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.

---

'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%.

---

Multiple Sclerosis

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.

Diagnosis

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.

Treatment

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).

1. Indicators of poor prognosis are demographic and environmental factors. Older age, male sex, low Vitamin D levels, smoking and comorbid conditions worsen prognosis.
2. 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.
3. 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.

---

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:

1. Failure to set clear goals errors in risk assessment
2. Failure to identify comorbid conditions influencing clinical outcome
3. Underestimation of patients need
4. Low tolerance to uncertainity
5. Aversion to unknown risks/status quo
6. Herding (mistakenly following a colleague previous decision)
7. Nihilistic approach
8. 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.