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ORIGINAL ARTICLE
Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1062-1066
 

Evaluation of non-motor symptoms in wilson disease using the parkinson's disease nonmotor symptoms questionnaire: A pilot cross-sectional study and critical assessment


Department of Neurology, Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research (IPGME&R), Kolkata, West Bengal, India

Date of Submission05-Dec-2021
Date of Decision14-May-2022
Date of Acceptance18-May-2022
Date of Web Publication26-Jul-2022

Correspondence Address:
Atanu Biswas
Department of Neurology, Bangur Institute of Neurosciences and I.P.G.M.E&R, 52/1A, S.N. Pandit Street, Kolkata - 700 025, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_1040_21

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   Abstract 


Background: There is a dearth of studies on non-motor symptoms of Wilson's disease (WD) which is primarily because of the non-availability of a suitable scale. Objective: To assess the suitability of the Parkinson's Disease non motor symptoms questionnaire (PD-NMS Quest) in the assessment of non-motor symptoms of WD patients. Methods: In this case-control study, patients of WD above ≥12 years of age diagnosed by Leipzig's criteria and age and gender-matched control subjects were recruited. Critically ill patients, patients with severe hepatic impairment, or with pure hepatic WD were excluded. PD-NMS Quest was applied and relevant statistical analyses were performed. Results: A total of 18 cases and 25 controls were studied. Patients had a mean age of 22.6 years and a median disease duration of 8 years. WD patients had higher frequencies of all NMS than controls. Drooling (P = 0.0037), dysphagia or choking (P = 0.0088), nocturia (P = 0.0471), anxiety/fear (P = 0.0337), feeling sad or blue (P = 0.0020) and falling (P = 0.0197) were significantly higher in WD patients than controls. Conclusions: Although many NMS of WD patients are picked up effectively with PD-NMS Quest, some of them need detail assessment including cognitive, behavioral, and psychiatric symptoms, drooling and dysphagia, sleep as well as autonomic disturbances. Questions pertaining to sexual activity may be omitted from the questionnaire.


Keywords: Case-control study, non-motor symptoms, PD-NMS quest, pilot study, Wilson's disease


How to cite this article:
Chakraborty AP, Mukherjee A, Sarkar S, Sinharoy U, Biswas A. Evaluation of non-motor symptoms in wilson disease using the parkinson's disease nonmotor symptoms questionnaire: A pilot cross-sectional study and critical assessment. Ann Indian Acad Neurol 2022;25:1062-6

How to cite this URL:
Chakraborty AP, Mukherjee A, Sarkar S, Sinharoy U, Biswas A. Evaluation of non-motor symptoms in wilson disease using the parkinson's disease nonmotor symptoms questionnaire: A pilot cross-sectional study and critical assessment. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Feb 6];25:1062-6. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1062/352395





   Introduction Top


Wilson Disease (WD) was first described by S.A. Kinnier Wilson in 1912 as progressive lenticular degeneration leading to extrapyramidal syndrome with defective motility along with chronic liver damage leading to cirrhosis.[1] With time this was found to be an autosomal recessive disease with a mutation in the ATP7B gene (Chromosome 13) causing defective copper excretion in bile, leading to its deposition in different regions of the brain and liver.[2] Neurological WD is mainly characterized by movement disorders in the form of dystonia, rigidity, tremor, choreo-athetosis; dysarthria, diffuse pyramidal system, and cerebellar affection. Though many studies have enumerated the motor symptoms in WD,[3],[4] not many of them have quantified the nonmotor neurological manifestations.

On the other hand, Parkinson's disease (PD) is a degenerative disease, not only of nigrostriatal neurons in the brain, but also of structures not involved in motor control like the locus coeruleus, raphe nucleus, vagal nuclei, olfactory, limbic, and neocortices.[5] Lewy body pathology has also been demonstrated in the cardiac autonomic system and the myenteric plexus.[6] This has an implication for PD patients suffering from a number of nonmotor symptoms (NMS)[7],[8] including gastrointestinal and genitourinary problems, sleep disturbances, autonomic, psychiatric, and cognitive dysfunction. Similarly, in WD, there is evidence of copper deposition in the brain in multiple sites like putamen, caudate, globus pallidus, thalamus, hypothalamus, midbrain, pons, and medulla.[9] Moreover, though not visible on conventional T2 weighted magnetic resonance imaging (MRI), cortical mineralization has been demonstrated by susceptibility imaging,[10] in patients of WD. Similarly, white matter abnormality has been observed with reduced NAA/Cr and Ch/Cr ratio demonstrated in patients of WD.[11] This prompts us to delve deeper into the context of assessing nonmotor symptoms of WD from a patient perspective.

For PD, many scales[12] have been used in assessing the non-motor symptoms, sleep disturbances, autonomic symptoms, fatigue, cognitive dysfunction, health-related quality of life, etc. Out of them most notably, the PD-NMS Quest and PD-NMS scale[13] (Parkinson's disease non-motor symptoms questionnaire and scale respectively) provide a comprehensive assessment encompassing almost all domains of nonmotor involvement in PD patients. The scale has been validated by the Parkinson's Disease Nonmotor Group (PDNMG), an international group with multidisciplinary experts. Extra-motor affection is not uncommon in other movement disorders as well. But lack of dedicated scales for these disorders forced investigators to use PD-NMS Quest or PD-NMS Scale to assess nonmotor functions in them. Recently, we have used NMS Quest to assess nonmotor symptoms in patients of Amyotrophic lateral sclerosis (ALS), another neurodegenerative disorder with significant nonmotor burden.[14] Non-motor symptoms are also common in patients of WD, but there is a dearth of studies in the literature.

In this study, we have tested the PD-NMS Quest on WD patients along with healthy controls as an initial approach to assessing the utility of this scale from the perspective of WD.


   Materials and Methods Top


A cross-sectional case-control study plan was carried out enrolling participants aged 12 years and above who attended the inpatient and Movement Disorder Clinic of our institute. WD patients were selected on the basis of Leipzig's criteria.[15] Control participants were selected from the general population in an age and sex-matched distribution who did not have any neurological or psychiatric illness and no family history of the same. This study was approved by the institutional ethics committee and informed consent was obtained from patients and controls or their parents/legally acceptable representatives. Critically ill patients, patients with severe hepatic impairment, or with pure hepatic Wilson were excluded. A total sample size of 43 was obtained from the convenience sampling method. Out of 43 participants, there were 18 cases and 25 controls. The data from cases and control were collected by administering a questionnaire by interviewing the study participants. The PD-NMS Quest was used. Participation in the study was voluntary and anonymity was ensured. Questions pertaining to sexual activity in the NMS were excluded, as the majority of patients in the study were not sexually active.

Statistical analysis was carried out using standard software i.e., IBM SPSS statistics for Windows (v. 23). A comparison was made between the patient and control groups. Odds ratios (OR) were calculated and significance was achieved when the P < 0.05.


   Results Top


The patient group enrolled in our study had a mean age of 22.6 years (Range: 13-36 years) with a slight male predilection (M:F = 1.25:1). Patients were interviewed cross-sectionally at a median disease duration of 8 years (Range: 6 months to 21 years). Feeling of sadness or low mood (83%) was the most common nonmotor symptom (NMS) followed by drooling of saliva (61%) [Table 1].
Table 1: Prevalence of non motor symptoms as per NMS Questionnaire in 18 Wilson disease patients and control group

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Dysphagia or choking was reported in about half of the patients interviewed, which was not reported at all in the control group. Other gastrointestinal disturbances like nausea, vomiting (17%), and constipation (22%) were reported which were more prevalent than the control. Fecal incontinence was not reported and tenesmus was comparable to the normal population. Among urinary problems, nocturia was commonly seen (44%), which on further questioning did not reveal any symptoms of bed wetting. Other urinary complaints like urinary urgency were not reported significantly.

Unexplained non-specific pains were commoner than in the control group. On further questioning, one-third of the patients had a headache, which was diffuse, mild to moderate intensity, and tension-type in nature. This was more compared to the control population (33.3% vs 16%). Further, one-third of patients complained of low back pain which was not more than the control population. None of the patients in the study had any diagnosed arthritic complications.

Psychiatric disturbances were commonly reported in the patient arm, notably feeling of sadness or blue (83% vs 32%) and feeling anxious. Others like feeling panicky or fear (61% vs 28%) and loss of interest in what's happening in the surroundings (44% vs 32%) were also reported. The former two of the above were significantly higher than the control group as per statistical comparison. Hallucination and delusion were reported in only one patient each (5.6%). Sleep disturbance in the form of insomnia was reported in one-third of the patients with daytime somnolence in one-sixth of the patients. These were not reported in excess of the control population. However, one confounding factor may have been involved that most of the patients were taking some medications like trihexyphenidyl, clonazepam, etc., as anti-dystonia treatment during the time of the interview, leading to false negatives, owing to their sedative potential. REM sleep behavior disorders, and vivid dreams were not reported. Restless leg syndrome-like presentation was seen in two patients as compared to four subjects in the control group.

Other autonomic disturbances like dizziness (39% vs 16%) and excessive sweating were also seen. Falling was reported in 39% of the patients which was significantly higher than the control group. Double vision was not reported in any case.

Among the above, nonmotor symptoms in WD which were statistically significantly higher than the control group were: drooling (P = 0.0037), dysphagia or choking (P = 0.0088), nocturia (P = 0.0471), anxiety/fear (P = 0.0337), feeling sad or blue (P = 0.0020), and falling (P = 0.0197).


   Discussion Top


Drooling is a very common NMS in WD reported in nearly half of the patients in the presence of other neurological symptoms.[16] This is associated with endoscopically demonstrated swallowing difficulties including increased swallow latency and decreased swallowing capacity leading to pooling of saliva and drooling.[17] The presence of defective oral transit and increased post-swallow residual volume has also been demonstrated scintigraphically in WD,[17] and may be even present before the patient actually complains of choking or dysphagia. Drooling has been observed to be present in significant variations in WD patients with or without the presence of overt neurological problems. Cognitive and behavioral involvement[16] can also be responsible for increased swallow latency and transit times in addition to the defects of coordination, spasticity, and dystonia. Drooling needs further gradation of severity and frequency in order to treat and follow up.

Gastrointestinal (GI) problems in WD are mainly due to the involvement of the liver including cirrhosis leading to anorexia, nausea and vomiting (44%), jaundice, hematemesis, and melaena, ascites, and acute liver failure.[18] Studies are lacking in part on GI motility disorders in WD. Our study failed to demonstrate any significantly higher prevalence of GI motility disorders in neurological WD patients. GI side effects of drugs, mainly zinc sulfate are an important cause of gastric irritation leading to abdominal pain, peptic ulceration, anorexia, nausea, and vomiting. This association is much more prevalent in children than in adults.[19] On the other hand, the incidence of constipation among PD patients can be found in about two-thirds of the patients which is much higher than in WD patients in our study.[20]

Loss of weight in WD can be ascribed to hepatic disease leading to malnutrition and poor absorption of nutrients from the gastrointestinal tract. The systemic disease often gives rise to a catabolic state leading to muscle breakdown and weight loss. Poor feeding, depression, and GI side effects of drugs may also contribute to weight loss in WD.

Cognitive function in WD comprises most commonly of memory disturbances (25%).[21] Descriptions have been given of dementia in WD as of subcortical nature, with affliction mainly of the basal ganglia.[22] This dementia is also reversible with therapy given for WD. Patients have poor learning on Rey's auditory verbal learning test (RAVLT) with worse learning across stages of the RAVLT, with relatively preserved word recognition.[23] Our study with PD-NMS Quest revealed forgetfulness in one-third of the patients which was more prevalent than in controls, without achieving statistical significance. Verbal fluency is also affected in patients of WD, with phonemic fluency more affected than category or semantic fluency.[24] Executive function is also impaired by faulty performance in tests assessing them.[22] The PD-NMS Quest is inadequate in assessing cognitive function, in the sense that it has attributed a single question regarding forgetfulness to the entire cognitive domain. Further questions are required to assess the entire cognitive function in WD.

Psychiatric disturbances in WD can be depression due to stigma of the disease or organic, disorders of mood and affect,[25] personality disorder, schizophrenia like state, adjustment and conduct disorder.[26] Mood disorders[25] including bipolar disorder can present with hypomania and mania with bouts of aggressive behavior, antisocial behavior, violent episodes or overactivity.[27],[28] These disorders may present before the neurological or hepatic presentation of WD in many cases. Depression in WD has been previously reported in 20-60% of the cases, with a high incidence of suicidal attempts.[29] Depressive symptoms like loss of interest and feeling blue were reported in a higher amount of patients in our study, however, not all of them matched the diagnostic criteria for depression. Complex hallucinations and delusions occur in about 0.5-1% of the patients only.[30] In addition to the PD-NMS Quest, we think further questions to be asked in assessing WD patients regarding mania, personality problems, attention deficit behavior, conduct, and adjustment-related behavior.

Sleep disorders are reported in the setting of WD, with symptoms like daytime napping, excessive daytime sleepiness, poor nocturnal sleep, restless leg-like symptoms, sleep paralysis, cataplexy-like episodes, and vivid dreams.[31] Rapid eye movement sleep-related behavior disorders screening questionnaires (RBD-SQ) have found a higher score in both neurologic and hepatic WD. However, when compared with a healthy population, the incidence of periodic limb movements, sleep disordered breathing, or restless leg syndrome in WD are not much different.[32] Paradoxically, we found an abnormally low percentage of patients with sleep disturbances in our patients, which may be due to the current sleep medications they were already put on. Additional scales like the RBD-SQ, Epworth sleepiness scale, or the Pittsburg sleep quality index questionnaire are to be employed in assessing sleep disturbances in WD.

Autonomic involvement in WD is well reported previously. Higher resting heart rates, low baseline baroreceptor sensitivity, decreased Valsalva ratios and lesser rise in heart rate following sustained hand grip exercise have been documented in WD patients when compared to controls.[9] These abnormalities in autonomic function tend to remain stable over a period of years in treated WD patients. A reflection of these changes can be seen in our study with patients having an increased prevalence of dizziness than the control group. However, this is not statistically significant in the current study. Furthermore, excessive sweating was also not reported more than the normal population. Thus a detailed assessment of autonomic function encompassing cardiological, gastrointestinal, urogenital, secretomotor, and cutaneous systems is necessary for WD. Cardiovascular abnormalities like diastolic dysfunction and an elevated NT-pro BNP may also be found in WD patients.


   Conclusions Top


Our preliminary study showed a significant burden of nonmotor symptoms in patients with neurological WD. PD-NMS Quest was useful in detecting several of the NMS. However, it was not sufficient to comprehensibly assess the whole spectrum of NMS of WD. Moreover, some of the symptoms enquired by this questionnaire, such as fecal incontinence, REM sleep behavior disorder, swelling of legs, and double vision were not present at all in the WD patients. Others like anosmia, which are more associated with PD pathology were seldom encountered. This, however, does not totally exclude the possibility of these NMS in WD owing to the small number of patients in this pilot study. In WD, cognitive impairment should be evaluated by standard tools for cognitive assessment. A detailed psychiatric evaluation is also needed to be performed. Unlike PD, these can be the dominant presentation in WD patients. A dedicated tool for NMS in WD would indeed be helpful. This should encompass questions about cognitive function (attention and memory, planning, judgment, and multi-tasking ability), different psychiatric symptoms (including anxiety, depression, agitation/aggression, elation/euphoria, etc.), sleep (onset, efficiency, insomnia), drooling (severity and frequency), autonomic function (cutaneous, gastrointestinal, urogenital, and cardiovascular symptoms) and seizures (focal or generalized, frequency). Based on our understanding from current and other ongoing studies, the above questions should be the basic framework of a WD-NMS scale. Studies are needed for the validation of such a scale and to objectively correlate the NMS with disease severity, timing, and motor symptoms. However, as the present study indicates, the PD-NMS Quest can be utilized as a screening tool.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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