Rida Noor
Mubashir Hussain
Saad Khan
Muhammad Faiq Akram
Maham Maqsood
Ayesha Eman 
Abdul Basit
Shumaila Butt

Meningiomas are tumors that develop from the meninges, the protective membranes surrounding the brain and spinal cord. While typically slow-growing and benign, some meningiomas can be malignant. Their exact cause is unclear, though genetic predispositions, radiation exposure, and certain medical conditions are known contributing factors. These tumors are most commonly found along the brain's convexities, especially over the frontal and parietal lobes, as well as near the skull base and in the spinal cord. They can also occur along the falx cerebri and tentorium cerebelli. Risk factors include prior radiation, genetic conditions like neurofibromatosis type II, and female sex, as they are more common in women.

Meningiomas present with a nonspecific constellation of symptoms, with no pathognomonic signs. The symptoms largely depend on the tumor's location and are due to the mass effect. Common symptoms include headaches from increased intracranial pressure, focal neurological deficits, cranial nerve dysfunction, and seizures (either generalized or focal) caused by the tumor's mass effect. These symptoms typically develop insidiously over time(1,2). Contrast-enhanced MRI, showing a homogeneously enhancing extra-axial lesion, is the primary imaging method for suspected meningiomas and follow-up(3). CT with contrast is used for patients unable to undergo MRI(1). Surveillance involves gadolinium-enhanced T1-weighted sequences, while angiography is now only used for suspected sinus invasion. PET imaging with somatostatin analogs (68-Ga-DOTATATE or 90Y-DOTATOC) can detect meningiomas due to their somatostatin receptor-2 expression(3). This method, though not standard, helps distinguish tumors from healthy or postoperative tissue and monitors recurrence after radiation(1)(3).Meningiomas typically grow slowly and are rarely infiltrative, often leaving patients asymptomatic, which makes diagnosis challenging(2). These tumors are frequently discovered incidentally during imaging for unrelated conditions. The detection rates of incidental meningiomas have steadily increased, with incidental diagnoses rising from 0.6% in 2008-2009 to 0.7% in 2018-2019, largely due to the more frequent use of advanced imaging techniques. This trend complicates clinical decision-making regarding whether to monitor or proceed with surgical intervention(4).Meningiomas are incidentally detected on MRI in 0.9% to 1.0% of the general population. Current guidelines recommend annual MRI scans for 5 years for suspected or WHO grade 1 meningiomas, with the interval potentially doubled thereafter. The first-line treatment for growing or symptomatic meningiomas is surgical resection. In certain cases, radiosurgery or fractionated radiotherapy may be considered, particularly for well-circumscribed, small tumors or in elderly or critically ill patients, with SRS providing localized control comparable to Simpson Grade I resection for tumors ≤3 cm(3). 
Surgical resection is recommended for symptomatic patients with significant mass effect and elevated intracranial pressure(5). The surgery aims to relieve symptoms, improve quality of life, and obtain tissue for diagnosis(3). Guidelines suggest surgery for tumors ≥4 cm, initial growth rates of ≥20% per year for tumors <2.5 cm, and ≥1 cm³/year for tumors ≥2.5 cm. Warning signs include the absence of calcifications on brain CT and hyposignal intensity on MRI(6). Risks can be assessed using the ABC Surgical Risk Scale, which evaluates tumor attachment size, arterial involvement, brainstem contact, central cavity location, and cranial nerve group involvement(7).Radiation therapy is an integral part of the management strategy for meningiomas, used both as a primary treatment and post-operatively(8). It is primarily considered for skull base meningiomas that encase vascular and neural structures, such as the optic nerve or cavernous sinus(6).Health-related quality of life (HRQOL) is significantly impaired in meningioma patients, particularly due to impacts on physiological functioning, cognitive abilities, and psychosocial well-being. Factors affecting HRQOL include tumor size, location, histologic grade, seizure burden, and tumor recurrence. While patients may experience symptomatic improvement after treatment, their quality of life can remain depressed indefinitely(9). Progesterone treatments, particularly cyproterone acetate, significantly elevate the risk of developing a meningioma. Both the duration of treatment and the cumulative dose contribute to this increased risk. Studies indicate that tumor volume decreases following the cessation of progesterone treatment in 79% of cases, reinforcing the evidence that these therapies can influence tumor development and growth(10).

A 52-year-old female presented to the ER with tremors in hands and rigidity of left side of body. CT imaging of the brain revealed a space-occupying lesion with dural attachment, consistent with meningioma. Further investigations confirmed the diagnosis. The patient underwent planned brain surgery, and a benign tumor was successfully excised. Histopathology identified the tumor as a fibrous meningioma.
Notably, the patient reported regular use of oral contraceptive pills (OCPs). Post-surgery, her extrapyramidal symptoms resolved, and she is currently in a stable, good condition. Specific markers such as EMA (epithelial membrane antigen) help differentiate meningioma from other tumors. Since some meningiomas may be influenced by hormones, especially in patients using hormone replacement therapy or contraceptives, assessing hormone levels can provide additional insight. Genetic mutations, such as those in the NF2 gene, are sometimes identified in familial or atypical meningiomas.

Our team conducted a comprehensive search for electronic literature on extrapyramidal symptoms caused by meningiomas and the role of hormone replacement therapy across databases like PubMed and Cochrane. We used search terms such as “Extrapyramidal Symptoms Due to Meningioma” and “Role of Hormone Replacement Therapy in Meningioma” to identify relevant studies. We evaluated titles, abstracts, and reference lists based on specific eligibility criteria, including clinical trials, randomized clinical trials, and observational studies published in English. Studies that did not address extrapyramidal symptoms or hormone replacement therapy in meningiomas were excluded. Hormonal factors like pregnancy and hormone replacement therapy (HRT) can influence the growth of meningiomas due to the presence of hormone receptors, particularly progesterone receptors, in these tumors. Studies have shown that meningiomas may grow more rapidly during pregnancy or with the use of HRT, likely due to increased levels of circulating hormones(11).Genetic factors play a significant role in the development of meningiomas, especially in conditions like neurofibromatosis type 2 (NF2). Mutations in the NF2 gene, which encodes the tumor suppressor protein merlin, are commonly associated with meningiomas, particularly in patients with NF2. Sporadic meningiomas may also develop due to somatic mutations in the NF2 gene or other genes like TRAF7(12).The resolution of extrapyramidal symptoms after meningioma treatment depends on factors such as the size and location of the tumor, particularly its impact on structures like the basal ganglia, and the timeliness of intervention. Early surgical removal or radiotherapy to relieve pressure on motor pathways significantly increases the likelihood of symptom resolution. Delayed treatment or extensive damage to critical brain regions may lead to persistent symptoms(13). The timing of meningioma treatment significantly impacts the severity and persistence of extrapyramidal symptoms. Early intervention, such as surgical resection or radiotherapy, can alleviate pressure on critical motor structures like the basal ganglia, improving the chances of symptom resolution. Delayed treatment may lead to prolonged compression or damage to these areas, resulting in more severe and persistent extrapyramidal symptoms (14).Extrapyramidal symptoms can complicate the diagnosis and management of meningiomas by mimicking other neurological disorders, such as Parkinson's disease, which may result in misdiagnosis or delays in detecting the tumor. Additionally, these symptoms pose challenges in treatment planning, as the tumor's proximity to motor pathways must be carefully considered when deciding on surgical or radiotherapy approaches (15). Hormone receptor therapy for meningiomas requires different considerations for premenopausal and postmenopausal women. In premenopausal women, fluctuating endogenous hormone levels, particularly progesterone, can affect tumor growth, necessitating close monitoring during hormone treatments. In postmenopausal women, lower hormone levels may make them better candidates for hormone receptor therapies, but there is still a need to assess the risks, including potential tumor progression and side effects (16).Long-term hormone receptor therapy in meningioma patients can affect overall health and quality of life by influencing tumor growth and causing side effects. While it may help slow tumor progression in hormone-receptor-positive cases, extended use can lead to endocrine imbalances, weight gain, mood changes, and increased cardiovascular risks. Balancing these risks with the potential benefits is crucial to maintaining the patient's quality of life (17). Meningiomas can induce parkinsonism through several pathophysiological mechanisms. The mass effect from the tumor can compress adjacent brain structures, particularly the basal ganglia, disrupting motor circuits and leading to symptoms like bradykinesia and rigidity. Additionally, meningiomas may alter neurotransmitter dynamics, especially affecting dopamine pathways critical for movement control. They can also obstruct cerebrospinal fluid flow, increasing intracranial pressure and contributing to further neurological deficits. Lastly, the inflammatory environment surrounding the tumor can damage adjacent neural tissue, exacerbating motor symptoms.(18)Future research could clarify the role of hormone receptor therapy in meningioma management by conducting large-scale clinical trials to evaluate the efficacy and safety of these therapies in diverse patient populations. Identifying specific biomarkers related to hormone receptor expression could help personalize treatment by stratifying patients who would benefit most from such therapies. Additionally, exploring the molecular mechanisms behind hormonal influences on meningioma growth may reveal novel therapeutic targets and enhance understanding of tumor biology.(19)
The presence of hormone receptors in meningiomas is correlated with tumor aggressiveness and recurrence rates. Meningiomas that express estrogen and progesterone receptors often demonstrate less aggressive behavior and lower recurrence rates, as these receptors can influence cell proliferation and apoptosis. In contrast, tumors lacking these receptors or showing overexpression of specific growth factors may exhibit increased aggressiveness and a higher likelihood of recurrence. This correlation emphasizes the importance of hormone receptor status in prognostic assessments and treatment strategies.(20). The rarity of meningioma-induced parkinsonism impacts clinical practice and treatment decisions by limiting clinicians' experience in diagnosing and managing these cases, often resulting in misdiagnosis or delayed treatment. This scarcity also hinders the development of standardized treatment protocols due to insufficient clinical data. As a result, healthcare providers may need to adopt interdisciplinary approaches, combining expertise from neurology and oncology to create personalized treatment plans for affected patients.(21) Patients with meningiomas causing parkinsonian symptoms may experience adverse long-term outcomes, especially if the diagnosis is delayed. Prolonged exposure to the tumor's mass effect can lead to worsening neurological deficits and increased severity of parkinsonian symptoms, significantly impairing quality of life and increasing dependence on caregivers. Delayed treatment may also result in tumor progression and a higher likelihood of recurrence, complicating future management. Timely diagnosis and intervention are essential to improving patient outcomes.(22) Studies on the responsiveness of meningiomas to anti-hormonal therapies, such as anti-progestins and selective estrogen receptor modulators (SERMs), indicate potential benefits for specific tumor subtypes. Meningiomas expressing progesterone receptors have shown some responsiveness to anti-progestin therapy like mifepristone, which can stabilize tumor growth in certain patients, though the benefits vary. Research on SERMs, such as tamoxifen, is limited due to low estrogen receptor expression in meningiomas, with unclear efficacy. Overall, while these therapies show promise, further clinical trials are needed to determine their effectiveness and optimize treatment based on hormone receptor status.(23). Differential diagnosis is crucial when dealing with parkinsonian symptoms in patients with meningiomas because these symptoms can mimic various neurological disorders, particularly Parkinson's disease, leading to potential misdiagnosis and inappropriate treatment strategies. Accurate differentiation is essential to ensure timely intervention for the meningioma itself, as delayed treatment can result in further neurological decline and exacerbate the patient's condition. Additionally, understanding whether the symptoms are tumor-related or indicative of a primary neurodegenerative process informs treatment planning, including whether surgical or therapeutic measures should prioritize addressing the tumor or managing the parkinsonian symptoms.(24) The mass effect of a meningioma on the frontal lobe and basal ganglia contributes to parkinsonian symptoms through several mechanisms. Compression of the basal ganglia can disrupt motor control circuits, leading to symptoms such as bradykinesia, rigidity, and postural instability. Additionally, altered cerebrospinal fluid flow due to the mass effect may increase intracranial pressure, further affecting neurological function. This pressure can impact both the basal ganglia and frontal lobe, impairing motor planning and executive functions. Lastly, the inflammatory environment surrounding the tumor may lead to neurotransmitter imbalances, particularly in dopamine pathways, exacerbating motor symptoms.(25)

In conclusion, the interplay between meningiomas, extrapyramidal symptoms, and hormone replacement therapy (HRT) presents unique challenges for diagnosis and treatment. Meningiomas, particularly those located near the basal ganglia, can induce extrapyramidal symptoms, which often mimic neurodegenerative conditions like Parkinson’s disease. This overlap can lead to delayed diagnosis and treatment, exacerbating motor deficits and impacting patients' quality of life. Early detection and intervention, whether through surgery or radiotherapy, are critical in managing meningioma-induced parkinsonism and improving neurological outcomes. Moreover, hormone replacement therapy adds another layer of complexity, particularly due to the hormone sensitivity of many meningiomas. The expression of progesterone and estrogen receptors in these tumors may drive their growth, especially in patients undergoing HRT. While HRT offers significant benefits for managing menopausal symptoms, its potential association with meningioma progression necessitates careful patient evaluation. The risks and benefits of HRT must be carefully weighed, and future research should aim to clarify the mechanisms through which hormones influence meningioma growth. This will aid in refining treatment strategies, ensuring that HRT is used safely and effectively in patients at risk for or with existing meningiomas.

Figure 1. Gross specimen of Meningioma Tumor
Figure 2. CT imaging of Meningioma tumor.
Figure 3.  Fibrous Meningioma is a spindle cell with scant or no cellular whorls or meningothelial nests
Figure 4. SSTR2a is usually diffusely positive in fibrous meningioma