Demyelinating diseases

Demyelinating diseases

definition
Multiple sclerosis (MS) is a chronic disease characterized by inflammation , demyelination , gliosis and neuronal loss .
The course can be relapsing –remitting or progressive .
Lesions of MS typically occur at different times and different CNS locations (disseminated in time and place) .
Manifestation vary from a benign illness to a rapidly evolving and capacitating disease.

epidemiology

Multiple sclerosis is the most common
It affects 300,000 in USA
Highest in young adults
Peak incidence between 20-40 years ,women are affected twice as often as men
Prevalence rises with increasing distance from the equator .
Genetic predisposition is suggested by occurrence in twins , association with specific HLA alleles
The is occasional familial aggregation

Pathology

Development of focal perivenular scattered areas of demyelination ,reactive gliosis ,axonal damage and neuronal degeneration
It affects both gray and white matter of the brain and the spinal cord ,with predominant affection of the white matter


pathophysiology
The cause of MS is unknown
Tissue damage and neurologic symptoms are thought to be triggered by an immune mechanisms against myelin antigens
Viral infections may promote the entrance of T-cells
Into the CNS by disrupting the blood-brain barrier .
The T-cells attack myelin basic protein , myelin-associated glycoprotein or oligodendrocyte glycoprotien .
Immune attack on myelin denudes axons , which slows nerve conduction .
Together with loss of axon and nerve cell bodies , this leads to progressive neurologic symptoms .

Clinical findings

Initial or presenting symptoms : focal weakness ,numbness ,tingling ,or unsteadiness in a limb ; sudden loss or blurring of vision in one eye (optic neuritis ) ; diplopia ,disequilibrium ; or bladder-function disturbances (urinary urgency or hesitancy ).
Symptoms are often transient and disappearing after a few days or weeks .
Other patients presents with an acute or progressive spastic paraparesis and sensory deficits and should raise the possibility of underlying structural lesion unless there is evidence of more widespread disease .

Clinical findings

Subsequent course : there may be interval of months or years after the initial episode before further neurologic appear .
New symptom may develop ,or the original ones may recur and progress .
Relapses may triggered by infections and , in women , are more likely in the first 3 months or so after childbirth ( but are reduced during pregnancy itself ) .
A rise in body temperature can cause transient deterioration ( Uhthoff phenomenon )


Disease course
Relapsing –remitting : form 85% of cases in which progression doesn't progress between attack .
Secondary progressive :form 80 % of cases after 25 year of MS diagnosis in which gradual progressive course after initial RRMS course .
Primary progressive : form 10% of cases in which there is gradual progression of disability from the clinical onset .
Progressive –relapsing : occur rarely with acute relapses superimposed on a primary progressive course

investigation

CSF analysis : mild lymphocytosis , slight rise of protein concentration ( esp. after relapse ). CSF protein electrophoresis shows a discrete bands in IgG region in 90% of patients .
If the clinical lesion exists only in one area of CNS , a diagnosis of MS can't be made unless other region has been affected subclinically .
This can be done by detection of electrocerebral responses (Visual evoked potential VEP done by monocular visual stimulation ) ,brainstem auditory evoked potential BAEP done by monoaural stimulation by repetitive clicks , or somatosensory evoked potential done by electrical simulation of a perioheral nerve .


MRI use is indispensable in diagnosis of MS and detecting subclinical cases to confirm the diagnosis
T1-weighted images may reveal hypointense (black holes )that probably represent areas of permanent axonal damage. Hyperintense lesions are also found .
Gadolinium enhanced T1-weighted images may highlight area of inflammations with breakdown of blood brain barrier .
T2 weighted images provide information about the disease burden .
investigation

In patient with spinal form of MS and no evidence of disseminated disease , spinal MRI or CT myelography may be necessary to exclude spinal congenital anomalies as acquired surgical treatable lesion .
investigation


diagnosis
The diagnosis of multiple sclerosis requires evidence of at least two different areas of the central white matter have been affected at different times .
Clinically definite MS can be diagnosed in patient with a RRMS course and signs of at least two lesions involving different region of the central white matter.
Probable MS is diagnosed when pts. Have evidence of multifocal white matter disease but have only one clinical attack or have a history of two clinical attacks but signs of only single lesion .

Imaging can be used to show dissemination in time if there is a gadolinium – enhancing lesion at least 3 months after the onset of clinical attack , at a site other than corresponding to the clinical events , or if a new T2 lesion is found at any time when compared with the baseline scan obtained at least 30 days after the initial clinical event .
Dissemination in space require three of the following :
At least one gadolinium-enhancing lesion or nine T2 hyperintence lesion if there is no enhancing lesion .

diagnosis

One or more infratentorial or spinal cord lesions.
One or more juxtacortical lesions.
At least three periventricular region.

The diagnosis of primary progressive disease requires in addition to 1 year of disease progression , two of the following :
Positive MRI ( nine T2 lesions or at least four T2 lesion with with abnormal visual evoked potential .
Two or more focal T2 lesions on spinal MRI.
Positive CSF oligoclonal bands , increased IgG index or both .

diagnosis

When pts. Have had a single clinical event and thus do not satisfy criteria for MS , a diagnosis of a clinically isolated syndrome is made . These pts. Are at risk of developing MS in the future and they are indicated for follow up MRI to determined whether any new lesion has occurred .
diagnosis

Differential diagnosis

Acute demyelinating encephalomyelitis ( ADEM ).
Antiphospholipid antibody syndrome .
Behcet’s disease .
Human immunodeficiency syndrome .
Syphilis .
Systemic lupus erythematosus ( SLE ).
Cerebral autosomal dominant arteriopathy , subcortical infarcts , and leucoencephalopathy .
Stroke and ischemic cerebral vascular disease .

treatment

Acute episode, including relapse

Methylprednisolone , 1gm iv daily x 3-5 days .

Prednisolone , 1000 mg PO daily X 3-5 days .
Dexamethasone , 160 mg PO daily X 3-5 days .

relapse prevention, first-line treatment

Interferon
Beta-1a(Rebif),44 mirogram SC 3 times /week

Beta-1a (Avonex), 30 microgram IM once /week

Beta-1b(Betaseron, Extavia) ,0.25 mg SC on aternate days .

Glatiramer acetate (Copaxone), 20 mg SC daily

fingolimod,(Gilenya) 0.5 mg PO daily

Relapse prevention for disease activity despite use of first line treatment

Natalizumab (Tysabri), 300 mg IV monthly

treatment

Fingolimod ,0.5 mg daily .
Mitoxantrone 12 mg /m IV every three months .

High disease activity (typically with multiple gadolinium-enhancing lesions on MRI )

Natalizumab (Tysabri ), 300 mg IV monthly


treatment

Symptomatic treatment

It is useful for for improving quality of life , decrease the burden of disease and treat the complications , although they don’t alter the disease progression and activity

Ataxia and tremor : treated by clonazepam 1.5-20 mg/d ;Mysoline 50-250 mg/d ; propranolol 40-200 mg/d,
Spasticity and spasms :treated by physiotherapy ,baclofen (Lioresal) ;diazepam 2-40 mg/d ,tizanidine 8-32 mg/d.

treatment

Weakness : treated by potassium channel blockers such as 4-aminopyridine 40-80 mg/d
Pain : treated with anticonvulsants ( carbamazepine 100-1000 mg/d ;phenytoin 300-600 mg/d ; gabapentin 300-3600 mg/d , antidepressants like amitriptyline 25-150 mg/d
Bladder dysfunctions : management best guided by urodynamic testing : like oxybutinin 5-15 mg/d in detrusser hyperreflexia .
Depression : useful drugs include SSRI antidepressants like fluoxetine 20-40 mg/d ;sertraline 50-100 mg/d or tricyclic antidepressants like amitriptyline 25-150 mg/d or nortriptyline 25-150 mg/d .

treatment

Fatigue : may respond to amantadine 200 mg/d or modafinil 200 mg/d .

Cognitive dysfunction : may respond to donepezil hydrochloride 10 mg /d .

Constipation : high fiber diet and fluids .natural or other laxatives may help .

Heat insensitivity : ma respond to heat avoidance , air conditioning and cooling garments .
treatment

Sexual dysfunction : may be helped by lubricants to aid in genital stimulation and sexual arousal . Sildenafil 50-100 mg/d or tadalafil 5-20 mg/d are the standard treatment for erectile dysfunctions .
treatment

Neuromyelitis optica

Formerly called Devic disease.
It is associated with specific antibody marker NMO-IgG .
It is characterized by optic neuritis and acute myelitis associated with MRI changes that extend over at least three segments of the spinal cord .
some pts. With isolated myelitis or optic neuritis are also seropositive .
In contrast to MS the MRI doesn’t show widespread white matter involvement in typical cases .

treatment

Acute attacks are treated with IV methylprednisolone 1gm daily for 5 days followed by an oral prednisolone 1mg/kg/day for 1 week , with rapid reduction over the ensuing 1-2 weeks.
If there is no response , plasmapharesis is undertaken .

Acute disseminated encephalomyelitis (ADEM )

Uncommon disorder occur as a single episode of neurologic symptoms and signs that develop over few days in association with non specific viral infections including measles or chickenpox , or after immunization .It has the highest incidence in childhood .
initial symptoms often consists of headache , fever ,and confusion .Multifocal neurologic deficits are common .
The pt. is typically encephalopathic with disturbances in consciousness and occasional seizures.


Acute disseminated encephalomyelitis (ADEM )
Flaccid weakness and sensory disturbances of the leg , extensor planters , urinary retension are common manifestations of spinal cord involvement .
Other neurologic signs may indicate involvement of the optic nerves or cranial nerves , cerebral hemispheres , brainstem ,or cerebellum .
The neurorologic deficits resolves , at least in part , over few weeks .Most pts. make virtually a complete recovery , but some are left with severe residual deficits .

Acute disseminated encephalomyelitis (ADEM )

Investigations
CSF may be normal but may show increased mononuclear cell count , protein may increased , oligoclonal band may present, but glucose concentration is normal .
MRI shows asymmetric high signal lesions on T2 image , particularly in the hemispheric white matter, optic nerves ,brainstem ,cerebellum ,brainstem or spinal cord .

Acute disseminated encephalomyelitis (ADEM )

Differential diagnosis

Infective menigitis

Encephalitis .
Multiple sclerosis .
White matter ischemia

Acute disseminated encephalomyelitis (ADEM )

Treatment


Broad spectrum antibiotics and acyclovir are often administered until bacterial meningitis and herpes simplex encephalitis are excluded .
High dose IV methylprednisolone ( 30mg/kg/day )up to a maximum dose of 1 gm daily for 5 days is then usually given.
IV immunoglobulin or plasmapharesis is sometimes helpful if the response to steroid is incomplete .