Cerebral Dysfunction in Multiple Sclerosis

Dr. Mindaugas Petrašiūnas

Based on Wilkins A. Cerebellar Dysfunction in Multiple Sclerosis. Front Neurol. 2017;8:312(1).

Introduction

Multiple sclerosis (MS) is the most common chronic disease of the central nervous system (CNS) causing disability in young adults. Cerebellar damage associated with MS affects various brain functions and contributes to worsening disability. By affecting the cerebellum, MS can cause symptoms of either chronic or acute cerebellar dysfunction. Symptoms of cerebellar dysfunction, such as tremor, ataxia, and dysarthria, are difficult to treat and may also complicate other clinical manifestations of MS.

MS

MS is a heterogeneous disease that can manifest with numerous clinical and pathological features reflecting different mechanisms of CNS damage. Although the causes of MS remain unclear, inflammation, demyelination, and neurodegeneration are the main pathological mechanisms contributing to the clinical picture of the disease. The most widely accepted theory of disease pathophysiology is that MS begins as an inflammatory disorder driven by autoreactive lymphocytes and that, as the disease progresses, microglial activation and chronic neurodegeneration play an increasingly important role (1–3).

Among CNS disorders, MS is a common cause of disability in young adults. Women are more frequently affected by the disease: according to a 2008 systematic review, the female-to-male ratio is 2.3:1 (4). The average age at onset of MS is 28–31 years (5). Patients most commonly have a relapsing-remitting form of the disease, with an average age at onset of 25–29 years, which is often followed by secondary progressive MS, with an average age at onset of 40–49 years (5). In patients with secondary progressive MS, disability progresses slowly.

A small proportion of patients develop primary progressive MS. Primary progressive MS occurs in approximately 5–10% of patients, usually at around 39–41 years of age (5). Despite extensive research and a better understanding of the pathophysiological mechanisms of the disease, MS remains incurable. However, new therapies, such as natalizumab and alemtuzumab, have shown disease-modifying effects and provide hope for improved disease management (1, 5).

The disease most commonly presents clinically as a clinically isolated syndrome. This may manifest as optic neuritis or as a brainstem, cerebellar, or spinal cord syndrome. MS is more common in children, but in adults, encephalopathy characterized by headache, vomiting, seizures, and disturbances of consciousness may also occur rarely (6).

In MS, the cerebellum is frequently affected, including its efferent and afferent pathways, resulting in symptoms of cerebellar dysfunction. Cerebellar ataxia is a common symptom of progressive disease. Despite involvement of the entire CNS, several aspects of cerebellar damage may provide important insights into potential mechanisms of injury and possible therapeutic approaches (1, 6). This article reviews the clinical aspects of the disease, pathological changes, observation of cerebellar changes in MS, and treatment of cerebellar damage.

Pathological CNS Changes in MS

MS is a chronic inflammatory disease that leads to the formation of demyelinating plaques in the white and gray matter of the CNS. In addition to demyelination, varying degrees of neurodegeneration occur in the CNS, resulting in axonal loss in white matter and neuronal loss in gray matter (7). These processes contribute to significant loss of brain tissue and lead to brain atrophy.

For many patients, MS begins with an early relapsing-remitting form that progresses after 10–15 years. Patient age is a key factor in the transition from relapsing MS to progressive MS (8). White matter lesions formed as a result of the inflammatory process predominate during the exacerbation phase of the disease. As the disease continues and progresses, the inflammatory response decreases, new white matter lesions occur less frequently, and diffuse demyelination, widespread brain damage, and atrophy begin to predominate (9).

The pathophysiology of the disease is often explained primarily by inflammatory processes at the beginning of MS, but as the disease progresses, additional factors contribute to brain damage, including microglial activation and mitochondrial injury. All of these processes lead to tissue damage and neurodegeneration.

Similar changes occur in the white matter of the cerebellum. White matter lesions in the cerebellum are mainly localized in the cerebellar peduncles, dentate nuclei, and olivary nuclei. There are fewer lesions in the cerebellum than in the white matter of the frontal lobes. This appears to be related to the relatively smaller volume of the cerebellum (10).

Two different types of cortical-subcortical changes are observed in the cerebellar cortex, along with stripe-like changes. Stripe-like changes are more common in patients with progressive forms of the disease. These changes are distributed over long segments of the cerebellar cortex and do not extend into the subcortical white matter (11).

Stripe-like demyelination of the cerebellum in patients with MS is pronounced. On average, 30–40% of the cortex is affected, while some patients develop complete demyelination of the entire cerebellar cortex. Despite these findings, it remains unclear whether stripe-like cerebellar demyelination has clinical significance (11).

Clinical Signs of Cerebellar Damage

Patients with MS may present with impaired coordination. Coordination is most commonly affected because of pathology in the cerebellum or its pathways, particularly the proprioceptive afferent pathways. Because the cerebellum is connected with other regions of the CNS, including the brainstem, cortex, and spinal cord, cerebellar damage in patients with MS can produce a wide range of symptoms.

The exact prevalence of symptoms associated with cerebellar damage is unclear. According to studies, approximately 11–33% of patients with MS have symptoms of cerebellar dysfunction as the dominant clinical manifestation. Patients with MS may develop both acute symptoms of cerebellar dysfunction and chronic symptoms of cerebellar damage as the disease progresses.

Cerebellar pathology may cause limb, gait, or truncal ataxia depending on the precise location of the lesion, as well as other signs of cerebellar damage, such as nystagmus, dysarthria, and tremor. Patients who already have signs of cerebellar dysfunction at disease onset develop more severe disability.

During an exacerbation of MS, the connections between the cerebellum and brainstem are often affected. Cerebellar dysfunction at disease onset indicates an increased risk of cerebellar involvement during future exacerbations. Studies show that cerebellar symptoms at the onset of the disease are associated with a poorer prognosis. Approximately 10% of all relapses, occurring more frequently in men than in women, are related to cerebellar dysfunction. It is also important to note that patients with MS may experience paroxysmal symptoms of ataxia and dysarthria.

Ataxia occurs in approximately 80% of patients and is most common in those with progressive forms of the disease. Tremor in MS is likely caused by cerebellar and/or brainstem pathology. Tremor may affect the limbs, trunk, vocal cords, and head. Intention and postural tremors rarely develop. Although severe tremor can cause substantial disability, it is a relatively rare consequence of MS, occurring in 3% of patients.

The pathophysiology of tremor in MS is complex and involves connections between the cerebellum, cortical structures, and brainstem nuclei. In patients with an isolated cerebellar dysfunction syndrome without involvement of other CNS regions, alternative diseases that could cause these symptoms, such as metabolic or hereditary cerebellar disorders, should be excluded.

Gait ataxia is believed to develop because of damage to the anterior lobe of the cerebellum. Cerebellar dysarthria rarely occurs at the onset of the disease but is more common during the secondary progressive phase. Paroxysmal symptoms of MS are relatively rare.

Patients with MS should be evaluated for possible symptoms of cerebellar damage. Examination should include assessment of standing, gait, the finger-to-nose test, the heel-to-shin test, and other coordination tests. Particular attention should also be paid to nystagmus and changes in speech.

Relationship Between Cerebellar Damage and Cognitive Functions

Cerebellar dysfunction is associated with changes in neuropsychological functions, primarily affecting attention, working memory, and speech. It is known that MS is characterized not by global cognitive impairment, but by alterations in specific functions, including memory, speech, attention, and information processing speed.

However, the relationship between cognitive deficits and cerebellar dysfunction remains a subject of scientific debate because evidence supporting these associations is still limited. There is evidence that patients with signs of cerebellar motor dysfunction often experience more severe cognitive impairment than patients without symptoms of cerebellar dysfunction.

In addition, reduced total cerebellar volume is associated with poorer results on cognitive tests. Reduced volume of the posterior inferior part of the cerebellum is associated with poorer cognitive function, while reduced volume of the anterior part of the cerebellum is associated with motor dysfunction. It can therefore be stated that cerebellar damage contributes to cognitive impairment.

Monitoring of Cerebellar Damage

Most disability assessment scales used in MS include some form of ataxia assessment. One such scale is the Expanded Disability Status Scale (EDSS), which is the most commonly used disability assessment scale in MS studies.

Disability assessment using this scale is based primarily on motor dysfunction, although functional systems such as vision, bladder, and bowel function are also evaluated because impairments in these systems may contribute to the overall disability score. Because the cerebellar system is assessed as a functional system, worsening ataxia may contribute to a decrease in the overall EDSS score.

Other scales also assess cerebellar function. One such scale is the Multiple Sclerosis Functional Composite (MSFC), which includes the Nine-Hole Peg Test (9-HPT). Performance on this test depends on cerebellar function. The relevance of direct ataxia assessment scales has not been extensively studied in patients with MS because these scales were developed to assess isolated cerebellar or spinocerebellar syndromes.

Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) is the most important diagnostic tool for diagnosing MS and identifying infratentorial lesions. MRI using standard T1- and T2-weighted sequences, as well as FLAIR (fluid-attenuated inversion recovery), is widely used in clinical practice to assess focal lesions.

MRI confirms brain lesions in both relapsing-remitting and progressive MS. According to the McDonald criteria for the diagnosis of multiple sclerosis, infratentorial regions of the CNS are common sites of lesions in MS.

Diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) can identify changes in white matter tracts, particularly in the cerebellar peduncles. Changes in the cerebellar peduncles visible on T2-weighted MRI are associated with symptoms of cerebellar dysfunction.

A combined MRI and posturography study showed that gray matter atrophy in the superior cerebellar lobes correlated with poorer posturometric scores. Proper assessment of symptoms associated with brain lesions may be important in ensuring appropriate disease-modifying and symptomatic therapy for MS when specific brain lesions are present.

Treatment of Brain Lesions

Although MS is not curable, current therapeutic measures aim to maintain patients' independence, delay symptom progression, and prevent complications. MS treatment is divided into pharmacological treatment and physical rehabilitation.

Physical rehabilitation procedures, such as physiotherapy, occupational therapy, or physical therapy, complement pharmacological treatment for motor and balance impairments. Pharmacological treatment of MS may consist of symptomatic therapy or disease-modifying therapy, with the main goal of slowing disease progression.

Unfortunately, most studies of disease-modifying drugs do not examine their effects on brain functions. Studies generally evaluate annual relapse reduction rates and EDSS scores. As mentioned above, the EDSS scale is used to assess brain function, but its significance in determining the specific effects of medications on brain function remains unclear.

MS relapses dominated by cerebellar dysfunction are associated with an increased risk of disability progression compared with other forms of relapse. By reducing the number of relapses with disease-modifying drugs, the burden caused by brain disease is reduced.

Pharmacological methods for treating ataxia are less effective; therefore, alternative approaches are needed to address this clinical problem. According to a Cochrane review of ataxia caused by MS, the effectiveness of pharmacological therapy is poorly documented, and no recommendations are provided.

There is evidence of beneficial effects of isoniazid, propranolol, and levetiracetam on tremor, but the available research data are not reliable because of the small number of participants. Cannabinoids are another possible treatment option for tremor and may have a beneficial effect. In patients with paroxysmal cerebellar dysfunction, including ataxia and dysarthria, symptoms may be reduced with carbamazepine.

Interventional treatments for brain dysfunction have also been investigated, including stereotactic surgery and deep brain stimulation. Tremor decreased in all patients with MS immediately after thalamotomy or globus pallidus stimulation procedures. Unfortunately, tremor recurred in all patients after 6 months, although it was less severe, and the overall disability score remained unchanged.

In summary, interventional methods for treating tremor may be used for short-term symptom relief, but reliable evidence is currently lacking. Advances in neurosurgical techniques may help patients experiencing severe ataxic tremor.

Conclusion

Symptoms of brain dysfunction in MS are common, although most researchers have not emphasized the significance of brain lesions. It is becoming clear that symptoms of brain dysfunction related to both motor and cognitive functions contribute to worsening disability in patients with MS.

By studying the pathophysiology of brain dysfunction, there is hope that brain-related symptoms will be more effectively controlled.

Publication "Internist" No. 2, 2018

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