Associated Syndromes
In the classification section we described many antibody mediated neurologic diseases. Here you will find descriptions of the syndromes most commonly associated with antibody-mediated neurologic diseases.
Encephalitis
Encephalitis is a general term for inflammation of the brain, leading to problems with memory, cognition, and/or altered levels of consciousness. We focus on encephalitis caused by antibodies (or autoimmune encephalitis), but it may also be caused by other sources including viruses. Below you will find more detail on the most common forms of autoimmune encephalitis.
Paraneoplastic Encephalomyelitis
In paraneoplastic encephalomyelitis multiple areas of the nervous system are involved at the same time. Patients usually develop symptoms or deficits that combine those described into limbic encephalitis, cerebellar degeneration, brainstem encephalitis, and/or myelitis. In addition, some patients also develop sensory deficits caused by involvement of the neurons of sensory nerves.
There are several paraneoplastic antibodies and cancers associated with paraneoplastic encephalitis, the most frequently found antibodies are anti-Hu and anti-CV2/CRMP5. The best chance of improving or stabilizing these diseases involves treating the tumor and giving immunotherapy.
Paraneoplastic Limbic Encephalitis
Limbic encephalitis is a form of brain inflammation that mostly affects the limbic system. This part of the brain is involved in memory, emotion, and behavior. This includes the reactions of fear and anger, and emotions associated with sexual behavior. The limbic system is closely related to the hypothalamus, which regulates the autonomic nervous system (involved in the control of blood pressure, heart rate, salivation, pupillary constrictions, among others), endocrine function (hormones), body temperature, food and water intake, and sleeping and wakefulness.
Inflammation of the limbic system may cause a variety of symptoms such as:
- Mood changes (depression, irritability, anxiety)
- Problems sleeping
- Short-term memory problems
The symptoms associated with memory problems are always severe and should not be confused with mild problems sometimes caused by lack of attention, or with chronic memory problems that some patients (with other diseases) develop over months or years. In addition, many patients with limbic encephalitis develop seizures or spells (for example, sudden sensation of bad smell or taste, staring or lip smacking, cloudiness of consciousness) or sometimes, total loss of consciousness resulting in a 'grand mal seizure'.
The combination of clinical symptoms analysis of spinal fluid, and brain MRI and EEG findings usually suggest the diagnosis of 80% of patients. None of these tests however, indicates that the limbic encephalitis is caused by an antibody. The autoimmune cause is confirmed when an antibody is identified, or in the case that no antibody is identified, when other causes are excluded (for example viral encephalitis) and the presence of a cancer is demonstrated.
Paraneoplastic Brainstem Encephalitis
Paraneoplastic brainstem encephalitis affects the brainstem, which is located in the base of the brain. The brainstem connects the brain with the spinal cord and cerebellum. It is involved in critical neurological functions such as controlling eye movements, swallowing, breathing, heart rate, equilibrium, and level of consciousness.
Patients with brainstem encephalitis may develop:
- Vision changes (double or blurry vision)
- Vocal changes (slurred speech)
- Vertigo or dizziness
- Difficulty swallowing fluids or solids
- Problems controlling breathing
- Changes in the rhythm of the heart (dysrhythmias)
- Tremor and slow movements (that may resemble Parkinson's disease)
- Progressive decrease of consciousness
- Coma
Usually encephalitis of the brainstem occurs along with involvement of other areas of the brain or cerebellum, therefore the antibodies involved are usually the same as those associated with paraneoplastic encephalomyelitis.
The response to treatment of the tumor and immunotherapy is usually poor for brainstem encephalitis, but symptoms can stabilize if the disorder is treated promptly.
Paraneoplastic Cerebellar Degeneration (PCD)
Patients with Paraneoplastic Cerebellar Degeneration (PCD) develop severe problems in performing fine and smooth movements of the arms, legs, and muscles that control the eyes, speech, and swallowing. The movements appear to be fragmented and sometimes made worse by a tremor. For example, when a patient tries to reach for an object with one had, the movement 'overshoots' the location of the object. If the patient can walk the gait is unsteady, like a person who is drunk, but in most cases the unsteadiness make it impossible to walk.
Patients also have problems controlling eye movements, resulting in double vision or a sensation of 'jumpiness' of the vision. This makes tasks such as reading or watching TV difficult or impossible. Simple chores, such as writing, feeding oneself, or dressing can also be impossible to perform.
Paraneoplastic cerebellar degeneration is the most difficult of the paraneoplastic diseases to treat. Although some patients may notice mild improvement after treatment of the tumor and immunotherapy, most patients do not improve. At best, treatment may result in stabilizing symptoms. In very rare instances, dramatic improvement occurs.
Neuromyotonia, Isaacs' Syndrome, or Peripheral Nerve Hyperexcitability
Patients with these disorders typically develop cramps, muscle twitches (called fasciculations or myokymias), and/or muscle stiffness and spasms. Muscle relaxation can also be difficult, for example after making a fist it can be hard to open the hand. Some patients develop increased sweating and sensory symptoms caused by a neuropathy.
The diagnosis of this disorder is confirmed with electric tests (EMG/nerve conduction studies). Neuromyotonia is sometimes associated with thymoma and lung cancer, but it is not always associated with cancer.
Stiff-person Syndrome (SPS)
Patients with stiff-person syndrome may develop muscle stiffness and rigidity with painful spasms. These problems usually occur in the muscles of the lower back and legs, but may also affect the arms and neck. In some patients the initial symptoms can be in one leg, and then progress to affect other parts of the body. The spasms can be triggered or made worse by anxiety, loud noises, or simply by touch or trying to move.
The diagnosis of stiff-person syndrome is usually confirmed with electrical tests such as EMG and nerve conduction studies. Also, seeing how some medications (such as valium) improve the symptoms may help make the diagnosis.
Antibodies associated with stiff-person syndrome are anti-amphiphysin and anti-GAD, which can both be found in spinal fluid. Anti-amphiphysin antibodies are considered paraneoplastic and are frequntly associated with tumors of the breast and lung. Anti-GAD antibodies are not fully specific for stiff-person syndrome, meaning some patients with these antibodies will not have this syndrome. These antibodies may also occur in patients with thymomas, or those with some types of epilepsy, cerebellar degeneration, or diabetes.
It is believed that antibodies against GAD or amphiphysin disturb the function of neurotransmitters (chemicals involved in nerve cell interactions) called GABA and glycine. Therefore, treatments for stiff-person syndrome include:
- Drugs that enhance the function of these neurotransmitters (diazepam, baclofen, sodium valproate, tiagabine, vigabatrin)
- Immunotherapy
- Treating the tumor (if the disease is considered paraneoplastic)
Lambert Eaton Myasthenic Syndrome (LEMS)
This disorder result from impaired release of neurotransmitter acetylcholine at the site where the nerve and muscle connect to each other (called the neuromuscular junction). Because of this deficit, the muscles do not contract well and the patient becomes weak. The weakness usually occurs in the hips and shoulders but can also affect hands and feet. A frequent, but mild symptom is drooping eyelids (called ptosis) and double vision (diplopia). The muscles of the neck and sometimes the respiratory muscles that control breathing can also be affected.
LEMS is also linked with impaired neurotrasmitter release at other synapses, causing several 'autonomic symptoms' such as:
- Dry mouth
- Rapid decrease of blood pressure when the person stands up (orthostatic hypotension)
- Constipation
- Difficulty controlling bladder function
- Erectile (sexual) dysfunction
The most common clinical picture is a patient that develops weakness and a dry mouth. The weakness is mainly noted when the patient tries to stand up for chairs, walk upstairs, or raises the arms in tasks such as combing the hair. The neurological exam shows the motor weakness and an abnormal decrease of muscle reflexes.
Patients with LEMS have antibodies called voltage-gated calcium channel (VGCC) antibodies that cause the decreased release of acetylcholine. Detection of these antibodies is useful, but not necessary, for the diagnosis of LEMS. Approximately 60% of all patients with LEMS have small-cell lung cancer. Other types of tumors may rarely occur.
Treatment of LEMS includes:
- Drugs that make up for the decrease of acetylcholine, such as 2, 4-diaminopyridine (not commerically available in the in USA), or a combination of pyridostigmine and guanidine
- Strategies aimed at decreasing VGCC antibodies, such as plasma exchange or IVIg
- Long-term immunosuppression: prednisone alone or combined with azathiprine or cyclosporine
- Tumor treatment if the LEMS is paraneoplastic
LEMS may also occur in association with paraneoplastic cerebellar degeneration, in which case the tumor is almost always a small-cell lung cancer. In these patients, the above treatments may improve the LEMS but rarely improve the cerebellar degeneration.
Sensory Predominant Neuronopathy
The term 'sensory neuronpathy' refers to the neurons from which the sensory nerves start. These neurons are clustered in the dorsal root ganglia, which area located along the sensory nerve roots close to the spinal cord. Therefore, inflammation of these ganglia causes malfunction and degeneration of the neurons. This results in many sensory deficits and symptoms.
Symptoms of sensory neuronopathy usually start in an asymmetric fashion. This means, patients develop pain, numbness, or sensation of pins and needs in one foot, or hand, and in a matter of days or weeks these symptoms progress to involve the other side. Eventually both sides are involved.
The symptoms most frequently described by patients include:
- Lancinating pain (short-lasting, electric shock type of pain)
- Sensation of 'walking on sand'
- Cold numbness
- Sensation of burning in hands and feet
- Sensation in the face
- Changes in senses of taste and hearing
At the advanced stage of the disease all types of sensations can be severely diminished or lost including sensation of:
- Pain
- Pressure
- Vibration
- Temperature
- Ability to know where limbs are when the eyes are closed, what is referred to as sensory ataxia
Patients with sensory neuronopathy usually have anti-Hu antibodies. These antibodies are important markers of several forms of paraneoplastic encephalitis or encephalomyelitis. In many patients the symptoms of sensory neuronopathy are the first symptoms of encephalomyelitis. Patients with anti-Hu antibodies usually have a small-cell lung cancer, although other cancers can also be associated.
Treatment of anti-Hu associated sensory neuronopathy should be focused to the tumor. Immunotherapy should be considered at initial stages of the disease, or when there are signs of symptoms of disease progression, but results are usually mild and for the most part disappointing. There is some evidence that immunotherapy treatments directed at the T-cells (instead of only against the antibodies) may help some patients.