Case 8: Multiple Sclerosis

Case 8:  Multiple sclerosis

A 38-year-old woman presented with tingling, numbness and clumsiness of both hands for 1 week, with a band of numbness from the umbilicus to the axillae. Six months earlier, following an upper respiratory tract infection, she had experienced paraesthiae in the feet, numbness from the waist downwards and 'burning' pains behind the right ear. She was anxious because her maternal grandmother had suffered from multiple sclerosis. On neurological examination, she had absent abdominal reflexes with brisk tendon jerks and bilateral extensor plantar responses. Blood results  were normal: Haemoglobin, white-cell count and differential, erythrocyte sedimentation rate, vitamin B12 and folate levels and syphilis serology. The cerebrospinal fluid (CSF): Protein concentration 0.4g/l (NR 0-0.4g/l) , –Red blood cells:None, Lymphocytes 3 x 106/l (NR <5 x 106/l), IgG concentration 123mg/l (NR <60mg/l), Albumin concentration 470mg/l (NR <400mg/l), IgG/albumin ratio 26% (NR 4-22%), IgG index 1.07 (NR <0.7) , Isoelectric focusing Oligoclonal bands present .

Summary

Multiple sclerosis (MS) is primarily an inflammatory disorder of the brain and spinal cord in which focal lymphocytic infiltration leads to damage of myelin, oligodendrocytes and axons. Initially, inflammation is transient and remyelination occurs but is not permanent. The early course of disease is characterized by episodes of neurological dysfunction that usually recover. However, over time the pathological changes become dominated by widespread microglial activation associated with extensive and chronic neurodegeneration. Chronic neurodegeneration, which is progressive, leads to accumulation of sensory and motor disabilities.

Paraclinical investigations show abnormalities that indicate the distribution of inflammatory lesions and axonal loss, interference of conduction in previously myelinated pathways,and intrathecal synthesis of oligoclonal antibody¹.

Multiple sclerosis is triggered by environmental factors in individuals with complex genetic-risk profiles. Before 1980 it was found a greater incidence of MS in higher latitudes. However, later it was demonstrated also a high prevalence in lower latitudes, a fact that reveals a possible environmental influence². Other element that indicated environmental influences are an increased risk of MS among individuals with a history of mononucleosis, a marker of late infection with the Epstein-Barr virus, have an increased risk of MS³.

On the other hand, first-degree relatives had a sevenfold increased risk of developing MS, with an incidence of 0.5% in women and 0.3% for men. Furthermore, 20 identified loci have been linked to MS. DRB1 alleles and HLA-A gene variations are implicated with T helper development, being a determinant factor during MS pathogenesis⁴.

Determination of protein biomarkers is being correlated to MS, demonstrating potential predictors of the disease. Inward rectifying potassium channel KIR4 was identified as a target of IgG. Interestingly, serum levels of IgG to KIR4 were higher in patients with MS; leading to less KIR4 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of complement cascade at the sites of KIR4. Additionally, albumin is not synthesized in central nervous system; therefore, its presence in cerebral spinal fluid gives indication of blood brain barrier (BBB) disruption⁵.

T-helper 17 lymphocytes appear to be essential for inflammatory diseases. It was demonstrated the expression of IL-17 and IL-22 receptors on BBB endothelial cells (BBB-ECs) in MS lesions, demonstrating to play a role in the rupture of BBB tight junctions. Furthermore, T-helper 17 lymphocytes transmigrate efficiently across BBB-ECs, highly express granzyme B, kill human neurons and promote central nervous system inflammation through CD4+ lymphocyte recruitment⁶.

Although there is no cure for MS, immunosuppresants and steroids are used to treat the disease. Glatiramer acetate is believed to reduce the malfunction of lymphocytes by reducing its activation.  Oral administration of Laquinimod induces repair of damaged neuronal tissue, stimulating the release of brain derived neurotropic factor (BDNF). In addition, Teriflunomide inhibits the synthesis of pyrimidine, limiting the proliferation of lymphocytes. In this way, the immune system is suppressed, decreasing inflammation and myelin degeneration of the central nervous system.

Questions

Question 1: What neurological functions/structures are affected in the patient?

The patient currently presented with tingling, numbness, and clumsiness of both hands for 1 week and with a band of numbness from the umbilicus to the axillae. Sensory symptoms are common initial feature of MS, which include symptoms such as numbness, tingling, pins/needles, tightness, coldness, or swelling of limbs or trunk, which can de due to demyelination or lesion to sensory tracks in the CNS leading to the cerebral cortex. The patients clumsiness is due motor symptoms from the lesion of the descending motor tracts of the spinal cord and cerebellar pathways, which help originate and coordinate movement. The band of numbness from the umbilicus (thoraxic T10)-axillae (thoraxic T4) can be explained by a lesion to the spinothalamic tracts in the CNS.

The patient has a history of paresthesia in the feet, numbness from the waist down, and burning pains behind here right ear that after an upper respiratory infection, but then subsided after infection. In patients with MS, this is a sign called Unthoff’s phenomenon⁷.Unthoff’s phenomenon is due to an increase in temperature that temporarily worsens neurological symptoms in MS patients due to the effect of temperature on nerve conduction, an increase in temperature can impulse, slow or block nerve conduction. Once temperature decreases (after infection), the symptoms decrease or subside.

Upon neurological exam the patient had absent abdominal reflexes, which means she lost her superficial reflexes due to an upper motor neuron lesion. In addition, she showed to have a positive Babinski sign by bilateral extensor plantar responses, which are also a sign of an upper motor neuron lesion. These upper motor neuron lesions can be due to demyelination or lesion of a part of the corticospinal tracks that begin at the cerebral cortex and terminate at the ventral horns of the spinal cord.

 

Question 2: What type of immunological mechanisms can explain the alterations observed in the patient?

Inflammation, demyelination and axon degeneration are the major causes of the alterations observed in this patient and are commonly seen in patients with MS¹.   Initially, an unknown inflammation at the brain alters the blood brain barrier and disrupts the tight junctions, which allows leukocytes to enter. T-cells specific for CNS antigen activate complement, activate macrophages (microglia), and recruit more leukocytes. The T-cells are specific for myelin protein antigen, and oligodendrite antigens⁸. This t-cell medicated activation caused the tissue damage and demyelination of CNS axons, which led to motor and sensory deficits seen in the patient.

Risk Factors

There are a series of risk factors that make development of MS more probable. For example relatives of a person with the disease are at a higher risk than the general population. Differences in the human leukocyte antigen (HLA) system—a group of genes in chromosome that serves as the major histocompatibility complex (MHC) in humans— specifically DR15 and DQ6, increase the probability of suffering MS. On the other hand it is interesting to note that other loci such as HLA-C554 and HLA-DRb11 have shown a protective effect. Meaning that presence of these alleles actually reduces probability of contracting the disease.

Some viral infections have also been associated with development of MS. Human herpes viruses are a candidate group of viruses linked to MS. Also individuals infected with Epstein-Barr virus as young adults have a greater risk of developing the disease. Because of this there’s a higher incidence of the disease in places where these viruses are more common.

Below is a list of the most common risk factors for MS:

 

Virus	A viral infection can be a risk factor for MS.
Age	Multiple Sclerosis is more common in persons between 15 – 40.
Gender	Women have a higher risk of suffering MS.
Family History	There is a genetic factor involved in the risk of MS.
Weather	Multiple Sclerosis is more common in persons who live in cold weather.

 

 

 

 

Symptoms

Below is a list of the most common presenting symptoms in MS:

 

 

Clinical Correlations

Achieving an ultimate multiple sclerosis (MS) diagnosis is not always simple. Many neurological conditions may mimic MS symptoms and make diagnoses confusing. Vitamin B12 deficiency for example, is an absence in vitamin B12 which can cause myelin damage, including a myelopathy, and thus mimic MS.  Neuropathies involving the dorsal columns and the corticospinal tract may also mimic MS symptoms. For these reasons diagnosis of MS should be done through a careful collection of historical, genetic, evoked potentials, neuroimaging and laboratory information⁹.

MS is the result of an initial atypical inflammation on the central nervous system leading to T-cell CD4+ activation by microglial cells. Activation of T-cell CD4+ cells further increases attack on antimyelin antibodies for myelin oligodendrocyte glycoprotein MOG and myelin basic protein MBP are potential markers of MS activity and predictors of progression of MS¹⁰. Inflammation and damage to these tissues leads to the characteristic lesions (scleroses) seen in scans of MS patients. MRI tests are the gold standard in diagnosing MS, due to higher sensitivity for these lesions¹¹. Other tests to diagnose multiple sclerosis include a lumbar puncture to look for the presence of proteins, leukocytes, immunoglobulins. The presence of albumin in cerebral spinal fluid implies disruption of the blood brain barrier indicating inflammation. An abnormality of CSF IgG production is measured by the IgG index. IgG and albumin ration is next calculated and is an indicator of a positive test for MS¹². The presence of oligoclonal bands is common in 95% of patients with MS¹³. Oligoclonal bands are the result of chronic central nervous system infections, viral syndromes, and neuropathies.

 

Figures

 

 

 

 

 

References

 

1.  Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502–17. doi:10.1016/S0140-6736(08)61620-7.

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3. Hernan MA, Zhang SM LL. Multiple sclerosis and age at infection with common viruses. Epidemiology. 2001;12.

4. Nielsen NM, Westergaard T, Rostgaard K et al. Familial risk of multiple sclerosis: a nationwide cohort study. Am J Epidemiol. 2005.

5. Srivastava R, Aslam M, Kalluri SR, et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. The New England journal of medicine. 2012;367(2):115–23. doi:10.1056/NEJMoa1110740.

6. Kebir H, Kreymborg K, Ifergan I et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007.

7. Uhthoff_and_His_Symptom.2.pdf.

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9. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Annals of neurology. 1983;13(3):227–31. doi:10.1002/ana.410130302.

10. Berger T, Rubner P, Schautzer F, et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. The New England journal of medicine. 2003;349(2):139–45. doi:10.1056/NEJMoa022328.

11. Filippi M, Rocca MA. MR Imaging of Multiple Sclerosis 1 n STATE OF THE ART. 2011;259(3):659–681.

12. McLean BN, Luxton RW, Thompson EJ. A study of immunoglobulin G in the cerebrospinal fluid of 1007 patients with suspected neurological disease using isoelectric focusing and the Log IgG-Index. A comparison and diagnostic applications. Brain : a journal of neurology. 1990;113 ( Pt 5:1269–89. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2245296. Accessed May 10, 2013.

13. Statement AC. Recommended Standard of Cerebrospinal Fluid Analysis in the Diagnosis of Multiple Sclerosis. 2005;62(June).