taken on waking. 
What is the role of deep brain stimulation in the treatment of advanced PD?
Reply: Deep brain stimulation (DBS) is an effective treatment for select patients with advanced PD. DBS for PD involves stereotactic surgical implantation of an electrode into deep gray nuclei globus pallidus interna (GPi) or subthalamic nucleus (STN). Chronic high-frequency stimulation is then provided through an implantable pulse generator residing in the anterior chest wall. Patients with advanced PD with good response to levodopa but with levodopa-induced dyskinesias, motor fluctuations, or medication refractory tremor are ideal candidates for DBS. The patient for DBS should be cognitively normal, in good medical health and preferably <70 years. 
Unilateral DBS is appropriate for patients with asymmetric parkinsonian symptoms including high amplitude tremors.  Bilateral DBS (either STN or GPi) is more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life. , The most common serious adverse effect associated with DBS is surgical site infection. Other adverse effects associated with DBS are falls and depression. 
It should be noted that DBS treats a specific set of symptoms (mostly levodopa-induced), has no effect on other important problems, such as postural instability, and does not alter the natural history of PD. 
Nonetheless, pallidal or subthalamic DBS is definitely more effective than best medical therapy in alleviating disability in patients with moderate to severe PD with motor complications responsive to levodopa and no significant cognitive impairment. 
What is "on-off" phenomenon?
Reply: On-off phenomenon is a motor complication of levodopa therapy seen in advanced Parkinson disease. The term "sudden off " is used when the patient suddenly becomes Parkinsonian (has bradykinesia, tremors, rigidity, immobility, and freezing). That is, the benefit from levodopa suddenly disappears, like turning off a light switch. The plasma levels of levodopa are in the declining phase when the "offs" appear. The sudden off is due to sudden and transient desensitization of dopamine receptors (the receptors switch from a high affinity to a low-affinity state). The patient can improve suddenly, even without taking another dose of levodopa. This random occurrence of "on" and "off" state is termed as "on-off" phenomenon. 
Sudden off phenomenon is difficult to overcome. Subcutaneous injections of the dopamine agonist apomorphine are effective in turning the patient "on." Oral administration of levodopa dissolved in carbonated water is also effective.
What are levodopa induced dyskinesias?
Reply: Levodopa-induced dyskinesias are unnatural, excessive, and abnormal involuntary movements due to levodopa. These are manifested as stereotypies, dystonia, and chorea. Peak-dose dyskinesias are due to too high dose of levodopa and are representative of an overdosed state. Thus to avoid peak dose dyskinesias the individual dose of levodopa needs to be reduced. The frequency of doses has to be increased since reducing the amount of individual dose also reduces the duration of benefit. Another method to reduce peak dose dyskinesia is to substitute higher doses of a dopamine agonist while lowering the dose of levodopa/carbidopa. Amantadine is also an antidyskinetic agent and can be used. Clozapine can suppress dopa-induced dyskinesias while simultaneously increasing "on" time without dyskinesias.  Diphasic dyskinesias are dyskinesias which develop as the plasma level of levodopa is rising or falling (but not during the peak plasma level). Use of dopamine agonists with longer duration of action can be beneficial for diphasic dyskinesias. 
What is the pathogenesis of motor complications?
Reply: Motor complications are seen in advanced (severe) PD in patients who are on long duration and high dose levodopa therapy. Various mechanisms for development of fluctuation and dyskinesias have been suggested. Presynaptic and postsynaptic mechasims at the nigrostriatal nerve terminals are responsible for development of motor complications. With more severe loss of dopaminergic neurons in the nigrostriatal pathway, there is reduced storage capacity for dopamine in the presynaptic terminals. Hence, fluctuations in plasma dopamine levels can no longer be buffered by reuptake into presynaptic terminals. The fluctuations in plasma L dopa concentration may now be translated into peaks and troughs in striatal dopamine concentration.
There can be increased sensitivity of dopamine D2 receptors to levodopa in patients with fluctuations. Long-term and intermittent/pulsatile (as compared to continuous) administration of levodopa contributes to the development of fluctuation. Levodopa and its metabolities (formation of free radicals) can alter the dopamine receptors and storage sites. 
The authors acknowledge Dean, T. N. Medical College, B.Y.L. Nair Ch. Hospital, Mumbai.
[Table 1], [Table 2], [Table 3]