Parkinsons Disease And Cryptogenic Epilepsy
Milton C. Biagioni
1The Marlene and Paolo Fresco Institute for Parkinsons & Movement Disorders, NYU Langone Medical Center, New York University School of Medicine, New York, NY, USA
2Department of Neurology, Baylor Scott & White Healthcare, Austin, TX, USA
Abstract
Epilepsy is an uncommon comorbidity of Parkinsons disease and has been considered not directly associated with PD. We present five patients who had concomitant PD and cryptogenic epilepsy. Although rare, epilepsy can coexist with PD and their coexistence may influence the progression of PD. While this may be a chance association, an evolving understanding of the neurophysiological basis of either disease may suggest a mechanistic association.
1. Introduction
Parkinsons disease is traditionally considered primarily a subcortical disorder with late cortical involvement. There is, however, mounting evidence of considerable cortical involvement, even in the early stages of PD . The damage seems to involve, at least in part, the simultaneous processes of both the diffuse progressive deposition of alpha-synuclein and the secondary biological changes that disrupt neural connectivity . These processes reinforce the concept of dysfunctional neural networks as a potential basis of symptomatology in PD .
2. Methods
3. Cases
| 1 | |
| H& Y stage at PD Dx | 1 |
| H& Y stage at epilepsy Dx | N/A |
| H& Y stage at last visit | 3 |
| 796 | 780 |
3.1. Patient 1
3.2. Patient 2
3.3. Patient 3
3.4. Patient 4
3.5. Patient 5
4. Discussion
Competing Interests
Neurodegeneration With Brain Iron Accumulation
Neurodegeneration with brain iron accumulation patients present with a progressive extrapyramidal syndrome associated with iron deposition in the basal ganglia. The two main syndromes are outlined here, although there are additional syndromes including neuroferritinopathy and aceruloplasminemia. The most common of the NBIA disorders is pantothenate kinase-associated neurodegeneration , resulting from mutations on the PANK2 gene, accounting for 50%. The classic syndrome manifests in early childhood with a combination of pyramidal and extrapyramidal features . PKAN can also rarely present in early adulthood. There are typical MRI findings, with a central hyperintensity with surrounding low signal on T2 images in the globus pallidus, giving the so-called eye-of-the-tiger sign .
The second main type of NBIA is PLA2G6-associated neurodegeneration . When onset occurs in infancy, PLAN causes progressive motor and mental retardation with cerebellar ataxia, seizures, and pyramidal signs. However, onset can occur later in life which leads to an atypical syndrome that may mimic PD, with rest tremor, rigidity, and bradykinesia and a good response to levodopa. However, patients also exhibit additional features including eye-movement abnormalities and pyramidal signs .
Relationship Between Disrupted Neuronal Connectivity And Epileptic Seizures
Epilepsy is considered a disease of network dysfunction.47,48 At a microscopic level, both simple and complex partial seizures involve disruptions in the excitatory interactions between cerebral cortex pyramidal cells.49 From a neurophysiology view, the EEG-graphic representation of an epileptic event is characterized by the paroxysmal onset of hyper-synchronized sharp waves disrupting the neuronal background activity. This activity is often multifocal, reflecting a broader network dysfunction.50,51 Moreover, TMS studies demonstrate similar neurophysiologic features between epilepsy and PD characterized by a state of increased cortical excitability as indicated by reduced intra-cortical inhibition and increased intra-cortical facilitation observed in both patient populations.25,52â55 As mentioned before, in PD, cortical neurons innervating the basal ganglia become hyperexcitable, possibly as a compensatory mechanism following the incremental rise in the output threshold of striatal dopaminergic neurons. As such, it would not be surprising if this putatively maladaptive phenomenon may eventually lead to the generation of epileptiform activity. While epidemiologically, epilepsy-increased comorbidity in patients with PD remains questioned,13,56 our group published the largest case series of patients with PD with concomitant epilepsy57 raising the possibility that epileptic activity in these patients may indeed be under-diagnosed and under-recognized.
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Symptoms Of Parkinsons Disease
The symptoms of Parkinsons disease and the rate of progression differ amongst individuals. Because of the similarity of signs, many people often mistake PD symptoms with the effects of normal aging. PD can be a complicated disorder to diagnose because no definitive tests are available to detect the disease.The early symptoms are typically subtle, difficult to identify, and occur gradually. For example, a person may feel slight tremors while getting out of a chair, notice that their handwriting has become slower or looks too cramped, feel as if they speak too softly, or face difficulty moving an arm or leg. This places a great responsibility on bystanders, as friends and family members may be the first to notice changes in a person with early Parkinsons. One key factor of identification is a lack of animations or expressions in a persons face.
Some common symptoms of Parkinsons disease are as follows:
Risk Of Seizures In Mds
Among the hypokinesias, Parkinsons disease is one of the most prevalent neurodegenerative disorders worldwide. The relation between PD and seizures has been controversial, with small studies showing a positive correlation, but generally with a low prevalence of seizures in patients with PD. However, a more recent study demonstrated that patients with PD who did not have any seizure-provoking comorbidity had an adjusted OR of epileptic seizures of 2.24 compared with PD-free individuals without any seizure-provoking comorbidity. Although the association between PD and seizures remains unclear, superimposed brain disorders such as cerebrovascular disease, infections, surgery and trauma tend to be more strongly associated with seizures in patients with PD.
DYT-ATP7B or Wilsons disease is a hepatolenticular degeneration due to mutations in the ATP7B gene leading to an impaired copper metabolism. Majority of patients exhibit neurological and hepatic symptoms. DYT-ATP7B may display hypokinetic or hyperkinetic movements. Seizures can occur in approximately 10% of patients, including generalised tonic-clonic and focal onset seizures. Patients with seizures more often have white matter changes than those without .
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Frontotemporal Dementia With Parkinsonism
Parkinsonism in frontotemporal dementia is usually seen in the behavioral variant, rather than in association with primary progressive aphasia, and can develop either before or during the development of the classical FTD syndrome. It can closely mimic idiopathic PD or have features suggestive of PSP or CBS. It is seen in association with underlying tau, TDP-43, or FUS pathology, as well as corresponding mutations in several genes, which include MAPT, PGRN, C9ORF72, FUS, and TARDBP. Rigidity and bradykinesia tend to be the more prominent parkinsonian features, with rest tremor occurring rarely. There is variable responsiveness to levodopa .
Subclinical Or Atypical Epileptic Seizures Could Masquerade As Non
While the non-motor questionnaire and non-motor symptoms scale 73,74 allow improved detection and tracking of NMD-PD, the symptoms often remain under-recognized and under-appreciated by clinicians and caretakers. Recently, six different clinical phenotypes of PD were recognized on the basis of prevalent NMS-PD.75 These non-motor signatures included cognitive impairment, apathy, depression/anxiety, REM behavioral disorder , lower limb pain, and weight loss/olfactory dysfunction. This distinction may help in promoting the incorporation of NMS-PD into routine assessments, emphasizing the importance of these features for an adequate appreciation of the patientâs clinical picture. On the other hand, a rigid categorization may challenge the flexible and consistent monitoring of these dynamic and overall nonspecific symptoms along the disease course.
In the following section, we will focus on clinical features frequently displayed by patients with PD that may signal an ongoing subclinical or non-motor epileptic event masquerading as NMS-PD.
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Potential Therapeutic Implications For Non
Current available therapies for treating NMS-PD include pharmaceutical therapies, exercise, and brain stimulation to improve various NMS-PD.88,89 Cognitive deficits contribute largely to the morbidity of NMS-PD and have remained without efficient therapy. AEDs have been proposed to prevent the cellular death and cognitive worsening associated with the presence of epileptic seizures in AD.90 In light of the aforementioned similarities between PD and AD constructs, we believe that the long-term impact and therapeutic implications of AEDs on the natural course of PD should indeed be adequately investigated through properly designed clinical trials in the future.
Many mechanisms of cognitive decline and other NMS-PD have been proposed in PD. These include progressive alpha-synuclein disease, affected neurotransmitter systems, synaptic changes, inflammation, mitochondrial dysfunction, genetic risk factors,91 white matter lesions,92 and network dysfunction.93,94 While studies in AD have begun to support the role of connectome dysfunction in accelerating cognitive decline through recurrent epileptic events, this possibility remains to be investigated in patients with PD. As such, properly designed studies should be conducted to better characterize these phenomena in this specific population.
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What Causes Alzheimers And Parkinsons Seizures
It is well known that damage to the brain can mean people start having seizures. Degenerative diseases such as Alzheimerâs and Parkinsonâs damage different parts of the brain and this is likely to be part of the reason why dementia and epilepsy sometimes occur together.
Looking specifically at epilepsy and Alzheimerâs disease, researchers have found that the condition makes certain chemical proteins build up in the brain. These proteins can make brain cells more âexcitableâ which may make seizures more likely too.
Read more: Why do people get epilepsy?
Mds That Look Like Seizures
These are MDs that look like seizures due to the occurrence of episodic involuntary movement. Subcortical mechanisms are involved, thus explaining why EEG does not show epileptic activity in most cases.
Hemifacial spasm is an MD of the seventh cranial nerve which is characterised by either brief or persistent, intermittent twitching of the muscles innervated by the facial nerve. Primary HFS likely results from compression of the seventh nerve at the root exit zone in the posterior cranial fossa by an aberrant or ecstatic vessel, whereas secondary causes are seen after VII nerve palsy or brainstem lesions. HFS may be mistaken for EPC involving the face .
Periodic limb movements are sleep-related phenomena characterised by periodic episodes of repetitive and highly stereotyped limb movements, which most often occur in the lower extremities. PLMS can be associated with brief arousals in sleep and autonomic reaction, and is defined as the presence of > 15 movements per hour and a complaint of insomnia and/or excessive daytime sleepiness with no other explanation for these symptoms. PLMS are frequently seen in restless legs syndrome but can also occur in sleep disordered breathing, narcolepsy and rapid eye movement sleep behaviour disorder, as well as in several medical conditions, like renal failure, essential hypertension and PD, or associated with medication intake . PLMS may mimic focal seizures, and in some cases further investigation is required.
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Epilepsy In Other Neurodegenerative Disorders: Huntington
Absence seizures and seizures caused by other pathologies, 95% CI = 8.74-17.48) or with > 1 seizure-provoking comorbidity that can affect their quality of life even more, Parkinsons disease is one of the most prevalent neurodegenerative disorders worldwide, the positive results of dietary interventions might offer Absence seizures are categorized into two typical and atypical, Some patients may make movements like chewing, SUBMIT RESPONSE 4 Review tested concept
Treatment For People With Dementia And Epilepsy
Researchers are still learning about the brain and how seizures and Parkinsonâs disease, Alzheimerâs and other kinds of dementia affect one another.
When it comes to treatment, there is good news. Studies have found that epilepsy drugs help reduce seizure activity in people with dementia and this boosts the quality of life.
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Parkinsons Disease Risk Factors
Hypertension and Type 2 diabetes were associated with an increased risk of developing Parkinsons disease in East London a stronger association was found between memory complaints in this group than previously observed. East London has one of the highest proportions of Black, South Asian, and other mixed/ethnic groups, which comprise 45% of residents in the area, compared to 14% in the rest of the UK. Furthermore, 80% of the studys participants were from low-income households.
Lead study author Dr Cristina Simonet, neurologist and PhD student at the Queen Mary University of London, commented: This is the first study focusing on the pre-diagnostic phase of Parkinsons in such a diverse population with high socioeconomic deprivation but universal access to health care. People from minority ethnic groups and deprived areas have largely been underrepresented in Parkinsons research up till now, but to allow us to get a full picture of the condition, we need to ensure research is inclusive and represents all those affected.
This study confirms that many of the symptoms and early features of Parkinsons can occur long before a diagnosis. Through our ongoing PREDICT-PD research, were hoping to identify people at high risk of Parkinsons even before obvious symptoms appear which means that we could do more than just improve quality of life for patients, and perhaps be in the position to slow down or cure Parkinsons in the future.
New Early Signs Of Parkinson’s Uncovered In Most Diverse Uk Study To Date
by Queen Mary, University of London
Hearing loss and epilepsy are early features of Parkinson’s, according to pioneering new research from Queen Mary University of Londonthe first UK study of the condition in such a diverse population, published today in JAMA Neurology.
Queen Mary researchers funded by Bart’s Charity used electronic primary healthcare records from over a million people living in East London between 1990 and 2018 to explore early symptoms and risk factors for Parkinson’s.
The researchers found that known symptoms associated with Parkinson’s, including tremor and memory problems, can appear up to ten and five years before diagnosis respectively. They also uncovered two new early features of Parkinson’s, epilepsy and hearing loss, and were able to replicate these findings using additional data from the UK Biobank.
Whilst early signs of Parkinson’s have been described previously, these studies have largely focused on affluent white populations, with patients from minority ethnic groups and those living in areas of high social deprivation largely under-represented in Parkinson’s research to date. The new study provides further evidence of risk factors and early signs of Parkinson’s, using data from such a diverse and deprived urban population for the first time.
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Emotional And Behavioral Changes
Depression, paranoia, anxiety, and other emotional changes are fairly common in PD patients. Patients may even undergo a 90-degree behavior change and may be unable to manage their feelings.Loss of or decrease in automatic movementsPatients may suffer from a decreased ability to perform conscious movements such as smiling, blinking, or even swinging their arms when talking. In severe cases, they may lose all automatic movements, resulting in partial paralysis.
Causes Of Parkinson’s Disease
Parkinson’s disease is caused by a loss of nerve cells in part of the brain called the substantia nigra. This leads to a reduction in a chemical called dopamine in the brain.
Dopamine plays a vital role in regulating the movement of the body. A reduction in dopamine is responsible for many of the symptoms of Parkinson’s disease.
Exactly what causes the loss of nerve cells is unclear. Most experts think that a combination of genetic and environmental factors is responsible.
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Parkinson’s: What Is It And What Are The Symptoms
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Parkinson’s occurs when proteins start clumping in the brain, causing the death of dopamine-producing neurons. The death of these cells directly affects movement, causing physical limitations, tremors and slowness. Catching the disease early is important, as some treatments are more effective when administered at this stage. According to one new study, epilepsy and hearing loss could be two previously unknown early factors of Parkinsons. The discovery could make earlier diagnosis a greater possibility in the future.
What Is Parkinsons Disease
Parkinsons disease is a progressive neurodegenerative disease that typically affects the predominantly dopamine-producing neurons in a specific brain region known as substantia nigra. Parkinsons disease significantly affects movement and causes tremors shaking, along with difficulties in balance and coordination. The symptoms begin gradually and may even start from a hardly noticeable tremor in just one hand.Although tremors are relatively common in PD, this disorder also causes the slowing of movement or stiffness of muscles. Patients may even suffer from behavioral and emotional changes as the disease progresses and may face sleeping difficulties, memory lapses, fatigue, and difficulty in talking.
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Causes Of Parkinsons Disease
Parkinsons disease typically occurs when nerve cells in the basal ganglia either die or become impaired. The nerve cells in the basal ganglia hold paramount significance as they produce an essential brain chemical known as dopamine.The death of nerve cells results in a decrease in dopamine production, which causes several movement disabilities that are commonly seen in PD patients. Despite extensive research, scientists have been unable to root out the reasons that cause the dopamine-producing cells to die.
Patients with Parkinsons disease also lose the nerve endings that are responsible for producing norepinephrine. Norepinephrine is the primary chemical messenger of the sympathetic nervous system and controls several body functions, including blood pressure and heart rate.However, a loss of norepinephrine can be considered the reason behind the non-movement symptoms that line PD. These include irregular blood pressure, a sudden drop in blood pressure at the slightest movements such as when a person stands up from a laying down or sitting position, and diminished movement of food through the digestive tract.