Secondary Parkinsonism

Authors:

Syeda Zuhaa Hassan MBBS,

Maheen Kalwan MBBS,

Adeel Memon MD

Introduction

• Parkinsonism is a movement disorder syndrome classically characterized by hypokinesia.

• The most common cause of Parkinsonism is Parkinson's disease (PD), but this is a neurodegenerative process and presents in a chronic manner.

• In contrast, Secondary Parkinsonism (SP) may present in an acute, subacute or chronic manner.

• Presents secondary to insults involving the Dopaminergic and Nigro-Striatal Pathway.

• Factors favoring a diagnosis of SP include sudden onset of symptoms at a young age, rapid progression with atypical findings on examinations as well as poor response to Dopamine therapy.

Etiology and Classification

• Etiological classification of Secondary Parkinsonism is multifactorial.

Table 1. Etiological Classification of Secondary Parkinsonism

Drug-Induced Parkinsonism (DIP)

• Defined as the occurrence of parkinsonian features secondary to drug intake (most commonly associated drugs are mentioned in Table 2).

Table 2. Drugs commonly associated with Parkinsonism

Epidemiology

• It is the second most common reason for the development of Parkinsonism, with percentages varying between 7.9-20% of all parkinsonian patients.

• Majority of patients present between 60-80 years of age.

Pathophysiology

• The offending drug leads to a decrease in Dopamine levels by either functionally or structurally blocking the Dopamine D2 receptors.

Risk factors

• Increasing age

• Female Gender

• Dosage, potency and duration of intake of the offending drug

• Cognitive dysfunction

Clinical manifestations

• Temporal relation to the start of medication and onset of symptoms

• Classically symmetrical and bilateral parkinsonism

• Comparatively more intense rigidity and bradykinesia

• Orolingual dyskinesia

• Minority of cases may present with asymmetrical parkinsonism and a resting tremor.

Diagnosis

• Must satisfy the following criteria;

1. Presence of parkinsonism AND

2. No history of Parkinsonism prior to usage of the offending drug AND

3. Onset of parkinsonian symptoms during usage of said drug

• DaT scan- Striatum shows symmetric uptake vs reduced DAT uptake in classical PD

Treatment

• Removal or a decrease in dosage of the offending drug.

• In case of Antipsychotic usage, shift to second generation antipsychotic and that, too, at the lowest possible dose.

• Anticholinergics may be added to the regime if a dose reduction or switching to an alternative drug is not possible.

• Majority of patients with pure DIP make a full recovery within 6 months of discontinuation of the offending medication.

Structural lesions

• Structural brain defects causing dysfunction of basal ganglia or their connections; most commonly of vascular origin.

Vascular Parkinsonism (VP)

• Previously known as arteriosclerotic parkinsonism, VP most frequently occurs due to lacunar infarcts, which may or may not be unilateral.

• Possible sites of lesions include basal ganglia and the subcortical white matter.

Epidemiology

• Vascular Parkinsonism is among the most common causes of Parkinsonism, with a prevalence of about 4-12%.

• The progressive/insidious onset VP is more common, and presents with white matter lesions.

• Majority of the affected individuals are over 65 years of age.

Risk Factors

• Increasing age

• Hypertension

• Prior stroke or transient ischemic attack

• Diabetes Mellitus

• Hypercholesterolemia

• Carotid artery disease

Pathophysiology

• Diffuse subcortical white matter (ischemic) lesions destroy connections between basal ganglia and the cortex.

Clinical Manifestations

• Classically presents as ‘lower body parkinsonism’, symmetrically affecting both the lower extremities.

• Gait and postural abnormalities are early features of the disease.

• Predominantly ataxic gait with comparatively wider stance but shorter stride.

• Upper motor neuron signs are present with step-wise progression of the disease.

• Common features include shuffling gait, postural instability, cognitive decline, incontinence, and pseudobulbar palsy.

• Presence of resting tremor and upper limb involvement is uncommon. The arm swing is normal.

• History might be suggestive of stroke, frequent falls and vascular risk factors.

Diagnosis

• Neuroimaging techniques, specifically MRI, may aid in localizing the lesion.

• MRI can display hyperintense signals around subcortical white matter and periventricular regions, microbleeds and cortical atrophy.

• Normal or symmetrically reduced binding on DaT scan (Dopamine transporter imaging), and preserved olfactory function may support the diagnosis.

Treatment

• Insufficient response to Levodopa.

• A trial of Levodopa up to 1g per day may be given for about 3 months to assess responsiveness.

• Antiplatelet therapy, physical exercise, and control of risk factors may improve outcome.

Normal Pressure Hydrocephalus (NPH), Trauma and Tumor

• Trauma is also referred to as Chronic Traumatic Encephalopathy (CTE).

• Table 3 entails information about other structural causes of AP; Normal Pressure Hydrocephalus (NPH), Tumor, and Trauma.

Treatment

• NPH: Removal of CSF and surgical shunting.

• Tumor: Tumor resection. Complete resolution of symptoms within 3 months, resting tremor may remain in a few.

• Trauma: Often fatal. Risk reduction and prevention is the only cure. No approved therapeutic drugs.

Toxic/Metabolic

• Features of Parkinsonism caused by exposure to certain toxins or metabolic disturbances within the body.

• Common toxins include Manganese, MPTP and Carbon Monoxide

• Metabolic insults causing SP include central and extra-pontine myelinolysis among other less common causes.

Manganese

• Parkinsonian signs and symptoms arising due to Manganese exposure are also termed Manganism.

Epidemiology

• There is a geographical correlation between manganese-associated parkinsonism and areas in the US where there are increased manganese emissions from specific industries.

Pathophysiology

• Build up of manganese in the Basal Ganglia of the brain leads to neuronal degeneration.

• The Globus Pallidus, in particular, is extremely sensitive to manganese accumulation.

Clinical Manifestations

• Initially, patients may present with non-specific psychiatric symptoms.

• “Cock walk”- straight spine and flexed elbows whilst walking on toes.

• Dystonia

• Falling backwards

• Rarely tremors

• Shows progression even after exposure is stopped.

Diagnosis

• Table 4 details differences between Manganism and Idiopathic Parkinsons Disease based on radiological findings.

Treatment

• Mostly experimental at this stage with varying results.

• Options include:
• Chelation with IV ethylenediaminetetraacetic acid (EDTA).
• Para-aminosalicylic acid or N-acetyl para-aminosalicylic acid.

Para-infectious

• Neuronal loss (basal ganglia and its projections) due to neuro-inflammatory processes triggered by infectious agents.

• Typically as a consequence of viral illness.

Autoimmune Disorders

• Parkinsonism is rare, but may accompany either systemic or localized autoimmune diseases.

• They usually do not respond well to Levodopa.

• Symmetrical onset is common.

Sjogren’s Syndrome (SS)

Epidemiology

• Centrally, 15% of patients have neurological signs and symptoms.

• Can present at any age.

• More inclined towards affecting female gender.

Pathophysiology

• Usually due to vasculitis in basal ganglia and its surrounding regions.

Clinical Manifestations

• Parkinsonian symptoms similar to those observed in SLE, except mutism.

• Rigidity, hypokinesia, and gait disturbances are among the most common symptoms, observed in more than 50% of the patients.

• Hypophonia is classically seen, among other speech abnormalities.

• Psychiatric manifestations are uncommon.

Diagnosis

• MRI may reveal hyperintense striatal or pallidal white matter lesions on T2/FLAIR (Fluid-attenuated inversion recovery) images.

• Physiological signs and symptoms, with autoantibodies specific to SS (Anti-Ro and Anti-LA).

Treatment

• Corticosteroids show complete resolution of the symptoms.

Rheumatoid Meningitis (RM)

• Rare manifestation of Rheumatoid Arthritis (RA).

Epidemiology

• Vasculitis is seen in less than 20% of patients with RM.

• Mostly occurs after the age of 50.

• No gender predilection.

Pathophysiology

• Basal ganglionic vasculitis secondary to rheumatoid meningitis.

Clinical Manifestations

• Rigidity and gait abnormality followed by other classical symptoms of Parkinsonism.

• Apathy is the single most common neuropsychiatric symptom.

• Small-sized meningeal and parenchymal vasculature is primarily affected.

• Presence of inflammation of pachy- and lepto-meninges is found in 95% of patients with RM.

• Other features of RM (headache, focal deficits, fever, and seizures) may or not be present.

Diagnosis

• Enhancement of leptomeninges with gadolinium staining on MRI, which may be diffuse.

• Seropositivity: presence of Rheumatoid Factor and Anti-CCP.

Treatment

• Steroids and immunosuppressive therapies are frequently effective.

Psychiatric

• Psychogenic parkinsonism may be seen in malingering, catatonia and conversion disorder.

Further Reading

1. Shrimanker I, Tadi P, Sánchez-Manso JC. Parkinsonism. [Updated 2021 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542224/

2. Al-Janabi WSA, Zaman I, Memon AB. Secondary Parkinsonism Due to a Large Anterior Cranial Fossa Meningioma. Eur J Case Rep Intern Med. 2019;6(4):001055. Published 2019 Apr 19. doi:10.12890/2019_001055

Bibliography

1. Fernandez H.H., Friedman J.H. (2013) Acute Parkinsonism. In: Frucht S. (eds) Movement Disorder Emergencies. Current Clinical Neurology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-835-5_2

2. Shin HW, Chung SJ. Drug-induced parkinsonism. J Clin Neurol. 2012;8(1):15-21. doi:10.3988/jcn.2012.8.1.15

3. Molho, E. S., & Factor, S. A. (2000). Secondary Causes of Parkinsonism. Parkinson’s Disease and Movement Disorders, 211–228. doi:10.1007/978-1-59259-410-8_15

4. Kim Y. Neuroimaging in manganism. Neurotoxicology. 2006;27(3):369-372. doi:10.1016/j.neuro.2005.12.002

5. Kulshreshtha D, Ganguly J, Jog M. Manganese and Movement Disorders: A Review. J Mov Disord. 2021;14(2):93-102. doi:10.14802/jmd.20123

6. Udagedara TB, Dhananjalee Alahakoon AM, Goonaratna IK. Vascular Parkinsonism: A Review on Management updates. Ann Indian Acad Neurol. 2019;22(1):17-20. doi:10.4103/aian.AIAN_194_18

7. McKee AC, Cantu RC, Nowinski CJ, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68(7):709-735. doi:10.1097/NEN.0b013e3181a9d503

8. Choi KH, Choi SM, Nam TS, Lee MC. Astrocytoma in the third ventricle and hypothalamus presenting with parkinsonism. J Korean Neurosurg Soc. 2012;51(3):144-146. doi:10.3340/jkns.2012.51.3.144

9. Saleh C, Akhalbedashvili N, Hund-Georgiadis M: Brain Tumor Presenting with Parkinsonism. Case Rep Neurol 2021;13:595-597. doi: 10.1159/000518198

10. Barba C, Alexopoulos H. Parkinsonism in autoimmune diseases. Int Rev Neurobiol. 2019;149:419-452. doi:10.1016/bs.irn.2019.10.015

11. Walker RH, Spiera H, Brin MF, Olanow CW. Parkinsonism associated with Sjögren's syndrome: three cases and a review of the literature. Mov Disord. 1999;14(2):262-268. doi:10.1002/1531-8257(199903)14:2<262::aid-mds1011>3.0.co;2-6

12. Pellerin D, Wodkowski M, Guiot MC, et al. Rheumatoid Meningitis Presenting With Acute Parkinsonism and Protracted Non-convulsive Seizures: An Unusual Case Presentation and Review of Treatment Strategies. Front Neurol. 2019;10:163. Published 2019 Feb 27. doi:10.3389/fneur.2019.00163

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