When PD Starts: Can We Diagnose Parkinson Disease Before The Onset Of Motor Symptoms?
A 53-year-old man, C.D., came to my clinic recently complaining of intermittent tremor of the right hand for the last six months. He had felt more tired than usual and was moving slowly during the previous year. His hand writing was getting small. When asked, he admitted that he had lost his sense of smell, and had constipation for at least a decade. He had experienced several episodes of violent nightmares during which he shouted and moved around and on one occasion hit his wife presumably thinking she was attacking him. Episodes like this had occurred frequently for more than 15 years. On examination, unilateral rest tremor was obvious and I diagnosed him with Parkinson’s disease. (PD)
A decade ago, most neurologists, if asked, would have said that C.D.’s PD had started about six months to one year before the onset of tremor. However, remarkable clinical investigations that have taken place in recent years have changed our minds and most of us would now establish the onset of PD in C.D. at least 15 years before the onset of tremor.
The idea that PD starts many years before the onset of motor symptoms (OMS) has received support from several areas of investigation. Pathological and imaging studies, for example, suggest that cell loss in the substantia nigra can be detected 5–10 years before OMS, and various observational prospective studies reveal that several non-motor symptoms occur in this pre-diagnostic phase. Epidemiological research such as the Honolulu-Asia Ageing Study, and control case studies using national electronic databases have shown that loss of smell, constipation, urinary urgency, excessive sleepiness or REM behavior disorder (RBD) (a sleep disorder characterized by violent nightmares occurring during the rapid eye movement (REM) phase of sleep) can antedate the OMS by a decade or more.
On the basis of these studies we now accept that several non-motor symptoms may antedate the OMS in PD by years or decades. The phase of PD in which such non-motor clinical manifestations take place, but classical motor symptoms have not yet developed is frequently referred to as prodromal PD. Prodromal symptoms were initially considered risk factors for the development of PD, but since these prodromal symptoms occur in manifest PD, in conjunction with motor symptoms, we now consider them clinical manifestations of PD that occur in the earliest stages.
The diagnosis of PD is based on the presence of classical motor symptoms (e.g. rest tremor and bradykinesia) and after the exclusion of other known causes, such as drug induced Parkinsonism. When diagnosing PD, physicians are implying that the person in question has a condition that will gradually worsen, with motor and non-motor symptoms developing with the passage of time, and that the medications and surgical interventions available can greatly alleviate the symptoms. We are also assuming that synuclein aggregates (so called Lewy bodies) are present in the nervous system of such person. We may not be able to give a precise prognosis, but overall, we know what the natural history of PD is once the motor symptoms appear, and know the factors that modify the natural history and can convey this information to the person with Parkinson’s.
Can we diagnose PD before OMS, in the prodromal or preclinical phase? An early, pre-motor diagnosis of PD is a key priority in research. One important reason is that promising therapeutic interventions are being tested in trials and there will be great pressure for their implementation in pre-motor phases of PD to delay or forestall the onset of motor symptoms if found effective. Identifying candidates with prodromal PD among subjects in the general population with symptoms such as constipation, excessive sleepiness, depression or loss of smell will be of enormous importance.
While advances in our understanding of pre-motor PD have been enormous, diagnosis of PD at this early stage still remains difficult, if not impossible.
The main limitation for the diagnosis of pre-motor PD is the fact that we have no valid markers that have predictive validity for PD diagnosis at this stage. For the most part, the list of symptoms identified as possibly prodromal are quite nonspecific and can have many causes other than PD. They are unlikely to prove sufficiently specific on their own to qualify as biomarkers of prodromal PD. Equally, imaging, biochemical and other biomarkers are, in isolation, not sufficiently accurate (ie, sensitive and specific) to identify and track disease progression before a diagnosis of PD can be made.
But we are approaching a stage when certain combinations of clinical, imaging and biochemical measures will likely identify a proportion of individuals at risk for developing PD. And valid laboratory tests of ongoing synucleinopathy have been developed and are being tested in prodromal PD and we are eagerly awaiting the development of imaging techniques that detect synuclein pathology in the brain before the OMS. The results of these investigations will hopefully make it possible to diagnose pre-motor PD. Our knowledge of the causes of PD, and where and when the disease starts will be greatly enhanced.
While awaiting these developments I do not diagnose people with presumed prodromal symptoms but without parkinsonism as prodromal or pre-motor PD. When people come to the clinic with complaints such as loss of smell, constipation or violent nightmares, I tell these subjects that they may have a higher risk to develop PD in the future when compared with other people without these problems, but that as far as I know, they do not have PD. I do not order in daily practice imaging tests such as a DaT SPECT as part of the work up of these non-motor symptoms in patients without parkinsonism unless in the framework of a research project. No medical intervention has been shown to delay or slow down pre-motor PD progression. I suggest to these possibly prodromal PD people to visit their family doctor or to seek my advice should any new problems or questions arise.
Eduardo Tolosa, MD presented at the First, Second, and Third World Parkinson Congress and has been involved in the WPC Program Committee twice. He is currently Director of the Parkinson Research Group in Barcelona of CIBERNED, a Research Network on Neurodegenerative Disorders of the Instituto de Salud Carlos III .
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®