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Paraneoplastic syndrome refers to multiple disorders of the nervous system and muscle that occur in conjunction with identifiable or occult cancer.
Diseases associated with PNS include subacute cerebellar ataxia, Lambert-Eaton myasthenic syndrome, polymyositis, dermatomyositis, acute nectrotising myopathy, motor neuron disorders, peripheral neuropathies, chronic gastrointestinal pseudo-obstruction, and neuromyotonia.
Paraneoplastic syndrome is associated with less than five percent of reported cases of stiff-person syndrome.
The initial presentation resembles classic stiff-person syndrome: stiffness, rigidity, and painful spasms beginning in the muscles of the lower back and legs. Superimposed spasms are triggered by anxiety, loud unexpected noises, or light physical contact. Symptoms may grow progressively worse and involve the arms and other muscles of the body. Symptoms restricted to the upper limbs have been reported. SPS symptoms may precede the cancer by several years.
The addition of paraneoplastic syndrome symptoms include:
w Focal cerebellar degeneration (neuronal loss of the cerebellum)
w Multifocal limbic and brainstem encephalitis (inflammation of the brain)
w Sensory neuropathy (pins-and-needles, pricks, tingling and numbness, or shooting pain sensations)
w Rigidity (increase in muscle tone leading to a resistance to passive movement throughout the range of motion)
w Opsoclonus-myoclonus (rapid, involuntary, fast eye movements and involuntary twitching of a muscle or muscle group)
w Retinal degeneration (progressive and eventual death of the cells of the eye’s retina)
w Spinal cord, dorsal root ganglia, anterior horn cell myelitis (inflammation of white matter or gray matter of spinal cord)
w Acute necrotizing myelopathy (destructive inflammation of the thoracic portion of the spinal cord with sensory deficits, sphincter dysfunction, and spastic paraplegia)
In cases of paraneoplastic stiff-person syndrome, patients are found to have an underlying malignancy, rapid progression, and severe disability.
Patients exhibiting progression over a few months, upper limb involvement, and severe joint deformities or immobility should be screened for a paraneoplastic connection. The rapid onset can be mistaken for a stroke.
Patients with chronic inflammatory demyelinating polyradiculopathy with atypical features including resistance to first line treatments, an unusually aggressive course, or the presence of myopathy in long tract signs should be investigated for an underlying cancer.
Standard blood tests, MRI, CSF analysis, and neurophysiologic studies are not definitive for PNS but are useful to rule out other differentials such as structural lesions, meningeal infiltration, other autoimmune diseases, Sjögren's syndrome, and inflammatory, vasculitic, or granulomatous central nervous system disease.
Nerve conduction studies show a mixed sensory and motor axonal neuropathy and occasionally typical demyelinating features that respond well to IVIG.
Evaluation of cognitive function, such as the Mini-Mental State Examination or Kokmen Short Test of Mental Status, reveal impairments in one or more categories of memory, attention, reasoning, calculation, and praxis.
Multifocal neurological symptoms can point to autoimmune etiology. The presence of epilepsy, ataxia, parkinsonism, brainstem signs, myelopathy, or peripheral nervous system disorder could also point to an autoimmune cause or toxic, nutritional, metabolic causes, or an inflammatory disorder.
Electromyography (EMG) is nonspecific for autoimmune diseases.
Electroencephalogram (EEG) monitoring is useful in patients presenting with a seizure disorder to establish diagnosis and provide a pre-treatment baseline.
EEG may show abnormalities such as focal or generalized slowing or spike-and-slow wave epileptiform discharges, mesial temporal abnormalities, or extratemporal abnormalities.
If malignancy is suspected, CT scans of chest, abdomen, and pelvis, or mammography may be warranted. Whole-body PET scans should be reserved for patients with paraneoplastic antibodies when conventional imaging fails or lesions are difficult to biopsy. The cerebrospinal fluid is usually acellular in contrast with sensory neuropathy. Protein is usually raised. The autoimmune basis for paraneoplastic syndrome is based on onconeuronal antibodies, inflammatory cerebrospinal fluid findings, and T-cell infiltration in the affected part of the central nervous system on pathologic examination. The specific role of the onconeuronal antibodies is not clear.
Paraneoplastic neuronal antibodies are consistently found only in cases of paraneoplastic syndrome as opposed to other conditions. They are sufficient to cause disease. As such, they are considered diagnostic, whether or not they are pathogenic. They arise in response to aberrant expression of antigens common to tumors and neurons. Serology is important in identifying the underlying cancer. These antibodies are associated with a restricted range of cancers.
Broad screening for antibodies is more effective than a singular test. If an occult tumor that is not typically associated with autoantibodies is found during a work-up, an attempt should be made to investigate for further tumors. Paraneoplastic symptoms are a form of early-warning system since they are often found prior to the discovery of the tumor itself.
Diagnosis rests on the demonstration of an underlying malignancy or the presence of circulating paraneoplastic neuronal antibodies in the serum and cerebrospinal fluid. Either may be positive when the other is negative. Up to fifty percent of patients with true paraneoplastic syndrome test negative for onconeural antibodies. A negative paraneoplastic screen does not exclude paraneoplastic syndrome. If both are negative, repeat investigations are warranted every six months for up to four years until a definitive diagnosis is made. Tumors may be small and localized.
Antibodies to 128-kd synaptic protein localized in neurons and concentrated at synapses were found in three women with stiff-person syndrome and breast cancer. All were anti-GAD negative. None had concurrent autoimmune disease. Patients with stiff-person syndrome and paraneoplastic syndrome most often exhibit antibodies to anti-GAD65, anti-amphiphysin, anti-gephyrin, and anti-GABARAP.
It is most often associated with cases of breast cancer, small-cell lung cancer, types B1 and B2 thymoma, and Hodgkin's lymphoma. Because stiff-person syndrome symptoms often develop before the cancer, it is important to monitor patients closely. There is potential for improvement of the symptoms after treatment for the cancer.
Paraneoplastic stiff-person patients respond poorly to benzodiazepines but many improve with steroids. In patients with stiff-person syndrome plus paraneoplastic syndrome, treatment is based on resolving the underlying malignancy, use of IVIG, plasmapheresis, intravenous corticosteroids, diazepam, and baclofen.
Patients presenting with seizures refractory to antieleptic drugs are most often associated with VGKC complex, GAD-65 and CRMP-5 IgG antibodies. Two-thirds became seizure free with immunotherapy. If a patient shows response to immunotherapy, chronic maintenance therapy should be considered.
Paraneoplastic syndromes rarely improve with immunomodulation therapies. The poor response is attributed to irreversible pathologic changes of the peripheral nerves and neuromuscular junction as opposed to neuronal degeneration.
In patients presenting with peripheral nervous system symptoms with antibodies known to be pathogenic, immunosuppressant therapies such as IVIG and plasmapheresis can be effective. This is also the case in patients with central nervous system symptoms that are likely antibody mediated. The treatments help most in the early stages. In later stages, the treatments usually fail. In those patients, rituximab and cyclophosphamide can be effective.
Early detection and treatment is the best way to stabilize the paraneoplastic symptoms. The majority of patients stabilize after a few months, but remain severely disabled due to neuronal cell death. Early detection and treatment can limit cell death.
STIFF-PERSON SYNDROME PLUS PARANEOPLASTIC SYNDROME