Parkinson’s Disease Information

What are the symptoms that may be clues to the onset of Parkinson’s disease?

There are many potential symptoms and/or signs that may herald the earliest features and/or evidence supporting a diagnosis of Parkinson’s disease.  It is estimated that a person must lose approximately 60% (or more) of the dopamine producing cells in the brain (referred to as the substantia nigra- or known in Latin as the black substance), before noticeable changes will be detected.  This cell loss always occurs befor the symptoms that set off the suspicion in patients, family members, or even doctors .  This situation of a “threshold” of cell loss that must be eclipsed for appearance of symptoms can be compared to what may occur in patients who experience kidney failure.  When a kidney begins to malfunction, approximately 75% or more of its cells are lost, and those cells are unrecoverable.  Frustratingly, for kidney failure failure patients, the routine laboratory tests are almost never abnormal, and only hint abnormality when the failure process has already begun.  In Parkinson’s disease, as in kidney failure, a “threshold” of cells must be lost before one manifests symptoms.

Many scientists have turned their attention to searching for pre-symptomatic screening tests.  These tests have been designed to try to detect Parkinson’s disease prior to the loss of a large number of these important brainstem located substantia nigra cells.  Pre-symptomatic research has focused on areas such as smell testing, cognitive screening, imaging, and blood markers.  Currently there is no reliable biomarker for Parkinson’s disease, with the sole exception the small number of families who carry known genetic mutations for the disease..

Sometimes the symptoms of Parkinson’s disease can be very obvious, such as a resting tremor.  In many instances however, they are subtle and may manifest in ways a general doctor may not immediately identify with Parkinson’s disease (for example smaller than normal handwriting (micrographia), shoulder pain, or a decreased arm swing).  The easiest symptoms to detect are considered to be the common “motor” symptoms and these usually occur more prominently on one side of the body.  The reason(s) why Parkinson’s disease is worse on one side of the body as compared to the other body side (asymmetric symptoms) remain a mystery.

The common motor symptoms of Parkinson’s disease may include:

Tremor (shakiness), stiffness (rigidity), slowness (bradykinesia), soft voice (hypophonia), shuffling steps (and the shuffling steps may be accompanied by festination, or chasing the center of gravity with short steps—the patient may appear to be tripping in a forward direction), freezing, balance problems, start hesitation, small handwriting (micrographia), or loss of facial expression (masked face). Parkinson’s disease was sketched by a famous neurologist Sir William Richard Gower’s in 1886.  Below is a picture from his textbook of neurology(Gowers 1866): It is important to keep in mind that 20% of patients will not have resting tremor, and also that a small number of patients may present initially with depression or sleep disorders (Alves, Forsaa et al. 2008; Antoniades and Barker 2008; Chaudhuri and Naidu 2008; Jankovic and Aguilar 2008; Lewitt 2008; Reichmann 2008; Schapira 2008; Sommer and Stacy 2008).

When Does Parkinson Disease Really Start?

This is one of the million dollar questions in Parkinson’s disease research.  We actually don’t know the answer. From the clinical trial or research perspective, we arbitrarily base the answer on either the occurrence of the first symptom or alternatively the date of diagnosis.  The date of diagnosis is however biased, and largely based on obvious motor symptoms such as tremor, stiffness, or slowness. We know that this estimate therefore is grossly inaccurate. In fact, by the time a Parkinson’s disease patient manifests the first symptom (e.g. tremor of the fingers), significant degeneration of the dopaminergic neurons in the brain has already occurred.

We now know that the loss of the sense of smell, constipation, depression, personality changes, sleep problems, and even anxiety may long precede the motor symptoms of Parkinson’s disease. The problem with using these symptoms as diagnostic markers however, is that they commonly occur in the general population, making it very difficult to judge what is part of Parkinson’s disease, and what is not(Jankovic, Shoulson et al. 1994; Jankovic 2001; Jankovic 2008).

Complicating the picture as to the onset of Parkinson’s disease has been the discovery that many patients may have rapid eye movement sleep disorders (REM sleep disorder) many years prior to the onset of motor symptoms(Berg 2006; Kumru, Santamaria et al. 2007; Manni, Terzaghi et al. 2007; Marion, Qurashi et al. 2008).  Additionally, Braak and colleagues have recently proposed that the degeneration in Parkinson’s disease actually starts well before dopaminergic cells in the midbrain begin to die(Braak, Del Tredici et al. 2002; Braak, Del Tredici et al. 2003; Pirker, Holler et al. 2003; Uitti, Baba et al. 2005; Braak, Bohl et al. 2006; Braak, Muller et al. 2006). The cells that die in Parkinson’s disease are deep in an area called the brainstem.

What is the history of Parkinson’s disease?

Parkinson’s disease, sometimes erroneously termed paralysis agitans, was described in the Indian medical system of Ayurveda (called  Kampavata), and also by Galen (A.D. 175) who referred to it as the “shaking palsy”.  Perhaps the most interesting reference came from Shakespeare who wrote in Henry VI “why dost thou quiver man.”  The character in the story responds by saying “the palsy and not the fear provokes me.”  The use of the term Parkinson’s disease was largely credited to the highly influential 19th century French Neurologist Jean-Martin Charcot, although it should be noted that many people prior to Parkinson himself described the disease.  James Parkinson (1755-1824) a Londoner and son of an apothecary and surgeon is credited with the eponym for his 1817 essay on the shaking palsy.  His descriptions included six cases only three of which were actually examined (two were met on the street and one simply observed)(Thomas 1978; Goetz 1986; Herzberg 1987; Hagglund 1992; Finger 1994; Kowa 1994; Tanaka and Fukuda 1994; Horowski, Horowski et al. 1995; Yanagisawa 1996; Jones 2004; Stien 2005; Hornykiewicz 2006; Zhang, Dong et al. 2006; Kempster, Hurwitz et al. 2007; Williams 2007).

How do you approach a treatment plan for Parkinson’s disease?

What is the history of the discovery of Levodopa?

There were several seminal discoveries that led to the development of levodopa as a therapy for Parkinson’s disease:

  • 1911 – First synthesis of its D,L racemate and the isolation of its L-isomer from the seedling of Vicia faba beans
  • 1913 – Isolation from legumes (pea plant family)
  • 1930 – L-Dopa was shown to have an effect on Rabbit glucose metabolism
  • 1938 – L-dopa decarboxylase described and enzymatic conversion to dopamine demonstrated
  • 1940 – Studies on the effects of L-Dopa on blood vessels
  • 1950 – Studies began to consider the use of dopamine on the brain
  • 1960 – Consideration was given to Parkinson’s disease treatment which was found to be related to dopamine (throughout the 1960’s there were inconsistent responses to treatment)
  • 1967 – High dose levodopa was verified for treatment of patients suffering with Parkinson’s disease (Dr. George Cotzias)
  • 1970’s – Dopamine decarboxylase was added to the regimen to improve the side effect profile and absorption

Many scientists have worked on the development of levodopa and levodopa therapy and the list of their names is too long for a short book such as this.  Arvid Carlsson from Sweden won the Nobel Prize in 2000 for his work on the administration of levodopa to animals (1950’s), and Oliver Sacks (the famous neurologist who wrote, The Man Who Mistook His Wife for a Hat, wrote about the treatment of post-encephalitic parkinsonism with levodopa in his book Awakenings. Oleh Hornykiewicz, who also played a key role in the development of levodopa, published a recent paper reviewing the discovery of dopamine deficiency(Thomas 1978; Finger 1994; Tanaka and Fukuda 1994; Yanagisawa 1996; Hornykiewicz 2006).

What is the best test for my doctor to order to diagnose Parkinson’s disease?

There is no reliable blood test to diagnose Parkinson’s disease.  The best way to make a diagnosis is to have a neurological examination by someone experienced in the care of Parkinson’s disease patients.  There are diagnostic criteria for the diagnosis of Parkinson’s disease (UK Brain Bank Criteria), which usually include:

 I: Is Bradykinesia (slowness of movement present?

 II: Are two of the below present?

___ Rigidity (Stiffness in arms, leg, or neck)

___ 4-6 Hertz resting tremor

___ Postural instability not caused by primary visual, vestibular, cerebellar,

proprioceptive dysfunction

III: Are at least 3 of the below present?

___ Unilateral onset

___ Rest tremor present

___ Progressive disorder

___ Persistent asymmetry affecting side of onset most

___ Excellent response (70-100%) to levodopa

___ Severe levodopa induced dyskinesia

___ Levodopa response for 5 years or more

___ Clinical course of 5 years or more

Very rarely, there exists confusion about the diagnosis, and in these cases other tests such as Positron Emission Tomography, and Beta SPECT scanning may be useful(Hughes, Ben-Shlomo et al. 1992; Hughes, Daniel et al. 1992; Hughes, Daniel et al. 1993; Jankovic 2008; Jankovic and Aguilar 2008).  

Learn more about Parkinson Disease and its treatment by watching videos from our Parkinson Symnposiums …

Read more about Parkinson’s Disease in Dr. Michael S. Okun’s Book, “Ask the Doctor about Parkinson’s Disease”.  Dr. Okun works at the University of Florida Gainesville, and also serves as the National Medical Director for the National Parkinson Foundation.