Practical nuggets on Parkinsonism & MS from 2019 World Congress of Neurology: Dr. Prithika Chary
M3 India Newsdesk Dec 16, 2019
Dr. Prithika Chary provides bites of information and her commentary on the major advances in Neuroscience- Parkinson's Disease (PD) and Multiple Sclerosis (MS), presented at this year's World Congress of Neurology.
Therapies and a new book on Parkinsonism
Parkinsonism occurs due to depletion of neurotransmitter dopamine in the substantia nigra leading to a syndrome of motor and nonmotor symptoms. Symptoms include motor slowing, rigidity and difficulty in walking, speaking and swallowing, tremors of the hands and legs and sometimes the jaw, a stooped posture and imbalance due to a propulsive gait. Current advances suggest that Parkinsonism is not merely a nigrostriatal disease, but involves various other parts of the nervous system.
The disease has a prodromal phase of constipation and hyposmia or anosmia followed few years later by depression and onset of tremors and/or motor slowing. The pathogenesis is now believed to be inflammation and accumulation of alpha synuclein aggregates. Olfactory and gut factors seem to play an important role in this accumulation and the gut microbiome is being increasingly important in this.
Genetic variants are seen only in 10% of patients with Parkinsonism, but this is not of predictive value as there are over 90 variants with over 70 loci which modify the manifestation.
Selegiline and Rasagiline have been in use to slow progression of PD. Another exciting advance in this direction is that Exenatide – GLP1 receptor agonist antidiabetic is showing promise. It has undergone Phase 2 trials – now in Phase 3 – once weekly leads to improvement in some weeks – the possible mechanism – reduced neuroinflammation triggered by alpha synuclein aggregates via microglia – appears to inhibit a neurotoxic cascade which destroy neurons.
'Parkinson’s Disease in India – from clinic to bench'
The book edited by Madhuri Bihari and S.P.Gorthi is worth reading. The crude prevalence of PD is 33.53 per 100,000 in India. The mean age of patients is 56.87 years + 11.64 years. Onset at or before 40 years of age was seen in 23.6%. Female to male ratio 1:3.21. Asymmetrical onset on one side of the body, especially in the upper limbs is seen in 75% of cases. Akinetic rigid subtype of disease showed faster rate of progression than tremor predominant patients. Gait disturbance is a major cause of disability, and falls are reported in 4% of PD patients. Family history was present in 21%.
The literature on various aspects of MS is enormous and here outlined are some of the practice points useful for clinicians in this article summarising the session in symposia, plenary lectures and the teaching course on MS at the WCN 2019.
Advances in management of Multiple Sclerosis has seen an amazing level of explosion in the past decade, when several old and new injectables and new oral drugs have become available as disease modifying therapies. It is still unfortunate that the decision to treat is often delayed because of the vague initial symptoms of the disease and the lack of biomarkers to identify early relapses or progression.
The iceberg concept is evident in making the diagnosis, as the disease may be more severe than it apparently seems clinically. New T2 MRI lesions, subclinical and subtle clinical signs and symptoms, brain and spine atrophy, etc may indicate more severe disease. In making diagnosis, physicians should follow the 2017 new McDonalds criteria.
The relative nonavailability of suitable biomarkers to detect early worsening makes diagnosis difficult. A high number of T2 lesions, the presence of IgG and IgM oligoclonal bands in the CSF, high levels of neurofilament light chain in the CSF and serum, retinal nerve fibre layer thinning detected with optical coherence tomography maybe useful.
The optimal time to start treatment is as early as possible within 6 months of disease onset. A decision has to be made as to whether to opt for induction therapy, hitting it hard and early when side effects may be more or stepwise escalation with fewer side effects. Induction therapy is preferable for more aggressive forms and stepwise escalation for suboptimal disease or more chronic forms.
Ocrelizumab is the only approved drug for rapid neurological worsening in primary progressive MS. For inactive MS Glatirmer, interferon beta, teriflunamide and dimethyl fumarate are used to treat.Early identification of nonresponders and modification of treatment improves prognosis. The goal of treatment is to treat windows of opportunity as safe and effective drugs are available today. Several clinical scores such as the RIO score, the RoAD score, EDSS etc are used to evaluate progression. Followup should indicate NEDA (No evidence of disease activity – no relapse, no lesion, no change in EDSS) or NEPA (no evidence of progressive activity – atrophy and response to treatment).
- Indicators of poor prognosis are demographic and environmental factors. Older age, male sex, low Vitamin D levels, smoking and comorbid conditions worsen prognosis.
- On the MRI a high number of T2 lesions, a large T2 lesion volume size, presence of gadolinium enhancing lesions, presence of infratentorial lesions, presence of spinal cord lesions, whole brain atrophy and grey matter atrophy are all indicators of poor prognosis.
- Clinical factors indicating poor prognosis include:
- primary progressive disease subtype
- a high relapse rate
- shorter interval between the first and second relapses
- brainstem, cerebellar or spinal cord onset
- poor recovery from the first relapse
- a higher expanded disability status scale (EDSS) at diagnosis
- polysymptomatic onset
- early cognitive deficits
Patient factors which influence treatment decisions include clinical prognosis, pregnancy, safety and efficacy of medication, and patient preference. Less important factors include comorbidities, sequencing considerations, monitoring, route of administration, dosing frequency, cost, and risk tolerance.
RRMS and SPMS
Identifying progression of patients from CIS (clinically isolated syndrome) and RRMS (relapsing remitting MS) to SPMS (secondary progressive MS) is a challenge, because there is no consensus on SPMS definition, the average time from RRMS to SPMS is 10-15 years, and duration of activity is a risk factor.
Pointers to progression may be cognitive deficits, fatigue, reduced ambulation, impaired visual and arm functions, urinary incontinence all indicate transition to SPMS. There is 70% delay in diagnosis as there are no clear biomarkers to guide.
Should SPMS be diagnosed earlier?
Definitely yes - predictors - motor onset, males, high number of relapses in first 2 years, less relapses in RRMS phase, more lesions in MRI with atrophy. The newly released MS ProDiscuss tool (MS Progression Discussion tool), free on the internet, is a questionnaire based tool which enables physicians to identify progression earlier.
There are no clear clinical, imaging, immunologic or pathologic criteria to determine the transition point when RRMS converts to SPMS. It is generally diagnosed retrospectively by a history of gradual worsening after an initial relapsing disease course, with or without acute exacerbations during the progressive course. Recognition to enable early intervention is necessary as upto 40% of patients with RRMS transition to SPMS within 6-10 years of disease onset.
SPMS is characterised by:
- reduced ambulation; >90% of patients with SPMS require walking assistance within 3 years of onset of progression,
- Cognitive impairment in up to 80% of patients with SPMS,
- impaired visual and arm function, and
- urinary incontinence
In comparison with RRMS there is greater disruption of everyday life, less employment due to burden of disease and higher hospitalisation rates.
Drugs available readily to treat patients in the absence of poor prognostic factors are-
- Injectables: SC or IM interferon beta 1A, SC PEG interferon beta 1A, SC interferon beta 1B, Glatirmer acetate
- Oral: Teriflunamide, Dimethyl fumarate
Drugs to treat patients in the presence of poor prognostic factors are-
- Infusions: Natalizumab, Alemtuzumab, Ocrelizumab
- Oral agents: Fingolimod, Cladribine
Physicians should beware of developing therapeutic inertia while treating patients with MS. It is the absence of treatment initiation or intensification when treatment goals are unmet.
Factors influencing development of therapeutic inertia are physician factors such as:
- Failure to set clear goals errors in risk assessment
- Failure to identify comorbid conditions influencing clinical outcome
- Underestimation of patients need
- Low tolerance to uncertainity
- Aversion to unknown risks/status quo
- Herding (mistakenly following a colleague previous decision)
- Nihilistic approach
- Knowledge gaps (lack of awareness of clinical guidelines)
Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.
The author, Dr. Prithika Chary is a Neurologist, Neurosurgeon, and Epileptologist from Chennai.
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