White Matter, Neurodegenerative Diseases and Hydrocephalus

Virchow-Robin spaces (perivascular spaces) – Invaginations of subarachnoid space associated with leptomeningeal vessels. Seen in basal ganglia, around atria, near anterior commissure, corona radiata, centrum semiovale, peri-insular, central brainstem, medial and posterior reticular portion of substantia nigra. They are linear and follow CSF intensity (low T1, high T2, low FLAIR/PD).

Multiple white matter lesions are nonspecific, but DDx includes small vessel ischaemia, demyelination, vasculitis, migraines and idiopathic causes.

Demyelinating Disease

Acquired inflammation injuring ± destroying white matter esp oligodendrocytes which wrap around axon and form myelin sheath. This is caterorised into:

  • Primary – Multiple sclerosis
  • Secondary
    • Allergic/immunologic – ADEM
    • Infection – HIV-associated encephalitis, PML, SSPE, Lyme disease, neurosyphilis.
    • Vascular – Binswanger disease, CADASIL, postanoxic encephalopathy, PRES.
    • ?Ischaemic (most) – Deep white matter infarcts, lacunes, vasculitis (including sarcoidosis, lupus), dissection, thromboembolic infarcts, migranous ischaemia, moyamoya, postanoxia.
    • Toxic and metabolic – Central pontine myelinosis, Marchiafava-Bignami, Wernicke-Korsakoff, radiation, necrotising leukoencephalopathy, drugs, heavy metals and other toxins.
    • Trauma – DAI

Multiple Sclerosis (MS)

20-40yo, F:M 2:1, 1:1,000, increased risk with higher socioeconomic status, higher geographic latitudes, 1st degree relative. Autoimmune with chronic inflammation causing myelin loss. Multiple CNS lesions separated in both time and space. Any deficit, commonly limb weakness, parasthesia, vertigo, visual/urinary disturbace. Unpredictable relapses and remissions. Oligoclonal banding, raised IgG index and myelin basic protein on CSF. Lesions are well-defined, grey-tan, irregularly shaped plaques. Commonly have symptoms without corresoponding lesions. Active lesions have axonal transections, infiltration of lipid-laden macrophages (gitter cells with PAS-positive debris), perivascular inflammatory cuffing with T/B-lymphocytes, plasma cells. Tends to be centred on blood vessels. Primarily depletes oligodendrocytes, with relative preservation of axons. Surviving oligodendrocytes may attempt to remyelinate, causing an ill-defined zone continuous with demyelinated lesion (shadow plaque). Inactive plaques are hypocellular without inflammation. Scars/gliosis in old inactive plaques are focal proliferation of astroglia.

Clinical courses:

  • Relapsing remitting (85%) – Excerbations followed by remissions, but later excerbations result in incomplete recovery. After 10-25yrs secondary/relapsing progressive phase with little remission between exacerbations.
  • Primary/chronic progressive (5-10%) – Present later with progressive findings, occasionally plateaus and temporary improvements, but no distinct relapses. Tend to have smaller lesion load, fewer new/enhancing lesions.
  • Progressive relapsing (rare) – Continuing progression with periods of clear acute relapses.
  • Benign MS – Initial symptoms, but no progression after 10-15yrs.
  • Malignant MS – Rapidly progressive with significant disability or death shortly after onset.
  • Monosymptomatic patients – Single episode of deficit (eg optic neuritis, transverse myelitis, brain stem syndrome). Many later develop MS, esp if there are asymptomatic lesions on MRI.

Associated syndromes:

  • Devic disease (neuromyelitis optica) – Acute variant of MS with synchronous or near synchronous transverse myelitis and bilateral optic neuritis simultaneously or separated by days/weeks.
  • Balo diseae (concentric sclerosis) – Alternating concentric demyelination and normal brain.
  • Diffuse sclerosis (Schilder disease) – Acute rapidly progressive MS with bilateral symmetric demyelination. Almost always <40yo. Large areas of demyelination, well circumscribed, centrum semiovale and occipital lobes.
  • Marburg variant MS – Repeated relapses with rapid deterioration, immobility, lack of pharyngeal reflexes and bladder dysfunction.

Differing clinical and MRI criteria for diagnosis. MRI criteria lesions disseminated in space with at least 3 of: 1 enhancing or 9 T2 foci in brain/spine, infratentorial/spine lesion(s), juxtacortical lesion(s), >/= 3 periventricular lesions; and disseminated in time with at least one of: enhancing lesion >/= 3/12 after presentation in a different location, or new T2 lesion from MRI >/= 30/7 ago.

Best seen on FLAIR (doesn’t detect posterior fossa lesions as well as T2), T2, STIR. Round/oval (aligned perpendicular to ventricles, along perivenular spaces) periventricular/subcortical high T2 (including subcortical U-fibres), iso/low T1. Mostly white matter, may also involve grey matter (has myeniated fibres running through). Predilection for periventricular, corpus callosum (sag FLAIR/PD), optic nerves, visual pathways, posterior fossa (brain stem, cerebellar peduncles), cervical cord. 60% of spinal cord lesions are in the cervical region, 70-80% of spinal cord lesions have associated plaques in brain. Spinal cord lesions are peripheral, do not respect grey-white boundaries, 90% <2 vertebral body segments in length, occasionally cord swelling and atrophy. New lesions initially enhance (active demyelination with disrupted BBB) in ovoid/nodular pattern then ring/arc as it breaks down. Increased sensitivity with delayed 15-60min, triple dose Gad or magnetisation transfer (MT). Enhancement usually from 2nd-8th week, unusual to persist for >3/12. Dawson’s fingers – lesions at callosal-septal interface from inflammatory changes along medullary veins, high specificity and sensitivity (from vascular disease). Tumefactive MS – large conglomerate plaque, often showing leading edge crescentric/horse-shoe enhancing rim (front of active demyelination), may have mass effect mimiking tumour (but no increased perfusion, veins course through), associated with seizures. Rarely haemorrhage into lesions (more common in tumours, strokes). Low T1 (dark lesions, black holes) associated with severe myelin loss and worse Sx, may cause dark/CSF FLAIR signal. Peripheral high T1 uncommon, ?paramagnetic haemorrahge, myelin catabolites, free radicals or focal protein. Chronic cases show diffuse loss of white matter with thinning of corpus callosum, ex vacuo dilatation of ventricles, iron deposition in thalamus and basal ganglia (low T1 and T2). Reduced NAA (indicating axonal-neuronal loss), increased Cho (myelin/membrane breakdown, inflammation and remyelination), reduced Cr, high lipids in acute lesions. MS load usually more than seen on MR, as normal-appearing white matter (NAWM) is not normal in MS. MT and MTR ([[Magnetic Resonance Imaging (MRI)#Magnetisation Transfer (MT) Imaging|see MT imaging]]) is reduced in demyelinating plaques, as well as NAWM; highest in homogeneously enhancing lesions and lowest in central portion of ring-enhancing lesions. Acute plaques show diffusion restriction, > NAWM (but both increased cf normal).

Unidentified bright objects (UBOs) – High T2 white matter foci common, 10% of 0-39yo, 80% >70yo. Generally up to 1 per decade of life. ?Gliosis from prior trauma/ischaemia/inflammation, perivascular demyelination around arteriosclerotic vessels, myelin pallor, dilated perivascular spaces, or small lacunar infarcts. DDx accelerated small-vessel ischaemic change, vasculitis, migraine headache (predominantly subcortical frontal and parietal ?platelet aggregation/microemboli, rarely infarcts), Lyme disease. Ischaemia is uncommon in medulla and peduncles.

Spinal cord lesion DDx: MS, ADEM, vascular lesion (esp dAVM), infarction, collagen vascular disease (esp lupus myelitis), neoplasm (primary or met), infection (toxoplasmosis, AIDS, herpes), lupus, trauma (haematomyelia), diffuse leptomeningeal coating (sarcoid, lymphoma, other tumours).

Acute Disseminated Encephalomyelitis (ADEM)

(Perivenous encephalomyelitis). Acute monophasic demyelinating disease typically 1-2/52 following viral infection, vaccination (esp measles, mumps, rubella, varicella) or spontaneously, ?autoimmune cross-reaction with viral protein. Fever, HA, meningeal signs, seizures, stupor, coma (cf focal sligns in MS). Most resolve sopntaneously, but permanent sequale in 25%, mortality 10-20%. Most common in childhood, but can be any age. Increased WCC/lymphocyes and myelin basic protein in CSF. High T2/FLAIR in white matter, brainstem, cerebellum, basal ganglia; centred around vessels (perivenular). Usually multiple, but few in number with ‘at least one large dominant leison’. Symmetric deep grey matter and cortical lesions. Optic neuritis common. 30% involve spinal cord. Solid or ring enhancement. Similar to MS, but monophasic clinical course (no new lesions after 6/12), favours subcortical and deep white matter regions (no Dawson’s fingers), regresses with treatment. Tx steroids with full recovery. Occasionally recurrent ADEM (>3/12 in same region) or multiphasic ADEM (>3/12 in different retion), which aren’t monophasic. New symptoms within 3/12 is still classified as monophasic.

Acute haemorrhagic leukoencephalitis (Hurst disease, acute necrotizing haemorrhagic encephalomyelitis ANHE) – Severe variant of ADEM, often fatal, usually young adults/chidlren. Perivenular lesions similar to ADEM with hdestruction of small blood vessels causing haemorrhagic necrosis esp centrum semiovale, rapid progression and coalescence of white matter lesion over a few days. Spares subcortical U fibres. Death after ~6/7 of onset due to oedema and herniation.

Ischaemic Demyelinating Disease

See Cerebrovascular Disease

Infectious Demyelinating Disease

See CNS Infection

Central Pontine Myelinolysis (CPM)

(Osmotic demyelination). Demyelination of central pons in electrolyte abnormality esp rapidly corrected hyponatraemia (most common, osmotic demyelination syndrome), diabetes, leukaemia, transplant recipients, chronic debilitated patients, chronic malnutrition. Generalised encephalopathy with hyponatraemia, transient correction with elecrolyte correction, then rapidly evolving corticospinal syndrome (quadriplegia, acute change in mental status, ‘locked-in’ state, coma) 2-3/7 later from myelinolysis. Disturbance in osmolar balance in oligodendroglial cells with high T2 from intramyelinitic splitting, vacuolisation, rupture of myelin sheaths. Monophasic, symmetric, within central pons (sparing tegmentum and ventral) and extrapontine myelinolysis in basal ganglia esp thalamus, globus pallidus, putamen, lateral geniculate body, caudate, internal/external/extreme capsules, claustrum, amygdala, cerebellum. Sparing of periventricular and subpial regions. Preservation of neurons and axons, no inflammatory reaction (cf MS). Variable diffusion restriction which may predate T2. May spare descending corticospinal tracts causing 2 central symmetric isointensities. 1/3 die or have significant neurological deficits, 1/3 some deficits, 1/3 full recovery.

Marchiafava-Bignami Disease

Rare, most common in alcoholics. ?Osmotic demyelination, ?variant of extrapontine myelinolysis. May be acute (seizures, neurologic dysfunction, coma) which is usually fatal; subacute (sudden dementia -> chronic vegetative state); or chronic (progressive dementia, disconnection syndrome). Demyelination of central fibre (medial zone) of corpus callosum or other white matter tracts (anterior and posterior commissures, centrum semiovale, middle cerebral peduncles).

Posterior Reversible Encephalopathy Syndrome (PRES)

(Reversible posterior leukoencephalopathy syndrome RPL, acute hypertensive encephalopathy). ?Temporary failure of autoregulation in vessels causing hyperperfusion (above the ‘break-through’ point) and thus breakdown of BBB and extravasation of fluid, maromolecules and RBCs. Causes include cyclosporin A, tacrolimus, ARF/uraemia, haemolytic uraemic syndrome, eclampsia, TTP, chemotherapy including interferon leading to endothelial injury and/or raised BP. HA, seizures, visual changes, altered mental state. Symmetric subcortical and cortical vasogenic oedema in parieto-occipital lobes (relatively poor sympathetic innervation of posterior circulation). No diffusion restriction to suggest infarction. Not always reversible. May cause haemorrhagic infarctions.

Binswanger Disease

(Subcortical arteriosclerotic encephalopathy). >55yo, M=F associated with HTN and lacunar infarcts. Demyelination with relative axonal sparing, arteriosclerosis, narrowing of white matter arteries and arterioles. Large regions of high signal white matter fronto-parieto-occipital regions extending into centrum semiovale. MTR is reduced, but not as severe as infarction. Sparing of subcortical U fibres (dual supply from involved medullary aa and uninvolved cortical aa). Different from multi-infarct dementia which is not primarily white matter.

Cerebral Autosomal Dominant Ateriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Rare, inherited (NOTCH3 gene on chromosome 19; 19 letters in leukoencephalopathy), 30-50yo. Variable multiple infarcts (less commonly haemorrhages), migraine HA with aura, depression, dementia. Concentric thickening of media and adventitia of white matter and leptomeningeal arteries, also non-CNS vessels. Focal or confluent subcortical U fibres, periventricular and deep white matter in frontal lobes, internal and external capsule, anterior temporal lobes in 75%; basal ganglia, brainstem. Lacunar infarcts in 80%, most have microbleeds. Diagnosis via skin/muscle biopsy or genetic.

Postanoxic Leukoencephalopathy

After anoxic episode severe enough to cause coma with patient recovering in 24-48hrs then declines over 2/52 until death. ?Allergic demyelination from exposure to myelin antigen during hypoxic period, causing demyelination and necrosis. High T2 throughout white matter esp corpus callosum, subcortical U fibres, internal/external capsules. Low T2 in thalamus and putamen with diffusion restriction.

Wallerian Degeneration

Antegrade destruction of axons and myelin sheaths after proximal axon or cell body injury. From infarction, haemorrhage, white matter disease, trauma, MS, neoplasm. High T2 and atrophy of the corresponding white matter pathway.

Disseminated Necrotising Leukoencephalopathy (DNL)

From combination of radiation and chemotherapy eg cranial/spinal radiation and intrathecal methotrexate for leukemia, adult sarcoma, SCC lung. Progressive reduced mental state, seizures, coma, death. Axonal swelling, multifocal demyelination, coagulation necrosis and gliosis. Marked hypodensity/high signal in periventricular and centrum semiovale sparing U foibres.

Hydrocephalus

Hydrocephalus causes convex bowing of lateral walls and inferior recesses of 3rd ventricle, enlarged temporal horns (may occur before lateral ventricles), acute angle of frontal horns (cf obtuse in atrophy), mamillopontine distance <10mm, thin distended rounded elevation of corpus callosum, flattened sulci, ballooning of tuberculum sella with erosion of floor, reverse cupping of the optic nerve/globe junction (clinically papilloedema), marked enhancement of the optic nerve heads (?from breakdown of blood-retinal barrier with sudden ICP rise). Acute hydrocephalus lacks compensatory mechanisms causing transependymal flow of CSF into periventricular white matter (interstitial oedema) esp angles of lateral ventricles, smooth and diffuse (DDx normal ependymitis granulosa at angles in middle-aged patients). Increased aqueductal flow with accentuated flow void in normal pressure hydrocephalus. Hydrocephalus may be due to overproduction of CSF (eg choroid plexus papilloma/carcinoma) or obstruction (at ventricles, outlets or arachnoid villi). Hydrocephalus ex vacuo is compensatory increase in CSF volumes and ventriculomegaly with loss of brain parenchyma.

Noncommunicating hydrocephalus from obstruction within ventricular system preventing exit, with dilatation of ventricles to the point of obstruction.

  • Colloid cyst – Typically anterior 3rd ventricle obstructing foramina of Monro. Hyperdense, high T1 and T2.
  • Clots, synechiae – From trauma, chronic infection. Synechiae (fibrous adhesions) in 3rd ventricle from ventriculitis or meningitis.
  • Aqueduct stenosis
    • Congenital – Most X-linked recessive, presenting early childhood with enlarging head circumference. ?Abnormal proliferation and differentiation of periaqueductal grey matter. Gliosis of aqueduct, forking into blind-ending sacs, webs, septa or diaphragms. May be associated with NF1 or CRASH syndrome (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus secondary to aqueduct stenosis).
    • Secondary from inflammation/neoplasm. Best seen on phase-contrast encoded to 10-15mL/sec. Interstitial oedema in periventricular zones.
  • Mass/tumour – Including pineal gland, tectal gliomas, occult vascular malformation, posterior fossa lesions (medulloblastoma, ependymoma etc).
  • Haematomas, infarcts – Esp posterior fossa.
  • Trapped ventricle – Temporal horn from atrium intrinsic/extrinsic mass. Selective 3rd ventricle uncommon, DDx ependymal/arachnoid cyst, craniopharyngioma. 4th ventricle from aqueduct and foramina of Magendie and Luschka obstruction.

Communicating hydrocephalus from obstruction at the arachnoid villi or incisura of foramen magnum, responds well to shunts. 4th ventricle may not be dilated due to confines of posterior fossa.

  • Obstruction at arachnoid villi – Subarachnoid haemorrhage, infectious meningitis, sarcoidosis, carcinomatous meningitis, chemical meningitis (fat, arachnoiditis, intrathecal medications), raised venous pressure from AV shunt or vein of Galen malformation, venous thrombosis, mucopolysaccharidosis.
  • Obstruction at skull base – Chiari malformation, achondroplasia, Dandy-Walker cysts, arachnoid cysts at foramen magnum.
  • Normal pressure hydrocephalus (NPH) – Chronic low-level hydrocephalus, triad of dementia, gait disturbance and urinary incontinence. Incomplete subarachnoid CSF occlusion, idiopathic or from previous SAH/meningitis. Clinical diagnosis with improvement after ventricular shunting. Diffuse ventriculomegaly esp temporal horns. Rate of improvement with ventriculoperitoneal shunting is 50%. Predictors of good response include absent central atrophy/ischaemia, dominant gait apraxia, upward bowing of corpus callosum with flattened gyri and ballooned 3rd veintriclar recesses, increased CSF velocity, stroke volume >42mL through aqueduct, history of intracranial infection/bleeding (nonidiopathic NPH), positive In-111 scan. On radioisotope cisternography (Indium-111 DTPA via LP) normal studies show tracer over convexities after 24-48hrs with no ventricular reflux; NPH shows early entry into lateral ventricles with none at convexities at 24 and 48hrs. Stroke volume measured on phase-contrast MR; during systole blood entering fixed intracranial space pumps CSF out of lateral ventricles; expansion throught to cause shearing strains on white matter and Sx.
  • External hydrocephalus (benign enlargement of the subarachnoid spaces in infants, benign extra-axial collections of infancy, extraventricular obstructive hydrocephalus, benign macrocephaly of infancy) – Neurologically intact 3-6/12 old with enlarging head circumference. ?Due to immaturity of arachnoid villi. Increased incidence in prematurity, history of IVH, some syndromes. Dilated CSF spaces mimicking chronic SDH esp frontal lobes and interhemispheric fissure, relatively normal ventricles. Usually regress by 3-4yo.
  • Pseudotumour cerebri (idiopathic benign intracranial hypertension, idiopathic intracranial hypertension) – From reduced arachnoid villi absorption, increased water content of brain or venous obstruction reducing drainage. Usually obese, black, young to middle-aged, female. HA, CN6 palsy, papilloedema, visual field deficits. May be associated with pregnancy, endocrine abnormality, metastases, veno-occlusive disease. Raised CSF pressure on LP. Ventricles normal or small, increased subarachoid space, subtly high T2 of white matter, venous sinuses may be small, enlarged and tortuosity of optic nerve sheath, may have expanded empty sella. Tx repetitive LP drainage, CSF shunting, lumbar drain, diuretics.

Shunt Failure

Nausea, vomiting, fever. 30% of VP shunts in 1st year, 50% in 1st 6 yrs; infection in 10% of 1st year. Evaulate change in temporal horn and 3rd ventricle sizes. Causes include obstructed ventricular tip, valve malfunction, kinks in tubing, obstructed peritoneal/atrial tip, component disconnection. 3rd ventriculostomy – hole between floor of 3rd ventricle and suprasellar cistern via fiberoptic endoscope or 3D-image guided; reduction in ventricular size over couple of weeks.

  • Shuntogram – 2-3mL nonionic contrast instilled into shunt reservoir, usually clears from tub within 3-10min children, 10-15min adults. If CSF cannot be withdrawn ventricular catheter is obstructed or valve faulty. Reflux into ventricle indicates faulty valve. If pumping required to get contrast to flow then incomplete obstruction or faulty valve-pressure system. If no intraperitoneal spillage or loculated then peritoneal obstruction.
  • Slit ventricle syndrome – Usually long-term shunt problems ?ventricles or brain lost compliance (?wall fibrosis) and cannot expand with increasing pressure. Or, chronic overdrainage or leakage with reduced pressure; associated with calvarial thickening, cranial sutures may close early -> brain growth narrows ventricles and no capacity to accommodate change in pressure.

Neurodegenerative Disorders

Progressive neurologic deterioration faster than expected for age. Many are of unknown aetiology, most have protein aggregates (inclusions) that are resistant to degradation. Atrophy from loss of brain tissue, which is cortical (aphasia, anomia, apraxia, visuospatial problems, memory loss), subcortical (psychomotor slowing, difficulty concentratin, impaired retrieval) or deep. Ex-vacuo ventriculomegaly from parenchymal atrophy, enlarging sulci and rest of CSF spaces proportionally. 3rd ventricle and temporal horns usually do not dilate, as not typically subject to significant atrophy. MCI = mild congnitive impairment, may be normal with aging due to progressive hippocampal atrophy.

Alzheimer’s Disease (AD)

(Dementia Alzheimer type, DAT). Most common, rarely symptomatic <50yo, prevalence doubles every 5 yrs with 1% 60-65yo, 40% 85-90yo, F:M 2:1. Late middle-aged dysfunction in memory, personality and thought; 1st defect is olfaction. Most sporadic, 5-10% familial, early onset in Down syndrome (gene encoding APP is on chromosome 21). Neuritic/senile amorphous plaques are 20-200μm spherical collections of dilated tortuous processes surrounding central β-amyloid peptide core. The amyloid core (stains by Congo Red) is predominantly Aβ derived from amyloid precursor protein (APP, cell surface protein). Neurofibrillary tangles (also found in other diseases) are bundles of tau protein (which is associated with microtubules) displacing or encircling the nucleus. Neuritic plaques, neurofibrillary tangles, cerebral amyloid angiopathy (CAA), granulovacuolar degeneration (intraneuronal vacuoles with argyrophilic granules), Hirano bodies (actin filaments) interfer with normal neuronal functioning with eventual neuronal loss and reactive gliosis. Diffuse cortical atrophy progressing from entorhinal cortex, hippocampus (esp subiculum), amygdala, temporal lobes, parietotemporal cortices. Enlarged temporal horns (>3mm), suprasellar cisterns and sylvian fissures. Reduced activity in parietotemporal lobes (esp posterior) on PET, reduced cerebral blood flow on SPECT. Reduced NAA, increased myoinositol.

PIB imaging – 11C-labeled Pittsburgh Compound B (11C-PIB) labels amyloid deposits, taken up in patients with AD, possibly preclinical AD; but amyloid deposition may be asymptomatic and not progress to AD.

Vascular Dementias

Those with vascular changes have lower threshold for plaques and tangles to cause cognitive impairment.

  • Multi-infarct dementia (MID) – Long standing risk factors for atherosclerosis. Unusual personality, incontinence, ataxia. Multiple white matter infarctions, severe deep grey matter lacunar disease from arteriosclerosis of penetrating aa, cerebral atherosclerosis and vessel thrombosis/embolisation. Progressive, episodic, stepwise downward course cf Binswanger disease.
    • Binswanger disease (subcortical arteriosclerotic encephalopathy) – Preferentially involves large areas of subcortical white matter, with myelin and axon loss. Slowly progressive.
  • CADASIL
  • Subcortical ischaemic vascular dementia – Lacunar and white matter infarcts. Cortical hypometabolism out of proportion of tissue loss ?due to disconnected axons.

Frontotemporal Dementias (FTDs)

Group of disorders with cortical atrophy of frontal and/or temporal lobe causing progressive deterioration of language and personality change. ?Constellation of diseases causing atrophy. Hypoperfusion on Tc-HMPAO SPECT.

  • FTD with parkinsonism linked to tau mutations – Associated with parkinsonism, mutation of MAPT gene encoding tau.
    • Pick disease (lobar atrophy) – Rare, early onset of symptoms. Anterior temporal lobe and inferior frontal lobe predominance with sparing of posterior 2/3 of superior temporal gyrus and parieto-occipital lobes. Severe atrophy with wafer-thin gyri (knife-edge appearance). Some surviving nuerons are swollen (Pick cells), others contain Pick inclusion bodies (contain tau similar to AD). Progressive decline over months-years.
    • Progressive supranuclear palsy (PSP, Steele-Richardson-Olszewski syndrome) – Severe supranuclear ophthalmoplegia with impaired downwards gaze, parkinsonism, surprised look to face with hyperextended neck and contracted facial muscles. Atrophy of globus pallidus, midbrain, periaqueductal grey matter, dentate nucleus with dilated 3rd ventricle, enlarged interpeduncular cistern. Iron deposition in putamen being lower T2 than globus pallidus (opposite to N).
    • Corticobasal degeneration – Elderly, cortical atrophy or motor, premotor and anterior parietal lobes causing knife-blade atrophy. Relative sparing of temporal and occipital lobes.
  • Frontotemporal dementias without tau pathology – Ubiquitin-containing inclusions in temporal and frontal lobes and dentate gyrus (FTD-U).

Degenerative Diseases of Basal Ganglia and Brainstem

Movement disorders with rigidity, abnormal posturing, chorea; reduction of voluntary movement or abundance of involuntary movement.

Normal midbrain cross-sectional area in midline sag is >100mm2; PSP </=60mm2. Normal axial AP diameter is 13mm.

Parkinsonism is clinical syndrome of reduced facial expression, stooped posture, pill-rolling tremor, muscular rigidity, bradykinesia, shuffling gait and loss of postural reflexes. From damage to the nigrostriatal dopaminergyic system.

  • Parkinson disease (PD) – Progressive L-DOPA (precursor to domapine) responsive parkinsonism in abscense of toxic or other aetiology. Increased risk with pesticides; reduced risk with caffeine, nicotine. Deficiency of neurotransmiter dopamine causing dysfunction esp pars compacta of substantia nigra with pallor/depigmentation. Lewy body inclusions composed of α-synuclein filaments. Sx develop when ~80% of cells die. MR relatively insensitive to tissue loss, but if severe may show thinning/absence of pars compacta progressing lat->med (high T2 band between pars reticularis anterior as part of the substantia nigra, and red nuclei posteriorly). With demenita there is enlarged ventricles and sulci. 18F-labelled levodopa (DOPA) PET shows deficit in putaminal DOPA uptake.
  • Parkinson-plus syndromes:
    • Dementia with Lewy bodies (DLB) – 10-15% of those with PD develop dementia, increasing with age. Lewy bodies diffusely through brain as well as deep grey matter. DLB (cortical) is dementia accompanying or preceding parkinsonism; PD dementia (subcortical) is onset after 1yr later. Greater degree of cortical atrophy cf PD, occipital hypoperfusion on SPECT
    • Multisystem atrophy (MSA) – Group of disorders with dominant symptoms of cerebellar (MSA-C, previously olivopontocerebellar atrophy), parkinsonism (MSA-P, previously striatonigral degeneration), or autonomic dysfuction (MSA-A, previously Shy-Drager syndrome). MSA-C is atrophy of cerebellum, peduncles, pons and medulla; MSA-P substantia nigra and striatum (esp putamen), MSA-A usually no gross findings (cell loss of nuclei in medulla and spinal cord). Iron deposition causing low T2 and bright T1 in posterolateral putamina. High T2 at putamen/external capsule junction. Hot cross buns sign – cruciform high T2 in pons with checkerboard low signal.
    • Progressive supranuclear palsy
    • Corticobasal degeneration
  • Postencephalitic parkinsonism – Late consequence of influenza pandemic of 1918.
  • Drugs – Dopamine antagonists and toxins may cause parkinsonism.

Huntington disease (HD) – Autosomal dominant progressive from 30s-40s with mortality in ~15yrs. HD gene on chromosome 4 encodes huntingtin. HD when there is >35 CAG repeats, with longer repeats associated with earlier onset. Movement disorder (choreoathetosis), dementia, emotional disturbance. Iron deposition in caudate and putamen with atrophy, atrophy also of frontal lobe, parietal and occasionally entire cortex. Dilated rounded frontal horns in characteristic heart-shape (loss of impression by caudate head). Caudate hypoperfusion on SPECT and hypometabolism on PET.

Spinocerebellar Degenerations

Spinocerebellar ataxias (SCAs) – Atrophy in cerebellum, brainstem, spinal cord and/or peripheral nerves. Many are due to expanded repeats in DNA.

  • Friedreich ataxia – AR, 10s, defect in mitochondrial protein frataxin (chromosome 9) causing gait ataxia, kyphoscloliosis, hand clumsiness, cardiac anomalies, areflexia, deafness, optic atrophy. Atrophy and gliosis in posterior columns. Degeneration of spinal cord, brainstem, cerebellum, motor cortex. Cardiomegaly, pericardial adhesions.
  • Ataxia-telangiectasia (Louis-Bar syndrome) – AR mutation in ATM gene (chromosome 11, role in response to DNA breaks), beginning early childhood. Increased sensitivity to XR induced chromosomal abnormalities with increased risk of leukemia, NHL other cancers (esp breast cancer). Telangiectatic lesions on face, mucosa, conjunctiva, CNS. Abnormality of IgA with recurrent sinus and lung infections. Cerebellar vermian and hemispheric atrophy with increased white matter signal.

Other causes of cerebellar atrophy:

  • Alcohol abuse (most common) – Whole cerebellum but esp vermis. With poor nutrition also brainstem and basal ganglia damage (Wernicke encephalopathy).
  • Long-term drug use – Phenytoin, phenobarbital. Reversible nstagmus, ataxia, peripheral neuropathy, slurred speech. Dilated 4th ventricle and cerebellar sulci, cerebellar folia appear to float within CSF. Phenytoin may thicken skull. Metronidazole may cause symmetric abnormal signal in dentate nuclei, brain stem, periaqueductal grey matter, basal ganglia, splenium.
  • Toxins – Minamata disease (mercury poisoning) from seafood causes severe atrophy of vermis, also visual cortex, cerebellar hemispheres, postcentral cortex.
  • MSA-C (olivopontocerebellar degeneration)
  • Cerebellar olivary degeneration – Selective atrophy of lateral cerebeullum (fish-mouth deformity) and superior vermis. Markedly enlarged 4th ventricle, primary semilunar fissure. Olives secondarily reduced in size.
  • Hypertrophic olivary degeneration – From ischaemia, trauma, neoplasm, vascular insult to triangle of Guillain and Mollaret (dentate nucleus, red nucleus, inferior olivary nucleus; connected by superior and inferior cerebellar peduncles, central tegmental tract). Initially high T2 then hypertrophy of inferior olivary nucleus. Later contralateral cerebellar atrophy.
  • Ischaemia – Chronic vertebrobasilar atherosclerosis causes cerebellar atrophy from multiple white matter foci, may be associated with supratentorial lacunar infarcts.
  • Paraneoplastic syndromes – Cerebellar atrophy is associated with neuroblastoma, Hodgkin disease, ovarian/GI/lung/breast cancer. From autoimmune anti-Yo antigen against Purkinje cells in cerebellum. Cerebellar degeneration precedes primary tumour discovery in 60%.

AIDS Dementia Complex

See CNS Infection

Degenerative Diseases of Motor Neurons

Affect lower motor neurons in anterior horns of spinal canal and brainstem; and upper motor neurons in motor cortex (Betz cells).

  • Amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease, motor neuron disease MND) – Relentless loss of motor strength, hyperreflexia, death from pulmonary infections (respitory muscle weakness) after 3-6yrs. No dementia. Loss of corticospinal tracts with high signal and atrophy at anterior/motor nerve roots and anterior horns, posterior limb internal capsule, occasionally atrophy/wallerian degneration along brainstem, cerebral peduncles, internal capsule, corona radiata, Betz cells of cortex; best seen on coronal FLAIR. Occasional iron deposition and reduced T2 in precentral gyrus. Atrophy of anterior horn cells in spinal cord, high T2 in lateral corticospinal tract.
  • Bulbospinal atrophy (Kennedy syndrome) – X-linked adult onset.
  • Spinal muscular atrophy

Dyke-Davidoff-Masson Syndrome

Hemiatrophy of one hemisphere with associated calvarial thickening, elevated petrous ridge and sphenoid wing, grossly enlarged frontal sinus. From cerebral injury ealy in life of in utero, usually MCA ischaemia. May be associated with Sturge-Weber syndrome.

Porencephaly

Focal encephalomalacia communicating with ventricles. When abuts skull, CSF pulsations may remodel the bone. Occasional ventricular synechiae with ball-valve effect -> progressive enlargement. Causes include trauma, infection, perinatal ischaemia.

Genetic Metabolic Diseases

Include neuronal storage diseases, leukodystrophies, mitochondrial encephalomyopathies. Often presents with children who miss developmental milestones.

Neuronal Storage Diseases

  • Mucopolysaccharidoses (MPS) – Mental retardation, peculiar facies, musculoskeletal deformities. Brain atrophy, abnormal white matter with cribriform/cystic areas, distended perivascular spaces. Thickening of dura at foramen magnum from mucopolysaccharide deposition. Some cause arachnoid cysts from glycosaminoglycans in leptomeninges causing ball-valve effect.
  • Neuronal ceroid lipofuscinoses – Lysosomal storage disease with accumlation of lipopigment in neurons. Subgrouped into infantile, late infantile, juvenile and adult onset. Volume loss esp cerebellum, hypointense thalami, high T2 periventricular white matter. Reduced NAA, increased myoinositol and glutamate/glutamine.
  • Tay-Sachs disease

Dysmyelination Syndromes

(Leukodystrophies). Rare inherited abnormal of formation or maintenance of myelin. Progressive destruction of myelin from acumulation of various catabolites. Progressive mental and motor deterioration. Increased T2 in white matter and/or grey matter ± associated atrophy. Confirmed with serum biochemical and enzyme analysis. Most not treatable.

  • Metachromatic leukodystrophy (MLD, most common) – AR lysosomal storage disorder, deficiency of arylsufatase A with failure of myelin to be degraded and reused, accumulation of ceramide sulfatide. Infantile form (most common) onset 1-2yo, juvenile 5-7yo. Diffuse white matter involved, initally centrally with sparing of subcortical U-fibres. Late atrophy. Death within 5yrs.
  • Adrenoleukodystrophy – X-linked recessive peroxisomal disorder, acyl-CoA synthetase deficiency in boys, onset 5-10yo. Accumulation of long-chain fatty acides in white matter and adrenal cortex, plasma and RBCs. Adrenal insufficiency or abnormal skin pigmentation. Starts in parieto-occipital region, progressing anteriorly into temporal and frontal lobes, corpus callosum. Active demyelinating front enhances with nonehnacing regions gliotic. Relative sparing of subcortical U fibres. Adrenomyeloneuropathy is spinal cord disease with degeneration of entire length of corticospinal tract and atrophy, average age 28yo onset, may occur with or without cerebral disease.
  • Krabbe disease (globoid cell leukodystrophy) – AR galactocerebroside β-galactocerebrosidase deficiency on chromosome 14. Accumulation of cerebrosides (from catabolised myelin) involving pyramidal tracts, white matter, deep grey, posterior corpus callosum, parieto-occipital white matter (these are 1st to myelinate). Relative sparing of U fibres. Hyperdensity with high T2. Elevated choline and myoinositol. Rapid patientrogression from 3-6/12, mortality <2yo.
  • Pelizaeus-Merzbacher disease – Rare X-linked. Arrested myelin development usually at neonatal stage. No destruction (cf other leukodystrophies). Hypodense white matter, pinpoint periventricular calcifications. Cerebral, cerebellar, brainstem and upper cervical cord atrophy, diffuse symmetric high signal white matter (complete lack of myelination). Low T2 in leniform, substantia nigra, dentate nuclei, thalamus from iron deposition.
  • Canavan disease (spongiform degeneration) – AR, deficiency in N-acetyl aspartoacylase causing buildup of NAA, with lack of acetate and aspartate used for fatty acid synthesis and myelination, <1yo. Megalencephaly, deep grey primarily globus pallidus with vacuolisation, diffuse white matter initially peripheral, mostly involving subcortical U fibres. Giant NAA peak. Death by 5yo.
  • Alexander disease (fibrinoid leukodystrophy) – Miscellaneous metabolic disorder <1yo with fibrinoid degeneration of astrocytes. Megalencephaly, high T2 involving frontal white matter progressing posteriorly, involves U fibres. Hyperdense caudate nuclei, hypodense white matter and internal/external capsules.
  • Childhood ataxia with CNS hypomyelination (vanishing white matter disease) – AR, children and teenagers. Chronic progressive decline, associated with episodes of minor infections and head trauma. White matter largely destroyed with cystic degeneration, some sparing of U fibres.

Mitochondrial Encephalomyopathies

Most are muscle diseases, with CNS also involved.

  • MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) – Most comon. Mitochondrial dysmetabolism. Seizures. Shifting stroke-like lesions that can be reversible and may not correspond to vascular territories. Acute swelling, high T2, bright DWI (variable ADC); subacute band T2 from laminar necrosis; chronic atrophy. Affects basal ganglia, temporo-parieto-occipital cortex with preservation of hipopcampus, entorhinal structures. Basal ganglia cancifications. Variable lactate doublet.
  • MERRF syndrome (myoclonic epilepsy and ragged red fibres) – Maternally transmitted. Atrophy of cerebellum.
  • Leigh disease (subacute necrotising encephalomyelopathy) – Mitochondrial enzyme defect (pyruvate carboxylase/dehydrogenase) usually <5yo ?inborn defect in thiamine metabolism similar to Wernicke encephalopathy. Motor abnormality, ataxia, nystagmus, ophthalmoplegia, spasticity, psychomotor retardation, cranial palsies, metabolic acidosis. Symmetric focal necrotic lesions in basal ganglia (esp putamina) and thalamus, subcortical white matter, periaqueductal grey matter (characteristic), may extend to midbrain, medulla, posterior columns of spinal cord. Sparing of mamillary bodies (cf Wernicke). Elevated lactate peak.
  • Kearns-Sayre syndrome (ophthalmoplegia plus) – Sporadic. Retinitis pigmentosa, opthalmoplegia, extraocular muscle weakness, cardiac conduction deficits, cardiomyopathy. Basal ganglia caicification. Spongiform change with high signal in basal ganglia, cerebral and cerebellar atrophy, diffuse white matter signal. Microcephaly, cerebellar hypoplasia, white matter demyelination.

Aminoacidopathies and Other Enzyme Deficiencies

Delayed maturation of brain. Swelling -> atrophy with abnormal myelination.

  • Glutaric acidemia – Macrocephaly, open opercula, high signal in basal ganglia (esp globus pallidus).
  • Homocystinuria – Cystathionine beta-synthase deficiency on chromosome 21. High plasma homocysteine causing multiple thrombotic events including strokes, premature atheroscleorsis. Lens subluxation (also seen in Marfan syndrome). Optic atrophy, osteoporosis, cataracts, scoliosis, biconcave vertebral bodies.
  • Maple syrup urine disease – Abnormal decarboxylation of branched-chain amino acids. Symmetric echogenic and oedema in periventricular white matter, basal ganglai (esp globus pallidi), thalami. Delayed myelination. Peak at 0.9ppm from branched-chain amino acid peaks.
  • Propionic acidemia (PPA) and methylmalonic acidema (MMA) – Disorders of tricarboxylic acycle causing metabolic acidosis. Atrophy and abnormal white matter, delayed myelination, basal ganglia lesions. Lactate peaks.
  • Phenylketonuria – Amino acid disorder; white matter initially central.

Toxic and Acquired Metabolic Diseases

  • Vitamin B12 deficiency may cause degeneration of ascending and descending tracts of the spinal cord.
  • Hypoglycaemia causes effects similar to hypoxia. Sensitive areas include motor neurons, hippocampus CA1, purkinje cells of cerebellum.

Wernicke Encephalopathy

Thiamine (B1) deficiency in malnutrition (chronic alcoholics), haematologic malignancy, recurrent vomiting, hyperemesis gravidarum, bariatric surgery, prolonged febrile infection, carcinoma, starvation/anorexia nervosa. Triad of acute ocular movement abnormality, ataxia, confusion. If associated with severe amnesia then Wernicke-Korsakoff Syndrome. Acutely high T2 or enhancement in mamillary bodies, basal ganglia, thalamus, periaqueductal grey matter. Chronic atrophy of mamillary bodies, midbrain tegmentum, 3rd ventricle dilatation. May have diffusion restriction if acute. Mamillary body and thalamic enhancement more associated with alcoholism as a cause. DDx Leigh disease (no mamillary body involvement).

Hallervorden-Spatz Syndrome

AR, abnormal involuntary movements, spasticity, progressive dementia. Accumulation of iron in globus pallidus, red nuclei, substantia nigra with reduced T2. High signal in globus pallidus and white matter ?gliosis or demyelination. Cortical and caudate atrophy. Eye of the tiger sign from low T2 iron and central spot of high T2 in globus pallidus; DDx basal ganglia calcification, toxins, PD, CO poisoning, NF, Leigh disease, Wilson disease, Shy-Drager syndrome, progressive supranuclear palsy.

Wilson Disease

(Hepatolenticular degeneration). AR inborn error of copper metabolism (ceruloplasmin deficiency) associated with copper deposition in various organs and causing hepatic cirrhosis, degeneration of basal ganglia. Dystonia, tremor, rigidity. Kayser-Fleischer ring is intracorneal deposit of coppor in 75% (diagnostic). Atrophy of caudate, brainstem. Copper or iron deposition in lentiform and thalami causing low T2. High T2 in outer rim of putamen, ventral nucleus of thalami, globus pallidus. High T1 in basal ganglia implies liver failure. Scattered white matter demyelination.

Hepatic Encephalopathy

Predominantly glial response. High T1 in basal ganglia seen in hepatic encephalopathy, portosystemic shunting without hepatic encephalopathy, disorders of calcium-phosphate regulation, TPN. Increased signal in the globus pallidus (?deposition of manganese bypassing liver), putamen, midbran, anterior pituitary, atrophy esp cerebellum. Reduced myoinositol and choline, elevated glutamine-glutamate.

Toxins

  • Methanol – Optic nerve atrophy, necrosis of putamen and subcortical white matter. May cause haemorrhage.
  • Ethylene glycol – Thalamus and pons.
  • Toluene – Atrophy of cerebrum, corpus callosum, cerebellar vermis. High T2 in white matter, poor grey-white differentiation, loss of signal in basal ganglia, thalamus.
  • Carbon monoxide – Low/high T1 and high T2 in globus pallidus (also seen in anoxic injury), white matter and hippocampus.
  • Ecstasy (3,4-methlenedioxymethamphetamine MDMA) – Bilateral globus pallidus necrosis ?from prolonged vasospasm
  • Cocaine – Ischaemia, vasoconstriction, vasculitis, hypertensive white matter changes, intraparenchymal haematomas, SAH, moyamoya vasculopathy. Increased risk with crack cocaine.
  • Organic mercury (Minamata disease) – Calcarine areas, cerebellum postcentral gyri.
  • Heroin inhalation (‘chasing the dragon’) – Diffuse symmetric white matter lesions sparing U fibres similar to PRES. Always involves cerebellar, pyramidal tract and globus pallidus.

Radiation Changes

Dose related, less common with greater fractionation. Weeks to years after radiation, usually 6-24/12, rarely <6/12 unless gamma knife used. May cause focal neurological deficit.

  • Radiation leukoencephalitis – Radiation induced small vessel arteritis (endothelial hypertrophy, medial hyalinisation, fibrosis) 6-9/12 after almost all treatments >40Gy. Confluent nonenhancing high T2 in white matter extending into subcortical U fibres in irradiated brain.
  • Radiation necrosis – Typically single/multiple ring enhancing lesion with mass effect in or near irradiated field, sometimes remote. May induce telangiectasia. May stabilise and regress or progress (similar to tumour recurrence). Elevated lactate and lipid peaks, absent/reduced choline, creatine and NAA peaks. Restricted DWI cf most tumours do not. Absent increase of perfusion, normal/decreased metabolic activity on PET (more acurate if original tumour grade III/IV).
  • Radiation arteritis – Endothelial hypertrophy, medial hyalinisation and fibrosis causing narrowing ± obliteration. Often cavernous and supraclinoid ICA, causing cerebral and striatal ischaemia. May have compensatory proliferation of lenticulostriate collaterals (‘puff of smoke’), similar to Moyamoya.
  • Mineralising microangiopathy – Synergistic effect with chemotherapy (esp methotrexate). Calcifiation of basal ganglia, ACA/MCA and MCA/PCA watershed zones, cerebellum; diffuse white matter signal abnormality.

Basal Ganglia Calcification

May be normal with aging (esp globus pallidus), other causes include:

  • Endocrine/metabolic – Hyper/hypo-parathyroidism, hypothyroidism.
  • Mitochondrial – Kearns-Sayre syndrome, MELAS syndrome, MERRF.
  • Fahr’s disease (idiopathic basal ganglia calcification) – Rare inherited calcification of areas controlling movemen including basal ganglia, cortex. Progressive neurologic deterioration.
  • Congenital – Cockayne syndrome, Down syndrome, trisomy 13.
  • Phakomatoses – NF, TS.
  • Inflammatory – TORCH infections, ischaemia (anoxia, CO).
  • Iatrogenic – Radiotherapy, methotrexate, retained shunt catheters.

Paraneoplastic Syndromes

Immune response against tumour antigens may cross-react with antigens in the CNS or PNS. Syndrome include:

  • Subacute cerebellar degeneration – Destruction of Purkinje cells, gliosis.
  • Limbic encephalitis – Gliosis along anterior and medial temporal lobes, occasionally brainstem.
  • Eye movement disorders
  • Subacute sensory neuropathy – May be associated with limbic encephalitis. Loss of sensory neurons in dorsal root ganglia.
  • Lamber-Eaton myasthenic syndrome – Antibodies againsed pre-synaptic elements of neuromuscular junction.

Epilepsy

Mesial Temporal Sclerosis (MTS)

(Hippocampal atrophy). Sclerosis of CA1 and to lesser extent CA4 of Ammons horn (the most sensitive areas), ?from ischaemia, febrile seizures, hypoglycaemia. Most present in adolescence. Atrophy is progressive with age. Bilateral in 20%. Mesial temporal lobe atrophy, high T2, loss of normal cortical interdigitations of hippocampal head. Reduced NAA, raised lactate and lipid (if scanned within 24hrs of acute seizure).

Status Epilepticus

Generalised seizures have LOC, partial do not; if consciousness is altered then is complex (cf simple) partial seizure. If imaged immediately after or during seizure, there may be meningeal enhancement, high signal in seizing temporal lobe, transient diffusion restriction. Temporal lobe seizures are usually partial (no LOC). 30% are idiopathic, 40% visible underlying lesion, 30% cryptogenic with unknown but probably underlying lesion. Causes include MTS, ganglioglioma, astrocytomas, caveronma, cortical dysplasia, heterotopia, oligodendroglioma. Seizures in other locations include neoplasms, vascular malformations, gliotic abnormality, cortical malforamtions, strokes.