Secondary Parkinsonism

Syeda Zuhaa Hassan (1), Maheen Kalwar (2), Adeel Memon (3)
1 - Dow Medical College, Karachi, Pakistan.
2 - Dow Medical College, Karachi, Pakistan.
3 - Dow Medical College, Karachi, Pakistan


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

Etiological Classification of Secondary Parkinsonism
Etiology
Classification
Typical antipsychotics/neuroleptics Atypical antipsychotics Gastrointestinal-Prokinetics Calcium channel blockers Anti-epileptics Dopamine depleters  NMS
Vascular Normal Pressure Hydrocephalus Tumor Trauma
MPTP Carbon Monoxide Manganese Pontine myelinolysis
Catatonia Conversion disorder
Influenza A virus Human Immunodeficiency Virus (HIV) Japanese Encephalitis Virus (JEV) West Nile virus (WNV) Coxsackie virus Others
SLE Sjogren's Syndrome Rheumatoid Arthritis
Table 1. Derived from; Movement Disorder Emergencies: Diagnosis and Treatment.

Drug-Induced Parkinsonism (DIP)

  • Defined as the occurrence of parkinsonian features secondary to drug intake (most commonly associated drugs are mentioned in Table 2).
☝️
It may also occur as one of the manifestations of NMS secondary to neuroleptic drug usage. For a detailed review, consult Neuroleptic Malignant Syndrome.

Table 2. Drugs commonly associated with Parkinsonism

Drugs commonly associated with Parkinsonism
Drug Type
Chemical Name
Haloperidol, Fluphenazine, Phenothiazine
Resperidone, Olanzapine
Valproic acid, Phenytoin
Metocloperamide, Levosulpride
Flunarizine, Cinnarizine
Reserpine, Tetrabenzine

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
  1. No history of Parkinsonism prior to usage of the offending drug AND
  1. 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.
☝️
For information on acute/subacute subtype of VP, consult the chapter Acute Parkinsonism.

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.
☝️
A clinical diagnosis of insidious-onset type may be made using the following proposed criterion:
  • Parkinsonism* with an insidious/progressive onset, AND
  • Diffuse white matter lesions on imaging, with symmetrical onset of symptoms, and early gait impairment.
* Parkinsonism is characterized by hypokinesia, in addition to one or more of the following; rigidity and postural instability.

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.
Table 3. Clinical manifestations and underlying features of non-vascular structural lesions.
Structural lesion
Clinical presentation
Patho-mechanism
Associated features
Diagnosis
Characterized by gait abnormality, urinary incontinence, and cognitive impairment, with ventriculomegaly.
Increased strain in the periventricular area, and insufficient blood supply to basal ganglia (especially nigrostriatal connections).
Parkinsonism, hypokinesia mainly, may be the presenting feature. Shuffling gait is observed.
Dilated ventricles on MRI, negligible cortical atrophy. Fluorodopa PET - decreased blood flow to basal ganglia. DaT Scan - reduced uptake in Striatum .
Tumors occupying supratentorial regions, and basal ganglia (Meningiomas > Gliomas > other types of tumors). Rarely, vascular space-occupying lesions may be present.
Compression and shearing of nigrostriatal pathways due to mass effects.
Parkinsonian features with resting tremor. Rare. Occurs in adults. Cerebral aneurysms and hematomas present in an acute manner.
MRI/CT to detect the site and the type of lesion, and its associated findings (mass effects and edema).
Classical history of repetitive head injury, usually as a consequence of playing contact sports. Concussion is a major risk factor.
Recurrent head trauma causes diffuse neuronal injury and loss, scarring, and tau protein deposition.
Cognitive impairment, mood disorders, changes in personality and behavior, parkinsonism, and gait and speech abnormalities are common.
Definitive diagnosis at autopsy – reveals deposition of neurofibrillary tangles, mainly in the cortex.
*Legend: > = more common than, PET = Positron Emission Tomography.

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.
*Provided there is a history of manganese exposure.

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.
☝️
For a detailed review on other causes such as MPTP and Carbon Monoxide induced Parkinsonism see chapter on Acute Parkinsonism.

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.
☝️
Parkinsonism secondary to an infectious etiology has an acute presentation. The chapter on Acute Parkinsonism covers it in detail.

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.
☝️
Systemic Lupus Erythematosus (SLE) presents in an acute manner. Thus, it is covered in detail in the chapter - Acute Parkinsonism.

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.
💡
Presents in an acute manner and is therefore covered in detail in the chapter for Acute Parkinsonism.

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/
  1. 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
  1. Shin HW, Chung SJ. Drug-induced parkinsonism. J Clin Neurol. 2012;8(1):15-21. doi:10.3988/jcn.2012.8.1.15
  1. 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
  1. Kim Y. Neuroimaging in manganism. Neurotoxicology. 2006;27(3):369-372. doi:10.1016/j.neuro.2005.12.002
  1. 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
  1. 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
  1. 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
  1. 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
  1. Saleh C, Akhalbedashvili N, Hund-Georgiadis M: Brain Tumor Presenting with Parkinsonism. Case Rep Neurol 2021;13:595-597. doi: 10.1159/000518198
  1. Barba C, Alexopoulos H. Parkinsonism in autoimmune diseases. Int Rev Neurobiol. 2019;149:419-452. doi:10.1016/bs.irn.2019.10.015
  1. 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
  1. 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
 
A Living Pocketbook of Neurology
A Living Pocketbook of Neurology
Applied, Concise, Practical, Up-to-date, Mobile-friendly, peer-reviewed & Open-Access Pocketbook of Neurology and related clinical specialties
Unleash the Digital Healer in You! >> 🌐 https://junaidkalia.com <<
Unleash the Digital Healer in You! >> 🌐 https://junaidkalia.com <<
Learn Digital Health, AI-in-Healthcare, ValueBased Care & More!
🎯 Follow Junaid Kalia MD [Editor-in-Chief]
"If anyone saved a life, it would be as if he saved the life of all mankind"
"If anyone saved a life, it would be as if he saved the life of all mankind"
An AINeuroCare Academy Project - Coaching Clinicians in Digital Healthcare
💡 Learn! 🎥 YouTube 💌 Newsletter 🎓Academy 📝 Blog
👨‍⚕️ Connect! 👥 Linkedin 👋 Facebook 🕊️ Twitter 📸 Instagram

Disclaimer: For Education purposes only. You must NOT rely on the information on this website as an alternative to medical advice from your healthcare provider

CC BY-NC-ND - Attribution-NonCommercial-NoDerivs - AINeuroCare PLLC ©️