MULTIPLE SCLEROSIS

Multiple sclerosis is a chronic autoimmune disease affecting the central nervous system (CNS) and is characterized by inflammation, demyelination, gliosis, and neuronal loss. Multiple sclerosis (MS) is the most frequently seen demyelinating disease, with a prevalence that varies considerably, from high levels in North America and Europe (>100/100,000 inhabitants) to low rates in Eastern Asia and sub-Saharan Africa (2/100,000 population). Knowledge of the geographical distribution of the disease and its survival data, and a better understanding of the natural history of the disease, have improved our understanding of the respective roles of endogenous and exogenous causes of MS. (https://pubmed.ncbi.nlm.nih.gov/26718593/) 

What is the pathophysiology of MS? 

MS refers to the formation of plaques in CNS along with inflammation, demyelination, axonal damage, and axonal loss. These plaques are located in the brain and spinal cord, mainly in the white matter surrounding the ventricles, optic nerves and tracts, corpus callosum, cerebellar peduncles, long tracts, and subpial area of the spinal cord and brainstem, as well as gray matter. Clinical symptoms characterized by acute relapses typically appear first in young adults, followed by a gradually progressive course leading to permanent disability within 10 to 15 years. 

 MS is likely the result of a complicated interplay between genetics, food, and the environment. MS is primarily caused by an autoimmune attack on the CNS due to hyper immunity. Numerous postulated pathways have been proposed, but the proposed "outside-in" mechanism involves CD4+ proinflammatory T cells. Researchers hypothesize that an unknown antigen promotes and activates 1 T-helper (Th1) and 17 T-helper (Th17), leading to CNS endothelium adhesion, blood-brain barrier (BBB) crossing, and subsequent immune attack through cross-reactivity. The "inside-out" theory posits that an innate malfunction of CNS produces and culminates in inflammation-mediated tissue destruction. The phenomenon of environmental impacts, such as latitudinal gradients in different countries, has been widely studied. A deficiency in vitamin D has been a possible explanation for susceptibility observed in populations living at higher latitudes. Individuals with relatives have a considerable chance of developing the disease. The expected range of heritability is between 35 and 75%. Human leukocyte antigen DRB1*1501 has a significant association with MS. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9888604/) 

What is the classification o MS? 

Multiple sclerosis presents various disease courses and is classified into 7 categories, as outlined below.

• Relapsing-remitting (RR): This initial onset is observed in 70% to 80% of multiple sclerosis patients and is characterized by the below-mentioned neurological presentation.
  • New or recurrent neurological symptoms that are consistent with multiple sclerosis
  • Symptoms lasting 24 to 48 hours
  • Symptoms developing over days to weeks
• Primary progressive (PP): This course presents in 15% to 20% of patients and shows a gradual deterioration from onset without relapses.
• Secondary progressive (SP): Following an initial relapsing-remitting course, this course is marked by a more gradual neurological decline. Superimposed relapses can occur but are not mandatory.
• Progressive-relapsing (PR): This course involves gradual deterioration with superimposed relapses and is seen in 5% of patients.

Additionally, the following 3 categories are sometimes considered within the spectrum of multiple sclerosis:

• Clinically isolated syndrome: This is often classified as a single episode of inflammatory CNS demyelination.
• Fulminant: This is characterized by severe multiple sclerosis with multiple relapses and rapid progression toward disability.
• Benign: This features an overall mild disability course with rare relapses. (https://www.ncbi.nlm.nih.gov/books/NBK499849/) 

What are the risk factors to get MS? 

Age, sex, race, heredity, geography, vitamin D deficiency, past injury to the nervous system, smoking and infections such as herpes simplex, chlamydia, and rabies are risk factors to get MS. 

What are the symptoms of MS? 

Multiple sclerosis signs and symptoms may differ greatly from person to person and over the course of the disease depending on the location of affected nerve fibres.

Common symptoms include:

• Numbness or weakness in one or more limbs that typically occurs on one side of your body at a time
• Tingling
• Electric-shock sensations that occur with certain neck movements, especially bending the neck forward (Lhermitte sign)
• Unsteady gait or inability to walk
• Partial or complete loss of vision, usually in one eye at a time, often with pain during eye movement
• Prolonged double vision
• Blurry vision
• Vertigo
• Problems with sexual, bowel and bladder function
• Fatigue
• Slurred speech
• Cognitive problems
• Mood disturbances

Lack of coordination

(https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269) 

What does the patient history and physical exam reveal in MS?

Multiple sclerosis presents with a broad range of symptoms reflective of the multifocal lesions of the CNS. The severity and diversity of symptoms are influenced by the burden, location, and extent of tissue injury. Interestingly, symptoms may not always align with MRI evidence of active plaques due to the involvement of repair mechanisms and neural plasticity in tissue injury and recovery processes.

Typical clinical manifestations noted in patient history include:

• Vision symptoms such as vision loss (either monocular or homonymous), double vision, symptoms relating to optic neuritis, and pain with eye movement.
• Vestibular symptoms such as vertigo and gait imbalance.
• Bulbar dysfunction, which manifests as dysarthria and dysphagia.
• Motor symptoms such as weakness (hemiparesis, monoparesis, or paraparesis), tremors, spasticity, and fatigue.
• Sensory symptoms such as loss of sensation, paresthesias, dysesthesias, and a band-like sensation around the chest or abdomen.
• Urinary and bowel symptoms ranging from incontinence, retention, urgency, constipation, diarrhea, and reflux.
• Cognitive symptoms such as memory impairment, executive function impairment, and difficulty concentrating.
• Psychiatric symptoms such as depression and anxiety.
• Brainstem symptoms such as facial muscle weakness and/or reduced facial sensations, diplopia, oscillopsia (jerking sensation in the visual field).
• The Lhermitte sign is often described as a shock-like sensation with neck flexion.
• Hyperreflexia, tremors, muscle spasms, and weakness.

Features considered atypical for multiple sclerosis include seizures, steady progression of symptoms, deficits developing rapidly within minutes, onset before age 10 or after 50, rigidity or sustained dystonia, cortical deficits such as apraxia, alexia, aphasia, or neglect, and early onset of dementia.

The relapsing-remitting course of multiple sclerosis, observed in a majority of patients, is characterized by exacerbation and relapses of neurological symptoms, with stability between episodes. The following features generally characterize the relapsing-remitting course of multiple sclerosis:

• New or recurrent neurological symptoms
• Symptoms developing over days and weeks
• Symptoms lasting between 24 and 48 hours

Symptoms from relapses frequently resolve. However, over time, residual symptoms relating to episodes of exacerbation accrue. This accrual of symptoms, generally after 10 to 15 years, results in long-term disability over time. (https://www.ncbi.nlm.nih.gov/books/NBK499849/) 

How is MS diagnosed?

Pathognomonic tests do not exist to diagnose multiple sclerosis. Diagnosis is established by considering the patient's history and physical examination, along with MRI findings, evoked potentials, and cerebrospinal fluid (CSF) or blood studies, while also excluding other causes of the patient's symptoms. Clinically, a diagnosis of multiple sclerosis is supported by evidence of one or more relapses, which can be confirmed through objective clinical evidence of one or more lesions or objective clinical evidence of one lesion with reliable historical evidence of a prior relapse.

Dissemination in space (DIS) and dissemination in time (DIT) are 2 key criteria for accurately diagnosing multiple sclerosis. DIS is assessed by integrating information from the patient's history and physical examination to determine the location of CNS involvement. MRI and evoked potentials also have vital roles in establishing DIS. DIT is established by charting the disease course with a thorough history and documenting the presence of multiple exacerbations over time. The 2010 McDonald criteria determined that new lesions can demonstrate DIT on a follow-up MRI compared to a baseline scan. 

DIS is established by observing at least a T2 lesion in 2 of the 4 following CNS sites—spinal cord, infratentorial, juxtacortical, and periventricular regions. Revisions in the 2017 McDonald criteria increased the sensitivity of diagnosis by introducing oligoclonal bands in the CSF analysis as a marker for establishing DIT. Symptomatic lesions were also included to establish DIT and DIS, and cortical lesions were used to demonstrate DIS. 

Evoked potentials help demonstrate slowed conduction indicative of subclinical involvement. These findings are often asymmetric. MRI, CSF, and blood studies are essential in ruling out other aetiologies. When possible, all patients should undergo an MRI. Additionally, specific blood studies such as complete blood count (CBC), thyroid-stimulating hormone (TSH), vitamin B12 levels, erythrocyte sedimentation rate (ESR), and antinuclear antibody (ANA) testing should be performed as part of the diagnostic workup.