The diagnosis of PD is made on the basis of the presence of the four cardinal symptoms, but these symptoms are not exclusive to PD. There are several disorders that even to an expert may initially be diagnosed as PD. The terms Parkinson-plus disorder (Parkinson disease plus other symptoms), Parkinson-like disorder, Parkinson Syndrome, or Parkinsonism are applied to those disorders that initially resemble PD.
On post-mortem examination of PD patients, the loss of dopamine cells in the substantia nigra is accompa-nied by a marker present in most of the dying cells. This marker is found in a part of the cell called the cytoplasm. Under the microscope it appears as a round body, almost filling the cell. It is called a Lewy body, after Friedrich Lewy, the doctor who first described it.
How the Lewy body is formed, whether it is a sign of death or recovery, and the composition of the Lewy body are questions which science is seeking to answer. As noted earlier, at birth we have 400,000 neurons in the substantia nigra, 200,000 on each side. The first symptoms of PD appear when there is a 60% loss of dopamine neurons.
In the PD-like disorders, there may be an equal or greater loss of dopamine neurons, which explains in part why these disorders are less responsive to levodopa. In PD, if levodopa is started early and used in relatively high doses, it results in dyskinesias: abnormal involuntary movements and chaotic dance-like movements called chorea, all of which are worse on the side of the body more affected by PD. However, in the PD-like disorders, levodopa does not result in dyskinesias.
We know that PD both starts and progresses slowly— from diagnosis to need for treatment may be one or two years. However, the PD-like disorders start and progress more rapidly, with less time from diagnosis to treatment.
Corticobasilar degeneration (CBD) and progressive supranuclear palsy (PSP) are two Parkinson-like dis-orders characterized by a loss of neurons in the sub-stantia nigra. However, the dying neurons do not contain Lewy bodies, as they do in PD. Instead, the dying neurons contain tangles of a protein called “tau.” These tangles have a distinct appearance under a microscope. In CBD and PSP, in addition to the death of substantia nigra neurons, target neurons in the putamen and globus pallidus also die. This explains why CBD and PSP do not usually respond to levodopa.
CBD may start asymmetrically (on one side), usually the right side. The right hand becomes rigid and the rigidity has a peculiar quality, called gegenhalten—it increases the more you move your hand. Sometimes the arm or hand does not do what you want it to do, as though it won’t obey you. You arm is not weak or slow, it just won’t do what you want. This is called a disconnection syndrome, or an “alien hand.” CBD progresses more slowly than the other PD-like disorders. It may start with a loss of balance and falls and may resemble PSP.
Progressive supranuclear palsy (PSP) gets its name from the degeneration of centers in the brain that are located above (supra) the nuclei (groups of neurons) that control eye-movements. In PSP, you’re unable to move your eyes, not because there’s something wrong with your eye muscles, but because the supra nuclear centers are paralyzed (or palsied). The inability to move the eyes, first in an up-and-down direction, then in a side-to-side direction, usually appears early and enables a neurologist to make the diagnosis. If the eye movements are involved late, the diagnosis is more difficult and may be confused with PD.
A specialist will test your eyes’ ability to follow figures or lines on a tape that is past them. Normally in following the tape your eyes beat rapidly, a response called opticokinetic nystagmus (OKN), the absence of which, in one or more directions, suggest PSP. PSP is also characterized by the early appearance of postural instability with falls, difficulty with speaking and swallowing, and a poor response to levodopa. In some patients, an MRI reveals shrinkage of the brainstem. Although there’s no specific treatment for PSP, a neurologist can suggest ways to minimize falls, improve swallowing, and make life more comfortable.
Multiple-system atrophy (MSA) is the most common of the PD-like disorders. There are three forms of MSA. The first, ShyDrager, or MSA with ANS involvement, may initially resemble PD. The absence of tremor, early and prominent symptoms of ANS insufficiency: dizziness on standing, difficulty swallowing, difficulty urinating, anterocollis (a flexed head), a relative lack of response to levodopa, and more rapid progression than PD, usually allows a neurologist to distinguish between the two.
Proper management of the symptoms of ANS insufficiency can greatly improve a patient’s quality of life. MSA with ataxia is a combination, in effect, of MSA with atrophy of the cerebellum. It can usually be distinguished from PD by the early appearance of postural instability (lack of balance), a voice that is difficult to understand, and a marked tremor of both hands that’s present on move-ment and absent at rest. An MRI may reveal shrinkage of the cerebellum. Striatonigral degeneration (SND) is the most difficult of the MSAs to distinguish from PD. The early appearance of a flexed neck and a poor response to levodopa eventually leads to the diagnosis. Proper understanding of MSA often leads to a better quality of life. Unlike PD, the MSAs do not respond to deep brain stimulation (discussed later).
Dopa responsive dystonia (DRD) was first described in Japan by Professor Segawa and is often called Segawa’s disease. DRD is an inherited disorder that starts in the teens, 20s, and 30s. It resembles PD except for the presence of prominent dystonia that may involve the neck, arms, legs, or trunk with accompanying tremor. DRD differs from other dystonias by its dramatic response to levodopa and differs from PD by its slower progression.
DRD results from an inability to change the small amount of levodopa in the diet to dopamine because a chemical, tetrahydrobiopterin, is missing in the brain. This can be overcome by giving levodopa in amounts comparable to those used in PD. Difficulty arises in dis-tinguishing PD with dystonia from DRD, although PD with dystonia is not inherited and usually starts at a later age. A PET scan or a SPECT scan may distinguish DRD from PD and PD with dystonia, as the DRD PET-scan will not reveal a deficiency of dopamine, as in PD, in fact it will be normal.
Wilson disease is an inherited disorder in which a mutation in a gene on chromosome 13 leads to a deficiency in a protein called ceruloplasmin, which carries copper in the body. A deficiency in ceruloplasmin results in an excess of copper in the blood that, in turn, results in deposits of copper in the liver, the eyes, and the brain. Patients with Wilson disease develop symptoms at an early age, below age 40, and depending on where their copper has deposited they may have symptoms of a failing liver, psychiatric symptoms, chorea or Parkinsonism.
PD patients who have a suspected family history of PD and whose symptoms develop at an early age should be examined for Wilson disease. The examination includes tests of liver function, a cerulo-plasmin level, a blood and urine copper level, an examination by an ophthalmologist for copper deposits in the eyes and an MRI. Although Wilson disease is rare, one patient with Wilson disease for 1,000 patients with PD, the diagnosis should be pursued because there are specific treatments for Wilson disease.