11.1 Epidemiology
Meningeal leukemia can be presented with intraparenchymal intravascular leukostasis, and nodular granulocytic sarcoma (chloroma) (12). In children, acute lymphoblastic leukemia is the most common cause of meningeal leukemia, while secondary meningeal leukemia in adults is linked to myeloid leukemia in its monocytic or blastic stages and chronic lymphocytic leukemia. It is believed that AML cells seldom reach the CNS and establish tumors in adult patients, unlike pediatric patients where it is a frequent occurrence (13). Risk factors for CNS leukemia include chromosome 11 abnormalities, such as trisomy with gene amplification, including myeloid, lymphoid leukemia (MLL), and chromosomal 16 inversions, resulting in core binding factor beta-myosin 11 heavy chain fusion protein (13). Additionally, hyperleukocytosis > 100000/microL, prominent monocyte components, and high serum LDH are risk factors that our patient has. APL with PML-RARA is also a risk factor for CNS involvement in AML (8).
11.2 Symptoms and pathophysiology
Contamination of CSF through the choroid plexus, invasion of leukemic cells from the brain parenchyma through capillaries, direct infiltration of the leptomeninges through bone lesions, or spread through nerve roots are some of the hypotheses proposed in the pathophysiology of CNS involvement in acute myeloid leukemia (14). The last hypothesis in our patient can be one of the causes of leptomeningeal involvement through optic nerve infiltration
Headaches, nausea, and vomiting are the most typical meningeal leukemia presenting symptoms, and they are occasionally accompanied by lethargy and irritability, sleepiness, coma, convulsions, and neck rigidity (15). In addition to these signs and symptoms, increased intracranial pressure leads to pressure on the cranial nerves. The most common nerves include the 3rd, 5th, 6th, and 7th cranial. Right sixth nerve palsy was found in our patient during examination. The circulation of CSF is hampered by diffuse meningeal infiltration, which may lead to communicating or obstructive hydrocephalus. The most typical symptom is papilledema; in young children, the sutures in the skull might separate. The spinal nerve roots or cranial nerves may get compressed or infiltrated by leukemic deposits, which then disseminate between the nerve fibers (15).The lower cranial nerves are infrequently afflicted, but the second, third, sixth, seventh, and eighth cranial nerves are the most frequently impacted. Chronic lymphocytic leukemia meningeal infiltration has been linked to oculomotor palsy with pupillary sparing. The invasion of leukemic cells in the CNS is primarily driven by the production of certain adhesion molecules by a subset of leukemic cells known as "sticky cells." These cells can interact with and attach to endothelial cells, such as very late antigen(VLA-4), inrtra cellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM), L-selectin, platelet endothelial cell adhesion molecule-1 (PECAM1), CD18, Lymphocyte function-associated antigen (LFA-1), CD58, CD44, and chemokine ligand (CXCL12) (15).
Additionally, the blood-brain barrier is broken, and the microenvironment becomes hypoxic, causing the release of VEGF-A by acute lymphocytic leukemia (ALL) or AML cells, which raises the permeability of the bone marrow's vasculature. Leukemic stem cells (LSCs) can withstand the new microenvironment due to their remarkable flexibility. The LCSs penetrate the arachnoid, move, and vigorously multiply in the CSF; after that, they permeate the brain parenchyma and perivascular spaces. Moreover, due to its favorable immune protection, the CNS can shield leukemic cells from chemotherapy. The most crucial surface molecule that leukemic stem cells frequently overexpress and allow them to invade the CNS is neural cell adhesion molecule(NCAM) of CD56 (13).
11.3. Diagnosis and prognosis
Confirmation of meningeal leukemia diagnosis is often done by identifying leukemic cells in the CSF. In about 90% of cases, elevated leukocyte counts are present in the CSF, and blast cells and mitotic figures can be identified through cytocentrifuge preparations. However, even with clear clinical signs of meningeal involvement, the CSF of 10% of patients may appear entirely normal despite an often-raised CSF pressure. Reduced CSF glucose and high protein contents are unreliable indicators of meningeal illness (15). Our patient's CSF examination revealed pyelocytosis, normal protein and sugar levels, but high LDH. Detecting central nervous system (CNS) leukemia primarily relies on CSF cytology, but false-negative and false-positive findings can occur (6, 12). Combining CSF flow cytometry and polymerase chain reaction methods can improve diagnostic sensitivity and specificity. The overexpression of CD56/NCAM, a crucial surface molecule, allows leukemic stem cells to invade the CNS. However, our patient's cytogenetic and molecular biology testing were positive for CD13, CD33, CD34, and CD117 (4, 16). There are varied opinions on the effect of CNS involvement on the success of long-term therapy. Still, according to Shihadeh et al., adult AML patients with CNS involvement have a poor prognosis (8).
11.4 Treatment
In Patients with cranial nerve abnormality or other neurologic impairment associated with leptomeningeal involvement intrathecal chemotherapy with radiotherapy or/and systemic chemotherapy have been recommended. Due to our patient signs and symptoms compatible with nerve palsy and signs or symptoms of ICP rising, she underwent concurrent intrathecal chemotherapy and systemic chemotherapy despite possible adverse effects. After chemotherapy, the patients had mild headache with nausea and vomiting, No serious adverse effects such fever, paresthesia or back pain reported. The patient was overall well tolerated, however the annoying adverse effects of chemotherapy should not be ignored.
11.5 limitations
It is important to note that there are some limitations to consider in our study. Other findings, such as skin rash and blasts in CBC, suggest that empirical treatment for chronic TB meningitis may not be necessary. However, dual diagnosis is not rare based on the endemic prevalence in Iran. Additionally, the patient's age falls within the borderline group, between teenage hood and young adulthood, making the findings' novelty less helpful.
Conclusion
Based on an indolent course of symptoms - one-month headache with additional 6th nerve palsy and weight loss, chronic meningitis was the first probable diagnosis in our patients. Iran is an endemic place for TB. Thus, empirical treatment was initiated before the result of the complete panel was ready. According to the results of CBC diff, peripheral blood smear, cerebrospinal fluid, specialized tests like flow cytometry for CDs, and radiological images, the patient was diagnosed with AML with meningitis presentation. Physicians should consider underlying malignancy in patients with meningeal symptoms, cranial nerve involvement, and/or resistance to conventional therapies. Thus, although rare in adults and more common in children, AML can be presented with CNS involvement in young adults like our patient.