Paraneoplastic Neurological Syndromes – Symptoms, Treatment

Paraneoplastic neurological syndromes (PNS) are rare but are potentially treatable. These disorders are associated with cancer but are not caused by the direct tumor invasion, metastasis, or consequences of treatment.[rx] They can affect any area of the nervous system, including the central, peripheral, and autonomic nervous systems. Although the system involvement is often multifocal, like encephalomyelitis, it can involve a single system, e.g. cerebellar degeneration. Mainly, the PNS precedes or follows the cancer diagnosis, although, in some cases, the primary cancer is not found even at autopsy.[rx]

The first description of PNS was in the 19^th century by a French physician M Auche’ who described the peripheral nervous system involvement in cancer patients in 1890.[rx] The first antibody described was PCA-1 (Purkinje Cell Antibody 1), by Greenlee and Brashear in 1983, in two patients with ovarian carcinoma and paraneoplastic cerebellar degeneration.[rx] More syndromes and antibodies have been subsequently described and the list of the syndromes and antibodies continue to increase day by day.

Types of Paraneoplastic Neurologic Syndromes

Some of the common paraneoplastic syndromes that develop include:

• Limbic encephalitis – amnesia, disorientation, psychosis (including hallucinations and paranoia), confusion, depression & anxiety. Patients may also develop seizures. The most common cancers to trigger limbic encephalitis are small-cell lung cancer (SCLC),  germ cell tumors of the testis, breast cancer, Hodgkin’s lymphoma, and teratoma.
• Subacute sensory neuropathy – upper limb pain or paraesthesia (tingling), sensory loss, sensory ataxia, and absence of reflexes. At a later stage, the neuropathy may also spread to the face, chest, and abdomen. Most cases of subacute sensory neuropathy occur due to SCLC, but also breast & ovarian cancers, sarcoma, or Hodgkin’s lymphoma.
• Cerebellar degeneration – severe truncal and limb ataxia, dysarthria (problem articulation of speech), nystagmus (involuntary eye movement), vertigo, and diplopia (double vision). Onset can be as rapid as a few hours to a few days and leads to the patient becoming bed-bound. Cerebellar degeneration occurs in association with ovarian cancer, breast cancer, Hodgkin’s lymphoma, and SCLC.
• Lambert-Eaton myasthenic syndrome – similar to myasthenia gravis but less severe; muscle weakness within the legs, before spreading upwards towards the top of the body, ptosis (falling of upper eyelid), ophthalmoplegia (eye muscle paralysis), dry mouth, dry eyes, impotence, constipation, and excessive sweating. Most commonly associated with SCLC.
• Peripheral nerve hyperexcitability syndrome – the most common paraneoplastic neurologic syndrome associated with thymoma, SCLC, Hodgkin’s lymphoma, and other cancers. It is characterized by twitching and cramping of muscles, muscle stiffness, muscle weakness, in addition to excessive sweating (sensory nerve-related). Other CNS features can include psychosis and autonomic disturbances (e.g. Morvan’s syndrome.

Diagnosis of Paraneoplastic Neurological Syndromes

Early diagnosis and treatment is important because any delay can result in rapid progression and irreversible neurological damage. Diagnosing PNS is often difficult. One of the reasons for the difficulty in diagnosis is the presentation of the PNS before the malignancy becomes clinically overt. Other reasons are the absence of a particular clinical pattern and absence of imaging and laboratory abnormalities that are specific for PNS. Biopsies are invasive, difficult, and nonspecific. A combination of clinical and laboratory evaluations has to be deployed to reach diagnosis early. Treatment of underlying cancer is important in the treatment of neurological conditions. A high index of clinical suspicion is essential to achieve this goal. A past or family history of cancer is important in this regard. The presence of systemic symptoms like anorexia, weight loss, fever, fatigue and dysgeusia are all important nonneurological clues. CSF often exhibit nonspecific abnormalities such as mild to moderate lymphocytic pleocytosis, elevated protein, and OCBs

Clinical exam

Your doctor or a neurologist will conduct a general physical, as well as a neurological exam. He or she will ask you questions and conduct simple tests in the office to judge:

• Reflexes
• Muscle strength
• Muscle tone
• Sense of touch
• Vision and hearing
• Coordination
• Balance
• Mood
• Memory

A patient should be evaluated with a complete panel of laboratory, imaging, electrodiagnostic studies and biopsy of specific tissues if required.

• Complete blood count with differential
• Comprehensive metabolic panel
• Urinalysis
• Tumor markers
• Ectopic hormones level like PTHrP, ACTH, ADH
• Cerebrospinal fluid analysis (CSF)
• Protein electrophoresis o serum and CSF
• Assay of paraneoplastic antibodies in blood and CSF
• Skin biopsy
• Muscle biopsy

Laboratory tests

Laboratory tests will likely include:

• Blood tests – You may have blood drawn for a number of laboratory tests, including tests to identify antibodies commonly associated with paraneoplastic syndromes. Other tests may attempt to identify an infection, a hormone disorder or a disorder in processing nutrients (metabolic disorder) that could be causing your symptoms.
• Spinal tap (lumbar puncture) – You may undergo a lumbar puncture to obtain a sample of cerebrospinal fluid (CSF) — the fluid that cushions your brain and spinal cord. A neurologist or specially trained nurse inserts a needle into your lower spine to remove a small amount of CSF for laboratory analysis.
• Computerized tomography (CT) – is a specialized X-ray technology that produces thin, cross-sectional images of tissues.
• Magnetic resonance imaging (MRI) – uses a magnetic field and radio waves to create detailed cross-sectional or 3D images of your body’s tissue.
• Positron emission tomography (PET) – uses radioactive compounds injected into your bloodstream to produce cross-sectional or 3D images of the body. PET scans can be used to identify tumors, measure metabolism in tissues, show blood flow and locate brain abnormalities related to seizures.
• PET plus CT – a combination of PET and CT, may increase the detection rate of small cancers, common in people who have paraneoplastic neurological disorders.