Diagnostic pitfalls in young onset parkinsonism and its unique challenges: A case report from rural Nepal

Abstract

Parkinson’s disease is a neurodegenerative disease resulting from the loss of dopamine-secreting neurons present in the substantia nigra of the brain. Parkinson’s disease is classified as early-onset and late-onset disease based on the time of its presentation. Since young patients with Parkinson’s disease have an atypical clinical presentation and have to deal with their careers, raising families, or both at the time of diagnosis and also have a higher risk of drug-related side effects, it poses unique challenges for the patient, clinical team, and community. We present the case of a 40-year-old female with young onset Parkinson’s disease from rural Nepal and the challenges faced during and after the disease in a resource-limited setting.

Introduction

Parkinson’s disease (PD) is a neurodegenerative disease resulting from the loss of dopamine-secreting neurons present in the substantia nigra of the brain. The disease is characterized typically by symptoms such as resting tremor, bradykinesia, and rigidity. ¹ Based on the age of onset of the disease, PD is classified as early-onset and late-onset. Early-onset PD (EOPD) can be further divided into (1) Juvenile PD: Onset of PD below 21 years of age and (2) Young-onset PD (YOPD): Between 21 and 40 years. ² It often displays different initial symptoms than older patients and may take longer to get a diagnosis. Certain genetic mutations of dominant genes like SNCA, LRRK2, GBA, and VPS35 and recessive genes like Parkin, PINK1, and DJ1 have been found to play a significant part in YOPD. Patients harboring mutations, particularly SNCA and the recessive genes mutation, are found with PD at an earlier age. ² The age- and gender-adjusted incidence rate of PD is 13.4 cases per 100,000 individuals. However, the incidence rates for different age groups, such as those aged 30–39, 40–49, and 50–59, are 0.5, 2.5, and 9.8 cases per 100,000 individuals, respectively.^3,4 The usual symptoms of PD, like tremors, bradykinesia, and rigidity, start gradually and typically begin after age 60. Symptoms such as dyskinesia (involuntary, uncontrolled movements, often writhing or wriggling) and irregular behaviors are more common in patients with YOPD. Often in younger patients, the diagnosis of YOPD is overlooked or delayed until PD is anticipated. Young patients diagnosed with PD face distinct challenges due to their atypical clinical presentation and the concurrent demands of managing careers and raising families. Additionally, they have a heightened risk of experiencing adverse effects from medication, further complicating their treatment. These circumstances create unique hurdles that must be addressed by the patients, the healthcare team, and the community. The challenges faced during and after the young onset of PD in a resource-limited setting are discussed here.

Case presentation

A 40-year-old female from rural Nepal presented to a primary care physician’s office with pain and stiffness in her bilateral wrist joints, more on the left side, for 6 months. The pain was mild, initially throughout the day, but with time, it gradually increased as the day progressed. There were no other symptoms associated with her pain and stiffness. She was a farmer by occupation. She smoked one pack of cigarettes daily for ten years and consumed alcohol occasionally.

On initial assessment, vitals were normal. The general physical examination was unremarkable. Her gait, coordination, and stance were normal. The laboratory examination revealed decreased hemoglobin (11.3 g/dl), leukocyte count (9800 cells/mm³), neutrophil (70%), lymphocyte (22%), and platelets 174,000 cells/mm³. Electrocardiogram (ECG) showed a normal rhythm. Other laboratory investigations including RA factor, Anti CCP, ANA, and X-ray of the bilateral wrist joints were normal.

She was initially managed symptomatically with nonsteroidal anti-inflammatory drugs. On follow-up, she presented without improvement and had additional tremors in her right hand, which she noticed while holding a cup of tea. Over time, the tremor had spread to her left hand, and she developed stiffness and slowness of movement. She complained of fatigue and difficulty sleeping. On examination, she had resting tremors in both hands, significant rigidity in her arms and legs with resistance to passive movements, and a marked reduction in rapid alternating movements. She had a shuffling gait with reduced arm swing and poor balance. She had a positive pull test in the backward direction but a negative pull test in the forward movement. Her cognition and mood were intact. Her pupils were round, regular, and reactive bilaterally. The cranial nerve examination was unremarkable. Her muscle bulk, tone, power, and deep tendon reflexes were normal in all the extremities. The plantar reflexes were down-going on both sides. The sensory examination was normal. Other systemic examinations were also unremarkable. Her family history was unremarkable for neurological diseases and musculoskeletal disorders.

The patient was then referred to a local neurologist. Magnetic resonance imaging (MRI) of the brain was done to rule out other organic pathology, including brain tumors and stroke. MRI scan of brain revealed mild hyperintensity of substantia nigra and red nucleus (Figure 1). Her Unified Parkinson’s Disease Rating Scale (UPDRS) ⁵ score was 11 (Table 1). She showed significant improvement on the levodopa challenge test (LCT) ⁶ and was diagnosed with YOPD.

Figure 1.

Axial T1-weighted MRI of the brain showing mild hyperintensity of substantia nigra and red nucleus.

Table 1.

Unified Parkinson’s Disease Rating Scale (UPDRS), on- and off-stage stage scale of our patient. ⁵

Non-motor		Score
(1) Intellectual impairment	Mild memory loss, with disorientation and moderate difficulty handling complex problems, mild but definite impairment of function at home	1
(2) Mood	Period of sadness or guilt greater than normal, never sustained for days or weeks	1
Motor
(1) Rest tremor right	Slight and infrequently present	1
(2) Rest tremor left	Moderate in amplitude and present most of the time	2
(3) Finger taps right	Mild slowing and/or reduction in amplitude	1
(4) Finger taps left	Mild slowing or reduction in amplitude	1
(5) Gait	Normal	0
Motor complication
(1) Off time	51%–75% of day	3
(2) Dyskinesia duration	1%–25% of day	1
(3) Dyskinesia disability	Not disabling	0
UPDRS score		11

The patient started on oral levodopa 100 mg and carbidopa 10 mg, which significantly improved her tremors, rigidity, and slowness of movement. She underwent outpatient physical and occupational therapy for gait training and fine motor coordination. On regular follow-up every month, the patient was doing well with no levodopa-associated side effects and resistance to treatment therapy.

Discussion

YOPD is diagnosed chiefly based on clinical symptoms. Most of the time, patients with early-onset PD present with atypical features and are left undiagnosed, or diagnosis takes longer. A recent study on YOPD reports time taken to diagnose younger patients’ PD with an average of additional 15 months. Our patient was initially diagnosed with arthritis. The patient developed classic Parkinsonian features as the disease progressed, which provided a clue for a YOPD and established the diagnostic pathway. However, a systematic review and meta-analysis conducted by He et al. ⁷ in 2022 found no significant links between gout, rheumatoid arthritis, or polymyalgia rheumatica and the subsequent development of PD. The diagnosis of YOPD requires a significantly higher number of neurologist visits and clinical investigations before confirming the diagnosis. The diagnosis of PD in a young patient presenting with the associated symptoms of PD should be actively considered to reduce delay in the diagnosis of YOPD and its subsequent impact. ⁸

Levodopa challenge—How was it helpful?

Early diagnosis of PD can be challenging as there is no definite investigation, such as a blood test, imaging modality, or a study of brain vessels to confirm the diagnosis. However, a levodopa challenge can be performed to confirm the diagnosis of PD. While taking levodopa medication, if the symptoms improve, then a diagnosis of PD can be established. In contrast, if the symptoms worsen or do not improve, they are likely to have another neurological condition.

To perform the LCT, a single dose of levodopa is administered to the patient, and their responses are assessed. According to most studies, a single dose of 250/25 mg of levodopa/decarboxylase inhibitor or a longer, slower escalating dose is preferred. A false negative rate of 40% was generally recorded in denovo PD patients in drug challenge tests. ⁹ According to one study, in 70%–81% of cases, the levodopa challenge could predict the clinical diagnosis of PD among patients with Parkinsonian symptoms without a specific diagnosis.^10,11 While performing LCT, additional care should be taken, especially in elderly patients, as they may experience orthostatic hypotension.

Implications of Levodopa therapy in YOPD

Levodopa is historically used for the treatment of PD and is effective in reducing the motor symptoms of the disease, including tremors, bradykinesia, and rigidity (slowed movement and loss of spontaneous movement). Following diagnosis, our patient was also placed on levodopa therapy. Levodopa is used to treat both late-onset and young-onset PD. Levodopa administration should not be postponed in the treatment of parkinsonism when symptoms indicate that therapy is necessary; doing so could lead to longer periods of untreated impairment and shorter intervals during which there are no motor complications. Starting the treatment with dopamine agonists and gradually increasing the dose until reaching maximum efficacy and tolerance is helpful. The results of the PDMED and levodopa in early Parkinson’s disease studies have largely allayed worries about the development of motor problems resulting from the early commencement of levodopa, which led to the emphasis on levodopa-sparing techniques.^12,13

YOPD is the strongest risk factor for early development of motor complications with levodopa and its treatment plan should consider looking at alternatives, such as starting dopaminergic therapy with a dopamine agonist. However, these are costlier than levodopa (available as generic medication), and most people cannot afford long-term treatment. The treatment plan with regular medicines is a challenge when most people do not have insurance plans in a developing country like Nepal, with low GDP per person compared to a developed country with high GDP. The treatment of dopamine agonists is not without side effects with worsening of impulse control disorders being the most. Should this course of treatment be chosen, vigilance and close clinical monitoring is necessary? Another optimal treatment modality for certain patients is deep brain stimulation, but owing to financial limitations, they are not being used. The absence of adequate medical insurance forces the patients to sell their property, in most cases, to afford surgery. Even after the surgery, they may not be able to afford the replacement of the battery. Since there are no definite curative treatment options available, patients may not be willing to take the medications, and they are likely to consult multiple doctors and alternative medicine for the cure of the disease. This leads to a delay in the appropriate management of the disease. We reiterate the need for a patient-centered approach in pharmacological treatment in YOPD after shared decision-making with patient and care providers.

Genetics and YOPD

There is a higher possibility of the transfer of genes linked to PD to offspring, but not all children who harbor such genes will develop the disease. Free and confidential Parkinson-related genetic testing and counseling are being provided by organizations such as Parkinson’s Foundation in the United States. Earlier identifications of genetic mutations responsible for PD have great future prognostic potential. For effective treatment in the future, clinical trials targeting various gene-specific interventions such as GBA and LRKK2 are currently undergoing.

The absence of specific diagnostic tests for PD and the need for repeated clinical assessments increase the importance of genetic testing. But in our scenario, diagnosis of YOPD is difficult, with limitations to genetic mutation analysis leading to disparities in access to primary care physicians and neurologists. Even though genetic testing has been made more accessible and relatively cheaper over the years, it is still unaffordable for many patients, especially those with no national health insurance plans. Most of these patients are reproductively active and bear children, so genetic testing is important beyond patient diagnosis and management.

Navigating the challenges of young-onset Parkinsonism

A patient with YOPD is in the most active and productive phase of life, and they are likely to live longer with the disease, putting them at a higher risk for nonmotor symptoms of PD. Dystonia and levodopa-induced dyskinesia can significantly hamper the ability to work, posing challenges in the workplace. ¹⁴ These patients face far more psychosocial issues than older patients with PD. So, the clinical team should address the patient's anxiety, depression, cognitive disturbances, relationship breakdown, employment, and medication therapy. ¹⁵ The patients should be counseled to prioritize self-care as it is vital in treating YOPD.

PD negatively affects the emotional stability of the patient and the whole family, interfering with relationships. It is necessary for the PD family to consult a movement disorder specialist or neurologist to find the appropriate medicine for the patient. The clinical team should include neurologists and specialists to help patients with their anxiety, poor sleep, and psychosocial problems. It is essential to have a plan for the future as it can alleviate stress and foster security, making it necessary to advise the patients on planning for legal-financial issues and long-term care insurance policies and familiarizing them with the disability.

Conclusion

YOPD has its unique challenges during and after diagnosis. The diagnosis may be overlooked or delayed in younger patients if PD is not anticipated. The ability to differentiate various causes of parkinsonism remains an unmet need, given the lack of reliable biomarkers to correctly diagnose these disorders. This has implications not only for clinical trials of neuroprotective agents that are needed to recruit patients in the early stages of the disease. The same medications are used to treat both late-onset and young-onset patients. However, younger patients are at greater risk of certain side effects. YOPD impacts the whole family. The unique challenges faced when living with PD at a younger age require individually tailored care.