Cognitive Dysfunction in Multi-system Atrophy

INTRODUCTION Multiple system atrophy (MSA) is one of the rapidly progressive synucleinopathies with clinically significant autonomic dysfunction.[1,2] Depending on the predominant motor manifestations, MSA is subclassified as a Parkinsonian phenotype (MSA-P) and a cerebellar phenotype (MSA-C).[3] MSA patients have a mean age of 50–60 years at onset and have a survival of an average of 8–9 years from the time of onset of motor symptoms, although some rare pathologically diagnosed cases survived more than 15 years.[4-6] While dementia is considered an exclusion criterion, according to the Consensus Guidelines 2018 for MSA, few unexpected cases with mild cognitive deficits like frontal lobe dysfunction have been reported in a few MSA individuals worldwide.[7] We hereby report a series of 3 cases of patients in their fifth and second decade with a clinical diagnosis of MSA-C with mild cognitive affection. It has been observed that 22%, 2% and 0.5% of pathologically confirmed MSA cases displayed mild, moderate and severe cognitive impairment, respectively.[8] These findings challenge the previously established concept of cognitive dysfunction as a core feature to re-appraise the primary diagnosis of MSA. CASE REPORTS Case 1 A 60-year-old female, with no previously known comorbidities, presented to us with the slowness of activities of daily living for the past 1 year 4 months, which progressed from lower to upper limbs over a period of 4 months. The patient also developed tremulousness for the past 8 months while performing activities like eating, leading to smearing of food around the mouth while feeding and overshooting while trying to brush but relieved completely on rest. She had slurring of speech for 7 months, which was not legible to attendants. The patient also developed episodic head reeling for the past 4 months of duration ~30–40 s, associated with postural change (more pronounced while standing from sitting, sitting from a supine position). In addition, the patient has increased urinary frequency and urgency and constipation for 4 months. She had inappropriate crying spells and increased irritability and self-muttering for 4 months. She had disturbance in sleep maintenance for 3 months with no features of REM sleep behaviour disorder (RBD). Over the past 2 months, the patient has had 5–6 episodes of unprotected falls, non-specific in direction, leading to a fracture left forearm. There was no associated weakness in using either limb, but it was associated with stiffness. There was no history of altered sensorium, fever, seizure, limb weakness, tingling/numbness, visual complaints, difficulty swallowing, any associated pain, buckling of knees or scissoring of gait. There were no associated palpitations, blurring vision, excessive perspiration, nausea, vomiting, aural fullness or tinnitus. There was no undue exaggeration of symptoms in dark/dim lights. The patient consumed a mixed diet and she attained menopause at the age of 50. There was no other history of any chronic drug abuse (therapeutic or recreational). On examination, there was no postural drop in systolic blood pressure (SBP)/diastolic blood pressure. Her mini-mental state examination (MMSE) was 18 (Education – 5TH Std.) and Montreal cognitive assessment (MoCA) was 16/30 with recall and language impairment. She had a bi-directional gaze that evoked nystagmus, broken pursuit and hypometric saccades. Motor bulk was normal, and power was full. Generalised and symmetrical rigidity was present (Grade 2 in all joints). Her finger-nose-finger test was impaired bilaterally and showed dysdiadokinesia bilaterally. The patient stood with one person’s support and walked independently, taking short steps, multiple steps and more time during turning, with decreased arm swing bilaterally and posturing of the left upper limb. On examining primitive reflexes, her Glabellar tap was positive, but the rest of the reflexes were not elicitable. In her cortical sensations, her two-point discrimination and tactile localisation were impaired on the left side. Magnetic resonance (MR) brain imaging of the patient was done [Figure 1]. USG KUB (Ultrasonography Kidney Ureter Bladder) showed a post-void residual urine (PVRU) of 130 cc. It showed a Hot Cross Bun sign suggestive of olivo-ponto-cerebellar tract involvement seen in MSA-C. Cerebrospinal fluid (CSF) examination showed no abnormalities.Figure 1: Magnetic resonance brain imaging of case-1 showing hot cross bun sign suggestive of olivo-ponto-cerebellar tract involvement seen in MSA-CCase 2 A 62-year-old male, a farmer by occupation, presented with increased frequency of micturition for the past 2 years, insidious in onset, gradually progressive, more pronounced during the night, initially 2–3 times to now 6–7 times overnight over the past 2 years, disturbing his sleep. He also gave 8–9 instances of bed wetting at night and waking up with remorse on realisation, over the last 1 year. There was no history of burning or painful micturition. The patient then developed the complaint of difficulty in walking – in the form of unsteadiness, insidious in onset, gradually progressive in nature, with a tendency to fall while walking, non-specific in direction over the past 2 years. The patient had difficulty walking through narrow spaces and took the support of a wall or railing while walking. He gradually started developing stiffness while walking and took longer than usual to move around the house and do his daily chores. He had clumsiness while holding a glass of water or reaching out to grasp objects, wearing chappals, clumsiness while sitting at the edge of the bed and was required to take support of the bed railing for the same. There was no history of any limb weakness. There was no undue exaggeration of symptoms in darkness. There was no history of any tingling/numbness or any other sensory complaints. There was no history of fall. The patient also complained of 5–6 episodes of head reeling, which was episodic (lasting for around 2–3 min), associated with a change in posture, which was more pronounced while sitting from supine and standing from sitting. It was associated with history of darkness in front of the eyes, palpitations and excessive perspiration. There was awareness of symptoms and improved on sitting/lying down for a few minutes. There was also history of slurring of speech, gradual in onset, progressive over the past 1 year, with gradually worsening comprehensibility of his words by the attendants. There was a history of constipation for the past 2–3 years. There was also an associated history of sleep disturbance, nightmares and screaming episodes in sleep for 1 year. There was no history of involuntary limb enacting associated/wandering. There was no history of memory abnormality, behavioural changes, hallucinations or delusions. There was no history of difficulty turning in bed, fever, visual abnormalities, dysphagia or anosmia. On examination, there was a postural drop of 15 mmHg in SBP after 10 min. His MMSE was 21 (Education – 5TH STD) and MoCA score was 14/30 with recall and language impairment. He had a bi-directional gaze that evoked nystagmus but normal pursuit and saccades. Motor bulk was normal, and power was full. Generalised and asymmetrical rigidity was present. According to UPDRS, Grade 1 in left side his pull test was Grade 3.On examination, His finger-nose-finger test and heel-shin test was impaired bilaterally and showed dysdiadokinesia bilaterally, showing bilateral cerebellar affection. He was able to stand without support on the first attempt, walked with mild stooped posture, broad-based stance, short steps, normal velocity and took more than 3 steps turning around with reduced “Bilateral” Arm Swing. On examining primitive reflexes, the left palmomental reflex was positive, but the rest of the reflexes were not eligible. Routine blood investigations and CSF examinations were normal. His USG KUB showed a significant PVRU of 250cc. MR of the brain imaging of the patient was done [Figure 2]. It was suggestive of diffuse cerebellar atrophy with predominant superior peduncle involvement, suggestive of MSA-C.Figure 2: Magnetic resonance brain imaging of case-2 showing diffuse cerebellar atrophy with predominant superior peduncle involvement, suggestive of MSA-CCase 3 A 58-year-old male, a farmer by occupation, known diabetic and hypertensive, presented with a complaint of head reeling for the last 1 and ½ years, episodic with a duration of ~ 15–20 s, which aggravated on standing, relieved on lying down. It was not associated with vomiting, ear symptoms, cold extremities, palpitations or diminution of vision. He then started developing gradually progressive slowness of activities of daily living, with freezing while walking and imbalance while walking, with a tendency to fall on either side while walking in narrow spaces and incoordination while using both upper limbs for the past 8 months. He also developed slurred speech for the past 6 months in the form of a low tone yet comprehensible. He also developed an increased frequency of micturition with a sense of incomplete bladder evacuation in the last 6 months with 5–6 instances of bedwetting at night, followed by remorse on realisation. There were no complaints of altered sensorium, fever, seizures, limb weakness or tremulousness. For the past 2 months, he now developed forgetfulness to recent events in the form of forgetting what he ate a few hours back, where he had placed certain objects inside the cupboard. However, he had no trouble in recalling remote events like his address, his birth date, his family members or relatives and his duty companions. There was no associated apathy or any other behavioural changes. Upon examination, there was a postural drop of 24 mmHg in SBP after 3 min of standing. Dysautonomia was further elicited positively in the form of impaired mathematical calculation and hand grip tests. His MMSE was 24 (Education – 5TH STD) and MoCA score was 16/30 with visuospatial ability and language impairment. Cranial nerves examination showed impaired hypometric saccades on vertical and horizontal gaze and broken pursuit. He had generalised and symmetrical rigidity present (Grade 2 in left upper and lower joints, Grade 2 in right side and pull test was Grade 3). There was no other motor or sensory deficit. His cerebellar signs (ike Finger-Nose-Finer, Heel-Shin test) was impaired bilaterally. His tandem gait was also impaired. He required assistance to stand but walked independently with a stooped posture, reduced bilateral arm swing with right lateral bending of the trunk (Pisa Sign), with freezing episodes. His USG KUB showed a significant PVRU of 150 cc. CSF studies were normal. MR imaging of the brain showed early olivo-ponto-cerebellar tract degeneration [Figure 3], seen primarily in MSA-C.Figure 3: Magnetic resonance imaging brain of case-3, showing evolving olivo-ponto-cerebellar tract degeneration, seen in MSA-CDISCUSSION Based on a review of existing English literature on PubMed for cognitive dysfunction in MSA, published between 1988 and 2023, it was agreed that cognitive impairment is present more frequently than recognised in MSA patients.[9] On average, it takes 7 years from diagnosis to clinically significant cognitive symptoms in MSA.[10] However, few cases with early cognitive impairment have been found, described in the literature.[11-13] Amongst patients beyond 8 years of initial presentation, almost half of them are reported to be cognitively impaired. It suggests that if MSA did not have such a rapid course of progression and longer survival years, the cumulative prevalence of dementia would be almost equal to that of Parkinson’s disease.[14-16] Upon further evaluation, among the cognitive domains, executive functions and fluency are the most commonly affected, followed by attention deficit and memory. Visuospatial impairment is one of the major difficulties encountered in MSA-C patients, while language is rarely affected.[17] All three cases, we described above, have presented above 55 years of age group. All three have been diagnosed as cases of MSA-C based on Consensus Diagnostic Criteria 2018, except dyscognition, which shows a preponderance in the older age group. The first two cases presented with the triad of Parkinsonism, dysautonomia and cerebellar dysfunction, with no symptoms of memory impairment, but cognitive assessment showed deficits. The third case presented with additional symptoms of forgetfulness, confirmed with cognitive assessment scales. MMSE and MoCA memory assessment scales were used. The first and third cases showed moderate cognitive affection while the second case showed a mild deficit. All three cases [Summarized in Table 1] showed noticeable memory impairment within the first 2 years of initial presentation, while radiologically significant multi-system atrophy was evident. Only the first case with females showed behaviour disturbances. None of them had RBD. In two cases, all three showed abnormal recall and visuospatial, language domain affection in one.Table 1: Table of clinical summary of the three casesDeafferentation from subcortical structures, progressing to involve cortical neurons, is currently hypothesised to play a role in cognitive decline. An extensive network of cortical regions was also activated in a pattern largely consistent with recognised anatomic connectivity. A cerebral cortex-cerebellar-thalamic-cortical circuit, a feedback loop that contains the extensive networks between medial frontal and left orbital frontal, left medial dorsal thalamus, left parietal and anterior cingulate, provides strong support for a role for the cerebellum and its connections in cognition, especially, consciously retrieved episodic memory.[18-20] CONCLUSION Through this case series of three MSA patients, we aim to add to the emerging literature to emphasise the importance of cognitive deficits and broaden our understanding of MSA. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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