CNS metastases in breast cancer have been associated with younger age, premenopausal status, infiltrating ductal histology, estrogen- and progesterone-receptor negativity, aneuploidy, altered p53, and epidermal growth factor receptor (EGFR) overexpression (6). Lobular type breast cancer has a predilection for LM compared to other histologic types of breast cancer, with one autopsy study showing LM to occur in 14% of all cases of lobular carcinoma (2). In a study done by Altundag et al. (7), 3.8% of 420 breast cancer patients with CNS metastases had a tumor of lobular histologic type, but 31.6% of these patients presented with isolated LM, compared to 7% of all patients in the series. Studies have shown an increased incidence of CNS metastases in women with HER2-positive breast cancer as high as 25% to 40% (8). This increase may be multifactorial and includes biologic factors as well as treatment-related factors. The use of trastuzumab, a monoclonal antibody directed against the HER2 receptor, is associated with increased systemic response rates, prolonged disease-free survival, and overall survival for patients with HER2-positive breast cancer. Due to its high molecular weight, it does not cross the BBB, which may explain the emergence of CNS metastases. It has been postulated, however, that trastuzumab does not increase the risk of CNS relapse directly but rather improves systemic control and overall survival, leading to
an unmasking of occult brain metastases that would otherwise remain clinically silent (9). In fact, other studies do not support a direct association between treatment with trastuzumab and increased CNS metastases (10). One study observed a lower rate of LM in patients with brain metastases and HER2-positive disease compared to HER2-negative patients with brain metastases (11).

A wide time interval between the diagnosis of breast cancer and the occurrence of LM has been reported; in large series, it ranges from a few weeks to more than 15 years (2). In rare instances, LM is the initial manifestation of breast cancer. Many patients with a solid tumor have widespread metastatic disease when LM is diagnosed but, in patients with breast cancer, the systemic tumor may be inactive or responding to chemotherapy. Of 48 patients diagnosed with LM reported by de Azevedo et al. (1), 34 (56.7%) had been treated with 3 or more chemotherapy regimens prior to the diagnosis of LM, and 51 (85%) had metastatic disease at the time of diagnosis.

The clinical hallmark of LM is the simultaneous occurrence of multifocal abnormalities at more than one level of the neuraxis (cerebral, cranial nerve, and spinal). A careful neurologic examination often reveals more signs than suggested by the clinical symptoms. Spinal symptoms are the most common presentation of LM (Table 78-1); limb weakness is frequent, usually involving the legs, and may be accompanied by paresthesias and pain in the affected limb. Neurologic examination may reveal asymmetric depression of deep-tendon reflexes, radicular limb weakness, and sensory loss. Signs of meningeal irritation, such as nuchal rigidity, are rare. The most common finding of cerebral dysfunction is a change in mentation. Seizures occur in fewer
than 10% of patients. Cerebral symptoms of LM often result from the obstruction of CSF flow and include headache, changes in mentation (lethargy, confusion, and memory loss), nausea and vomiting, and ataxia. These symptoms often indicate elevated intracranial pressure, which may occur with or without hydrocephalus. The most common cranial nerve symptom is diplopia. Hearing loss, visual loss, and facial numbness also occur. Paresis of the extraocular muscles is the most common cranial nerve abnormality, followed by facial weakness and diminished hearing (2).