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What is metachromatic leukodystrophy? What enzyme abnormality causes this?
- Deficiency of arylsulfatase A
- Enzyme deficiency results in deposition of sulfatides in tissues, resulting in widespread myelin breakdown
- Autosomal ressesive, 22q13.31-qter
What is seen clinically?
- Involve both the CNS and the PNS
- Disease is progressive, resulting in death at an early age
- Intellectual impairment, progression of disease similar to MS
- May have peripheral neuropathic features
- Infantile, juvenile, and adult forms
- All forms fatal within a few years
MRI in Metachromatic leukodystrophy
MRI: Bilateral T2 high intensity at periventricular white matter with classical sparing of subcortical U fibers, contrast not enhancing in demyelination area.
In central pontine myelinolysis, what are frequent clinical findings?
- Clinically, frequent observed symptoms are sudden para or quadraparesis, dysphagia, dysarthria, diplopia and loss of consciousness.
- The patient may experience locked-in syndrome where cognitive function is intact, but all muscles are paralyzed with the exception of eye blinking.
CPM is concentrated, frequently symmetric, noninflammatory demyelination within the central basis pontis.
In at least 10% of patients with CPM, demyelination also occurs in extrapontine regions, including the mid brain, thalamus, basal nuclei, and cerebellum.
MRI of CPM?
T2-weighted MRI demonstrating patchy areas of signal change within the pons that are consistent with demyelination or central pontine myelinolysis.
How do you prevent CPM?
CPM is prevented by the gradual, controlled treatment of low or high sodium levels there by reducing the risk of nerve damage in the pons. Avoiding medications that altered changes in sodium levels in the serum or preventing these levels from changing too quickly
What other systemic disease is progressive multifocal leukoencephalopathy associated with?
The disease occurs, rarely, in organ transplant patients; people undergoing chronic corticosteroid or immunosuppressive therapy; and individuals with cancer, such as Hodgkin’s disease, lymphoma, and sarcoidosis. PML is most common among individuals with acquired immune deficiency syndrome (AIDS).
What is progressive multifocal leukoencephalopathy? What organism causes it.
Polyomavirus JC (often called JC virus) is carried by a majority of people and is harmless except among those with lowered immune defenses.
(PML) is caused by the reactivation of a common virus in the central nervous system of immune-compromised individuals.
Clinical findings in PML
insidious onset of focal symptoms including behavioral, speech, cognitive, motor, and visual impairment .
More clinical findings in PML?
- Rare headaches, seizures, and neck stiffness.
- Subacute evolution over several weeks
- On physical exam, focal neurological signs include aphasia, hemiparesis, ataxia, cortical blindness, and less frequently head tremor. Focal signs tend to be related to posterior brain (eg, occipital lobes).
- Conjugate gaze abnormalities are common. This is the initial presentation in more than 30% of patients. Abnormalities may progress to quadriparesis and coma.
MRI of brain showed single or multiple confluent lesions without mass effects, most frequently in the parietooccipital white matter. Occasional infratentorial lesions are usually asymmetrical.
MRI of Brain in PML?
Sparing of subcortical U fibers is characteristic. Subcortical gray matter or spinal cord may be involved, but rarely. PML sometimes can resemble lymphoma, toxoplasmosis, or HIV encephalitis
Pathology of PML?
Multiple demyelinative foci may be seen in the cerebral, cerebellar, and brainstem white matter and at the gray-white matter junction; in severe cases, such foci may be seen in the cortical gray matter. Foci may become confluent. Perivascular inflammatory infiltrates are observed. Necrotic and cystic lesions may be present but are rare.
Pathology of PML - can you see nuclear inclusions?
Nuclear inclusions may be seen in large ballooned oligodendrocytes and rarely in astrocytes, both of which show bizarre-looking nuclei. The inclusions contain viruses as identified by electron microscopy and immunohistochemistry
Brain bx findings in PML? Sensitivity and Specificity?
brain biopsy has a sensitivity of 74-92% and a specificity of 92-100%. Mild cortical atrophy may be seen on biopsy specimens.
What is acute disseminated encephalomyelitis (ADEM)? In what clinical setting is it commonly seen? What is seen on MRI? What treatment options are available?
- Associated with vaccination/systemic viral infection
- Almost always monophasic
- Prodrome of fever, malaise, myalgia
- Characterized by abrupt development (several hours) of focal or multifocal neurologic deficits
Common features of ADEM
- bilateral optic neuritis,
- loss of consciousness/encephalopathy,
- temperature >100F,
- shooting limb pain
What is adrenoleukodystrophy (ALD)?
Leukodystrophies referred to as dysmyelinating diseases. In these diseases there is an abnormality in the formation or stability of myelin, rather than a process in which normal myelin is damaged.
Name the genetic abnormality and what accumulates in ALD?
Adrenoleukodystrophy (ALD) is one of leukodystrophies that cause damage to the myelin sheath. X-linked disorder, Xq28. mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body The loss of myelin in central nervous system, progressive dysfunction of the adrenal cortex and Leydig cells of the testes are the primary menifestations.
2 subtypes of ALD?
- Childhood Cerebral Adrenoleukodystrophy
Childhood form of ALD?
- The childhood form is the most severe, with onset between ages 4 and 10. The mean age of onset is approximately 7 years.
- Boys are normal at birth and have unremarkable development.
- early symptom is behavioral manifestations including inattention, hyperactivity, and emotional lability. It often becomes apparent through school difficulties.
- It progresses into visual symptoms, auditory processing difficulties, and motor incoordination.
- Once the neurologic manifestations appear, progression of the illness is tragically rapid and the child is often in a vegetative state within 1 to 2 years
What biochemical abnormality causes ALD?
The gene that is defective in X-ALD is called ABCD1, and encodes a protein called ALDP (which stands for ALD protein).
This protein resides in the wall of the peroxisome, and is involved in the breakdown of fatty acids.
In X-ALD, this ability is impaired, resulting in the accumulation of very long chain fatty acids, leading to the breakdown of the myelin sheath.
screening blood test in ALD?
very longchain fatty acids
What is adrenomyeloneuropathy? How does it present?
AMN, variant of X-ALD, causes slowly progressive paraparesis and sphincter disturbances.
- Symptoms typically start at 28 ± 9 years. Symptoms include progressive stiffness, weakness or paralysis of the lower limbs, and ataxia.
- Although adult-onset ALD progresses more slowly than the classic childhood form, it can also result in deterioration of brain function.
- A mild form of ALD is occasionally seen in women who are carriers of the disorder. Symptoms include progressive stiffness, weakness or paralysis of the lower limbs, ataxia, excessive muscle tone, mild peripheral neuropathy, and urinary problems.
People with pure AMN have what CNS involvement? Is there cognitive involvement?
- Patients with pure AMN present with only spinal cord and peripheral nerve involvement and sparing of higher cognitive functions.
- However, neuropsychological testing may show subtle deficits in psychomotor speed and visual memory.
- This variant has a prognosis better than that of other forms.
- AMN-cerebral (cortical involvement 50%) is used to describe increased impairment of neuropsychological function. Patients have various degrees of brain MRI abnormalities.
What is the relationship of Adrenomyoneuropathy to adrenoleukodystrophy?
It is an X linked variant of ALD
What are other names for Krabbe globoid leukodystrophy?
- Many other names for this disease
- Krabbe disease
- Globoid Cell Leukodystrophy
- Galactosylceramide beta-galactosidase deficiency
- Galactocerebrosidase deficiency
- GALC deficiency
What is Krabbe disease
- Autosomal recessive disorder, 14q31.
- caused by deficiency of galactocerebrosidase → accumulation of galactolipids (psychosine) in macrophages( hence named Globoid cell) → levels are 100 times that of healthy individuals →results in demyelination.
What is seen clinically in Krabbe?
- Infantile Form and late-onset form
- The majority of cases of Krabbe Disease appear within the first year of life,
- However it can appear at other ages as late as adulthood.
- The patients rapidly regress with little to no brain function, and generally die by two years of age usually due to respiratory infection or brain fever.
- Rule is earlier the symptoms appear worse the prognosis.
Most common features of Krabbe's
- Developmental delay
- Limb stiffness
- Optic atrophy: wasting of a muscle of the eye, resulting in vision diffculties
- Neurosensoral deafness
- Extreme irritability
- Spasticity: presence of spasms
- Ataxia: loss of the ability to control muscular movement
- Progressive psychomotor decline: progressive decline in the coordination of movement
What is Marchiafava-Bignami disease?
- A Very rare condition. So far, only 250+ total cases reported worldwide since it was first described in 1903.
- etiology unclear.
- A syndrome of interhemispheric disconnection with primary symmetrical demyelination and necrosis of the corpus callosum.
- The lesion may be found in hemispheric white matter, but the cortical involvement is extremely rare.
- Sudden onset stupor or coma, some present with seizures.
- Apraxia of the left (or nondominant) hand suggests interhemispheric disconnection
Diagnosis of Marchiafava-Bignami is based on clinical and MRI - findings include?
Acuter phase, corpus callosum is of low signal on T1 and high on T2; often enhances, subacute and chronic forms, the lesions involve the central part of the corpus callosum body most commonly and are hypo- on T1 and hyper- on T2. central pontine myelinolysis can be concomitant findings.
Who gets Marchiafava-Bignami?
- Chronic Alcoholics+ poor nutrition, more in male of 45 ys older.
- Rare cases can be seen in non-alcoholics
Most common Symptoms in definite MS:
- 50% of patients manifest with mix generalized type (involvement of optic nerves, brain stem, cerebellum, and spinal cord);
- 30-40% with spinal form;
- 5% each have predominantly cerebellar or pontobulbar-cerebellar form; some global dementia (more subcortical with prominent frontal lobe syndrome and abulia) or confusional-psychotic states.
How is MS affected by body temperature?
- Increase in body temperature worsen current or pre-existing MS symptoms.
- This phenomenon is presumed to be the result of conduction block in nerves. Normally, the nerve conduction safety factor decreases with increasing temperature until a point is reached at which conduction block occurs; this point of conduction block is reached at a much lower temperature in demyelinated nerves.
What is Lhermitte’s sign?
Transient electrical shock like sensation that radiates down the spine or into limbs on flexion of the neck attributed to dysfunction of the posterior columns
With what other pathological processes is it associated?
Other lesions of the cervical cord including tumor, cervical disc herniation, postradiation myelopathy, and following trauma.
What is the relationship of MS to dementia?
About 30-60% of pts with MS will have cognitive impairment.
Relationship of MS to Narcolepsy?
Has been seen in some case reports. Pt’s more likely to have fatigue, narcolepsy not typically associated with MS.
Relationship of MS to Trigeminal neuralgia?
Can be an early sign of MS especially in younger patients.
Relationship of MS to Intention tremor?
This can be noted in head and upper extr, more commonly when there is cerebellar pathway involvement.
What is the typical age of onset of MS? Lifespan impact?
The typical age of onset of MS is 29 to 32 years. Lifespan decreasing it to 82.5% of normal life span.
What prognostic factors are favorable in MS?
Good prognostic indicators are female sex, earlier age of onset, relapsing disease course, and impairment of only sensory pathways, or cranial nerve dysfunction including ON and sparing of pyramidal, brainstem and cerebellar symptoms in initial presentation.
What is myelin basic protein?
MBP, myelin basic protein, is a myelin membrane protein. It is elevated in the CSF with demyelination and seen in multiple sclerosis, CNS hemorrhage, encephalopathy, CNS trauma, CNS infection, and stroke.
What is experimental allergic encephalomyelitis (EAE)? How is EAE produced?
EAE is an animal model of the human CNS demyelinating diseases. An acute monophasic illness, it has been suggested that EAE is far more similar to ADEM than MS. It is produced by inoculation with whole CNS tissue, purified myelin basic protein (MBP) or myelin proteolipid protein (PLP), together with adjuvants in mice. It may also be induced by the passive transfer of T cells specifically reactive to these myelin antigens.
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