CHAPTER XIII
NEUROLOGICAL COMPLICATIONS OF
SYSTEMIC DISEASE
NEUROLOGICAL COMPLICATIONS OF
DIABETES MELLITUS (DM)

Diabetes Mellitus is a worldwide life long disease characterized by persistent
hyperglycemia secondary to lack of insulin, cellular resistance to the effects of insulin or
a combination of both.
 It has a wide range of complications such as renal failure, blindness, neuropathy,
peripheral vascular disease with gangrenous complications, coronary artery disease &
stroke.
Classification of Diabetes Mellitus
 Insulin-dependant DM (IDDM, type I):
Usually young, thin patient, absolute insulin deficiency; ketosis prone.
 Non-Insulin-dependant DM (NIDDM, type II):
Usually older obese patients; relative insulin lack & tissue resistance to insulin effects,
not ketosis prone; often have positive family history.
 DM associated with other conditions (secondary diabetes):
Hyperglycemia associated with other hormonal, metabolic or genetic disorders (e.g.,
acromegaly).
 Impaired glucose tolerance (IGT):
Hyperglycemia that is not of significant degree to meet the criteria for DM.
 Gestational diabetes mellitus (GDM):
Hyperglycemia associated with pregnancy & meeting the criteria for diagnosis of DM,
resolves after parturition.
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Both insulin-dependent DM (IDDM) & non-insulin-dependent DM (NIDDM) have
similar complications.
The incidence of complications increases with duration of disease & severity of
hyperglycemia.
The association of diabetic neuropathy, retinopathy & nephropathy is frequent &
suggests a common underlying mechanism for these complications.
Neurological Complications of DM include:
I. Peripheral N.S. Complications:
Diabetic Neuropathy.
II. Central N.S. Complications:
1. Metabolic Derangement:
Diabetic ketoacidosis.
Non-ketotic hyperosmolar coma.
Hypoglycemia.
1. Cerebrovascular Diseases:
HTN & Arteriosclerosis.
Stroke in Diabetics.
2. Other CNS abnormalities in DM.
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PERIPHERAL NS COMPLICATIONS OF DM
Diabetic Neuropathy
Pathogenesis of Diabetic Neuropathy:
 The pathogenesis of diabetic neuropathy is still uncertain.
 Neuropathy is commoner in poorly controlled DM of long duration.However, it may
occur in controlled DM of short duration.
 Three factors (metabolic, vascular & genetic) participate in the causation of diabetic
neuropathy:
1. Metabolic factors:
- (Sorbitol accumulation, myoinositol depletion & decrease Na,K-ATPase
activity).
- Persistent hyperglycemia (aldose reductase) → accumulation of Sorbitol within
the nerve → hypertonicity.
2. Vascular & Hypoxic factors:
- (Microvascular ischemia of nerve + endothelial hypoxia).
- Occlusion of vasa nervosum → mononeuropathy
- Ischemia →generalized polyneuropathy.
3. Genetic factors may explain the development of complications in some diabetics
irrespective of the control or duration of DM.
Classification of Diabetic Neuropathy
I. Peripheral Nervous System (Somatic Neuropathy)
 Polyneuropathy:
Acute sensory
Chronic sensorimotor
 Mononeuropathy:
Mononeuritis simplex
Mononeuritis multiplex
Truncal mononeuropathy.
 Proximal motor neuropathy (Amyotrophy).
II. Autonomic Nervous System:
 Autonomic neuropathy (Visceral neuropathy).
III. Central Nervous System:
 Cranial mononeuropathy.
Another Classification of Diabetic Neuropathy
 Symmetrical distal neuropathy:
Small fiber predominant (painful or anesthetic).
Large fiber predominant (ataxic or pseudotabetic)
Autonomic neuropathy.
 Asymmetrical neuropathy:
Cranial neuropathies (especially 3rd nerve palsy).
Plexopathies (including amyotrophy).
Mono- & polyradiculopathies.
Increased susceptibility to pressure palsy.
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Evaluation of Diabetic Neuropathy Symptoms
1.
Symptom
Sensory symptoms
o Negative symptoms
o
2.
Numbness, deadness, “cotton wool
feeling”, “walking on stilts”, “feels like I
am wearing gloves”, loss of balance
(especially with eyes closed), loss of
dexterity, inability to find or identify
objects in pocket or purse, painless
injuries, ulcers.
Burning, prickling, pain, super-sensitivity
to light touch, stabbing, electric shock,
tearing, tight, band-like.
Depends on severity & distribution
Positive symptoms
o Focal symptoms
Motor symptoms
o Distal weakness
o
3.
Common Description
Impaired fine coordination of hands,
inability to turn keys or open jars, toe
scuffing, tripping, foot slapping.
Difficulty with stairs, inability to rise from
chair or floor, falls due to knee “giving”,
difficulty working with or raising arms
above the shoulder.
Depends on severity & distribution.
Proximal weakness
o Focal weakness
Autonomic System
o Sudomotor
o
Cardiovascular
o
Pupillary System
o
Sexual
o
Bladder
o
Bowels
Loss of sweating, excessive sweating in
definite areas, gustatory sweating, dry skin.
Postural light-headedness, fainting,
micturition syncope, cough syncope &
exertional syncope.
Usually asymptomatic, poor dark
adaptation, intolerance of bright light.
Impotence, loss of ejaculation, retrograde
ejaculation, loss of ability to reach sexual
climax.
Urgency, incontinence, dribbling,
hesitancy.
Vomiting (especially of retained food),
diarrhea, nocturnal diarrhea, constipation.
Evaluation of Sensations in DM
 Sensory loss: extent, distribution, modality involved.
 Use defined points on the 4 limbs (e.g., the dorsum of digit just proximal to the nails).
 Assessment of threshold for vibration, light touch, joint position, pin sensation.
 Quantitation of sensory deficit using automated or computer-assisted techniques.
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Evaluation of Motor deficit in DM
Comparison of the Mayo & Medical Research Council (MRC) Muscle Strength Grading
Systems
Description of muscle strength
•Normal power
•Mild weakness (25% loss)
•Active but weak movement against
gravity & resistance
•Active movement against gravity but not
resistance
•Moderate weakness (50% loss)
•Active movement with gravity eliminated
•Severe weakness (75% loss)
•Flicker of contraction
•No contraction
Mayo grade
0
-1
MRC grade
5
-
-
4
-2
-3
-4
3
2
1
0
Evaluation of Autonomic Functions in DM
 Orthostatic hypotension:
Measuring BP in supine, sitting & standing positions
- A fall in systolic Bp > 20% on standing > l min.
- A fall in systolic BP > 25-30mmHg on standing
- A fall in diastolic BP > 10mmHg on standing
(All are considered abnormal)
 A “reflex tachycardia” should accompany the fall of BP.
 If the “pulse rate” does not , sympathetic denervation should be suspected.
 A “fixed tachycardia” which does not slow in response to the “Valsalva maneuver” may
indicate loss of parasympathetic vagal innervation to the heart.
 Dry skin may indicate loss of sudomotor function.
 The “thermoregulatory sweat test” measures distribution of sweating in response to
heating the body core temperature by 1oC.
 “Sudomotor axon reflex testing” is also helpful.
Electrophysiological Testing in DM
 N.C. Studies & EMG may aid in:
1. Confirmation of the clinically diagnosed diabetic neuropathy.
2. Identification of a pattern of changes characteristic of diabetes.
3. Monitoring of progression or remission of diabetic neuropathy.
4. Detection of asymptomatic cases or atypical cases e.g. purely autonomic, those
presenting with pain alone.
 Electrophysiological studies cannot specifically diagnose diabetic neuropathy.
 Patterns that are suggestive of diabetic neuropathy:
- Mild or asymptomatic cases →distal slowing of conduction.
- Clinically overt neuropathy →a mixture of changes suggesting both “demylination”
& “axonal degeneration”.
- Progressive worsening of the neuropathy → “axonal degeneration” predominance.
 Electrophysiological changes are usually more widespread than clinical signs.
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Reversibility of EMG & NCV changes can be accomplished by controlling the diabetes,
dietary supplementation with myoinositol or the use of aldose reductase inhibitors that
prevent sorbitol in nerve.
Clinical Patterns of Diabetic Neuropathy
 Approximately 2/3 of diabetics have some form of neuropathy:
- 66% of patients with type I (IDDM)
- 59% of patients with type II (NIDDM)
 Approximately:
- 1/2 of pts have “symmetrical polyneuropathy”
- 1/4 of pts have “carpal tunnel syndrome”
- The remainder have autonomic or other neuropathies.
 Symptoms of symmetrical polyneuropathy occur in:
- 15% of IDDM patients
- 13% of NIDDM patients
 Severe disabling neuropathy occurs in:
- 6% of IDDM pts
- 1% of NIDDM pts
 Carpal tunnel syndrome is clinically diagnosed in:
- 7.7% of diabetics.
Distal Symmetrical Neuropathy in DM
 It is the most common form of diabetic neuropathy.
 Symptoms:
 Negative symptoms:
- Loss of feeling.
- Charcot joints → progressive painless ankle & foot deformity
- Loss of balance (at night & with eyes closed)
- Burning & stinging sensations.
 Positive symptoms:
- Tight, band-like feeling around the extremities.
- An electrical tingling sensation.
 Signs:
- Distal symmetrical sensory loss
- Weakness of toe dorsiflexion & intrinsic hand muscles.
- Distal hyporeflexia or areflexia
 NCV & EMG:
- Distal slowing of both sensory & motor conduction
- Distal changes indicating chronic partial denervation with reinnervation.
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Clinical Features Suggesting a Non-diabetic Etiology For Neuropathy in Diabetic Pts
Clinical features
o Family history of neuropathy, painful
feet.
o Abrupt onset
o Pes cavus & hammer toes
o Monoclonal gammopathies in serum
o
o
CSF protein >100mg/dl
ESR, +ve RF, +ve ANA
(Antinuclear antibodies)
Consider
Hereditary motor & sensory neuropathy
(HMSN)
Inflammatory Neuropathy
HMSN
Primary systemic amyloidosis.
Myeloma
Lymphoma
Inflammarory Neuropathy
Inflammatory Neuropathy
Necrotizing angiopathy
Autonomic Neuropathy in DM
 It occurs in most pts. with diabetes & peripheral neuropathy.
 It may be asymmetric.
 Pupil abnormalities:
- Miosis & lost response to light or accommodation.
- May mimic Argyll-Robertson pupil of tabes dorsalis
 Sudomotor function:
- Loss of sweating;
- Loss of thermoregulation; +
- Compensatory hyperhidrosis or gustatory sweating.
 Cardiovascular abnormalities:
- Orthostatic hypotension & loss of compensatory tachycardia.
 Gastrointestinal function:
- Gastroparesis: nausea & vomiting.
- Diarrhea: explosive, nocturnal, painless & watery.
- Resistant constipation alternating with diarrhea.
 Diabetic bladder disease:
- Loss of afferent information from nerves in detrusor muscle, progressive bladder
enlargement.
- UT infection may precipitate renal failure.
 Impairment of sexual function:
- Erectile impotence or ejaculatory failure.
 Insensitivity to hypoglycemia:
- Hypoglycemia → epinephrine release & sympathetic activity.
- Epinephrine release is mediated by the splanchnic nerves.
- This response may be lost in pts. with autonomic neuropathy
Subacute Symmetrical Neuropathies in DM
 Acute Painful Neuropathy with Wt. Loss:
- Wt. loss → Cachexia.
- Severe pain, burning or stinging or electric shock-like.
- Depression.
- Impotence.
- Complete resolution of symptoms within 6-24 months.
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Hypoglycemic Neuropathy:
- Neuropathic symptoms begin or worsen following insulin therapy.
- Insulinoma or insulin shock therapy has a similar effect.
- Severe, prolonged hypoglycemia may cause neuronal or axonal damage.
Focal & Multifocal Neuropathy in DM
 Two types of focal neuropathy occur in diabetics:
1) Spontaneously occurring neuropathies:
At the level of root, plexus or individual nerve
2) Those occurring in nerves crossing common pressure points:
The underlying pathology in these cases is vascular.
Diabetic Radiculopathy & Polyradiculopathy
 Occur in long-standing DM.
 Uncommon below 40 years.
 Mononeuropathies may occur at any spinal level.
 Characteristically: thoracic & upper lumbar roots are involved.
 Acute or subacute pain, with minimal sensory loss.
 Burning & supersensitivity of the skin.
 Symptoms & signs may be entirely at one root level.
 Electrophysiologic changes are more diffuse e.g. fibrillation potentials in the paraspinal
muscles.
 Imaging: excludes a mass lesion.
 Prognosis: is excellent, pain resolves gradually in few months.
 Recurrent diabetic radiculopathy may occur.
 Polyradiculopathy may occur in some diabetics.
 DD: CIDP, AIDS, Lymphoma, Sarcoidosis.
(Differentiated by: NCV, CSF protein, cells & cytology).
Diabetic Plexopathy
(D.Amyotrophy; D.Myelopathy; D.Femoral Neuropathy;Proximal Motor Neuropathy;
Radiculoplexopathy)
Symptoms & Signs:
 Rapid onset.
 Pain in the anterior thigh.
 Buckling of the knee due to quadriceps weakness.
 Weakness & severe atrophy of quadriceps muscle.
 Sensory loss is minimal
 (Patchy hypoesthesia or hyperpathia over the thigh)
 Knee reflex is  or absent.
 + Evidence of distal peripheral neuropathy.
Cranial Neuropathy in Diabetics
 Isolated 3rd & 6th nerve palsies are frequent.
 Oculomotor Palsy:
 Rapid onset with pain in the forehead.
 Typical 3rd nerve palsy with ptosis, but sparing of the pupillary reflex.
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The underlying pathology is a vascular lesion.
DD: Compressive lesions → early loss of pupillary reflex.
Compression Neuropathies in Diabetics
Common Types:
 Carpal Tunnel Syndrome (CTS)
(Median neuropathy at the wrist)
 Ulnar neuropathy at the elbow.
 Peroneal neuropathy at the fibular head.
Their incidence is higher among diabetics.
Surgical decompression is reserved for patients with a significant deficit.
Treatment of Diabetic Neuropathy
I. Therapies to correct the underlying pathogenetic mechanism.
II. Symptomatic treatment.
I.
Therapies to correct the underlying pathogenetic mechanism:
 Control of blood glucose level:
 Normalization of blood glucose levels prevents microvascular complications
including neuropathy.
 Aldose reductase inhibition :
 Drugs that inhibit aldose reductase can reduce accumulation of alcohol sugars
in the nerves.
 Supplementary dietary intake of myoinositol may be useful.
II. Symptomatic Treatment
1. Physical Approaches:
- Foot care.
- Proper footwear.
- Treat local infection aggressively.
- Cessation of wt. bearing to allow healing of plantar ulcers.
- Alternating hot & cold soaks for painful foot.
- Avoidance of repeated trauma in compression neuropathy.
- Avoidance of crossing of legs & leaning on elbows.
- Nocturnal splinting for pts. with CTS.
- Avoidance of intra-operative pressure or traction trauma to nerves.
- Physiotherapy for pts. with focal neuropathies.
2. Pharmacological Approaches:
- Carbamazepine, (Tegretol): for the lancinating or lightning pains.
Dose: 100 mg. tid., to 200 mg. tid.
Action: It  membrane stability.
- Gabapentin (Neurontin), 400-800 mg tid for neuropathic pain
- Antidepressants e.g. Amitriptyline (Tryptizol) or Doxepin( Sinequan): for
burning steady pain.
- Mexilitine (Mexitil) improves peripheral nerve blood flow.
- Simple analgesics.
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CNS COMPLICATIONS OF DM
Metabolic Derangement:
 Diabetic Ketoacidosis.
 Non-ketotic Hyperosmolar Coma.
 Hypoglycemic Coma.
II. Cerebrovascular Disease:
 Hypertension.
 Atherosclerosis.
 Stroke in Diabetics.
III. Other CNS Abnormalities in Diabetes:
 Spinal cord lesions:
- Posterior column degeneration.
- Corticospinal tract degeneration.
- Diabetic myelopathy.
 Primary diabetic encephalopathy.
 Autonomic neuropathy → Orthostatic hypotension & Syncope.
 Diabetic nephropathy may → Uremic encephalopathy.
 Secondary diabetes may occur in Friedreich's ataxia & dystrophic myotonia.
 Risk of DM in Huntington's disease (HD).
I.
Diabetic Ketoacidosis
It results from hypoinsulinism.
It is characterized by:
 Hyperglycemia (>400 mg/dl)
 Dehydration (due to osmotic diuresis with thirst, polyuria, anorexia, fatigue).
 Metabolic acidosis (Bl. PH < 7.2) with ketone bodies in blood & urine.
 Hepatic fatty acid catabolism → Ketosis.
 Coma in 10% of cases due to:
- Serum hyperosmolality.
- Acidosis.
- Alteration of CBF.
- DIC.
- Hypoxia.
- Toxicity by fatty acids & lysolethicins.
- A defect in brain carbohydrate metabolism.
Complications of Therapy for Diabetic Ketoacidosis
They may contribute to CNS dysfunction
They include:
 Electrolyte disorders:
- Hypokalemia (with insulin & fluid replacement)
- Hypophosphatemia.
- Hyponatremia (with rapid correction of hyperosmolality).
 Thromboembolic disorders
- Precipitated by:
  Bl. viscosity due to dehydration
 Platelet adhesiveness
 Fibrinolytic activity
- Myocardial, cerebral. or mesenteric infarction may cause death
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Infection
Hypoxemia due to pulmonary edema
Cerebral edema is fatal due to  ICP with herniation
Non-Ketotic Hyperosmolar Coma
Hyperglycemia with hyperosmolality without ketosis → progressive mental obtundation
or coma.
Common in elderly diabetics.
Hyperglycemia ( > 800 mg/dl), osmotic diuresis & dehydration.
Hyperosmolality (serum osmolality > 350 mOsm/kg).
Some degree of renal dysfunction potentiates hyperglycemia.
No significant ketoacidosis.
It may be accompanied by serious diseases e.g. gram -ve pneumonia, MI, stroke, GI
hemorrhage, gram -ve sepsis, pulmonary embolism, uremia, pancreatitis.
Precipitating factors include: steroid therapy, thiazide diuretics, renal dialysis, severe
burns, heat stroke.
Seizures, focal neurological deficits & stroke-like syndromes are common.
Flapping tremors, hemichoreoathetosis, hallucinations & hemianopia.
Cerebral edema is rare.
Lactic acidosis is frequent (? vascular disease & CHF → tissue ischemia → lactic
acidosis).
Treatment:
 Lactic acidosis is treated by IV sodium bicarbonate & treatment of its cause.
 Non-ketotic hyperosmolar coma is treated by little insulin + fluid replacement.
Hypoglycemic Coma
It is commonly produced by excessive dose of insulin.
Post-prandial hypoglycemia may occur in early diabetics & in those with renal
insufficiency.
Sympathetic phase of hypoglycemia → dizziness, weakness, tremors & palpitations due
to endocrine release.
Neuroglycopenic symptoms → behavioral abnormalities.
Recurrent nocturnal hypoglycemia → dementia.
Hypoglycemia → 4 forms of acute metabolic encephalopathy:
1. Delirium, quiet or manic.
2. Multifocal brainstem dysfunction → neurogenic hyperventilation & decerebrate
spasms.
3. Stroke-like events + focal deficits + coma.
4. Seizures, single or multiple.
Hypothermia is common.
Recurrent or persistent choreoathetosis may occur.
Blood glucose < 30-40 mg/dl → confusion & behavioral changes.
Further  of blood glucose → stupor & seizures.
Blood glucose < 10 mg/dl → profound coma.
Hypoglycemia is corrected by oral or IV glucose.
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Cerebrovascular Disease in Diabetics
Ischemic stroke is 5-6 times more common in diabetics than in non-diabetics.
Cerebral atherosclerosis, HTN & IHD contribute to stroke in diabetics.
Hemorrhagic stroke is less frequent in diabetics.
Hypertension affects 50% of diabetics & is a major risk factor for stroke.
Hypertension is 1.5-3 times more common in diabetics
Atherosclerosis is associated with HTN.
Atherosclerosis is more common in diabetics.
Stroke in Diabetics
The incidence of ischemic stroke is higher in diabetics.
DM, HTN, hyperlipidemia & obesity are major risk factors.
The relative risk for ischemic stroke in diabetics is higher in women & may reach 13
fold in younger age groups.
Diabetic stroke pts. have a 20% 5-years survival, compared to 40% in matched age nondiabetic stroke pts.
DM appear to  the morbidity & mortality following stroke
Hyperglycemia promotes artherogenesis.
Alterations in platelet adhesiveness, coagulation factors & fibrinolytic activity,
contribute to atherogenesis in diabetics & thrombosis.
Good control of hyperglycemia & HTN reduce the risk of stroke.
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NEUROLOGICAL COMPLICATIONS OF
RENAL FAILURE
UREMIC ENCEPHALOPATHY
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Symptomatology differs in:
1. Early cases
2. Moderate cases
3. Severe cases
The symptoms are ameliorated by dialysis, & relieved after successful renal
transplantation.
Symptomatology of Uremic Encephalopathy
I. Early cases
 Anorexia
 Nausea
 Insomnia
 Restlessness
 Decreased attention span
 Inability to manage ideas
 Decreased sexual interest
II. Moderate cases:
 Vomiting
 Sluggishness
 Easy fatigue
 Drowsiness
 Sleep deprivation
 Labile emotions
 Paranoia
 Decreased cognitive function
 Inability to abstract
 Decreased sexual performance
III. Severe Cases:
 Itching
 Disorientation
 Confusion
 Bizarre behavior
 Slurring of speech
 Hypothermia
 Myoclonus
 Asterixis
 Convulsions
 Stupor, coma
Clinical Assessment & Investigations of Uremic Encephalopathy
 It occurs in renal failure, acute or chronic.
 Initial symptoms:
Apathy, fatigue, inattentiveness & irritability
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Later symptoms:
 Confusion, disorientation, disturbed perception, hallucinations, dysarthria &
asterixis.
 Toxic psychosis, with hallucinations, delusions, insomnia, or catatonia.
Symptoms fluctuate from day to day or even from hour to hour.
In anuric patients, symptoms develop abruptly → stupor & coma.
Gradual uremia → visual hallucination & inattentiveness.
Altered excretion of drugs in uremic pts. → their accumulation → toxic effects.
In acute RF, clouding of sensorium is associated with motor phenomena (the uremic
twitch-convulsive syndrome):
 Twitching & jerking.
 Convulsions.
 Asterixis.
The involuntary movements continue during both wakefulness & sleep.
As the uremia worsens → Uremic coma.
Metabolic acidosis.
Kussmaul breathing → Cheyne-Stokes breathing → death.
HTN is frequently associated with uremia & may cause “Hypertensive
Encephalopathy”
EEG → diffuse slowness.
CSF is normal.
 BUN & serum creatinine levels.
CT-scans & MRI → cerebral shrinkage in chronic RF. No cerebral edema.
Restoration of renal function → recovery of the neurologic syndrome.
Treatment of Uremic Encephaloparthy
 Dialysis or renal transplantation is mandatory in irreversible progressive RF
 Anticonvulsants in low doses to control convulsions.
 Hyponatremia makes seizure control difficult & must be corrected.
 We must be cautious in prescribing certain drugs for uremic pts., e.g.:
 Aminoglycosides (vestibular damage).
 Furosemide (cochlear damage).
 Nitrofurantoin, INH, & Hydralazine (peripheral neuropathy).
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THE DIALYSIS “DISEQUILIBRIUM SYNDROME”
It refers to a group of symptoms that may occur during & following hemodialysis or
peritoneal dialysis.
Symptoms include:
 Headache, bilateral & throbbing, or migraine-like, occur in 70% of pts.
 Nausea, vomiting, anorexia, blurring of vision.
 Muscular cramps, twitching
 Nervous irritability, restlessness, tremor.
 Agitation.
 Drowsiness, dizziness, disorientation.
 Convulsions.
It has been attributed to cerebral edema due to:
 Inappropriate secretion of ADH → water intoxication → shift of water into the
brain.
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 The reverse urea effect.
 Increased brain osmolality in rapid hemodialysis.
 Increased intracellular pH of cerebral cortex from production of organic acids.
It is ameliorated by:
 Decreasing the rate & increasing the frequency of hemodialysis.
DD: Subdural hematoma occurring in 3 - 4% of pts. undergoing dialysis.
DIALYSIS ENCEPHALOPATHY (DIALYSIS DEMENTIA)
A subacute progressive syndrome complicating chronic hemodialysis.
It is a form of aluminum intoxication (from the dialysate & aluminum gels).
Symptoms include:
 A hesitant, stuttering dysarthria, slurred speech.
 Dysphasia.
 Apraxia of speech.
 Facial & then generalized myoclonus.
 Focal & generalized seizures.
 Personality & behavioral changes.
 Intellectual decline.
 EEG: paroxysmal or periodic sharp wave or spike & wave activity, intermixed with
abundant theta & delta activity.
 CSF is normal, except for occasional protein.
 Diazepam (Valium) may → dramatic reversal of the clinical symptoms & EEG changes
in pts. with dialysis encephalopathy.
 Three forms of Dialysis Dementia are known:
1. Epidemic Form: is related to:
 Aluminum in dialysis water,
 Other trace elements in water (Mn, Mg, Fe, Cobalt, Tin) + abnormalities of the
B.B.B.
 Normal pressure hydrocephalus (NPH).
 Slow virus infection of the CNS.
 Regional alterations in CBF.
2. Endemic Form: is related to chronic hemodialysis for > 2 yrs.
3. Childhood Form: may be due to nonspecific effect of uremia on immature brain.
Treatment:
 Diazepam (valium) or Clonazepam (Rivotril) controls seizures.
 Desferoxamine improves other symptoms.
 Removing Aluminium from dialysate water prevents the epidemic form.
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UREMIC NEUROPATHY
Three types:
1. Uremic Polyneuropathies
2. Uremic Mononeuropathies
3. Uremic Autonomic Neuropathies
1. Uremic Polyneuropathies:
 Peripheral neuropathy is the most frequent neurologic complication of chronic RF.
 It affects 2/3 of all pts. about to begin dialysis.
 70% of those on regular dialysis have uremic polyneuropathy.
Symptoms & Signs:
 Painless, progressive, symmetrical sensori-motor paralysis of the legs, then the
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2.
arms.
 Muscle weakness & atrophy, areflexia & sensory loss.
 Uremic polymyositis with hypophosphatemia.
 Muscle cramps,
 Restless-leg syndrome (crawling, prickling, & pruritus sensations in LLs)
 Burning-foot syndrome (swelling sensations & tenderness of feet)
 Glove & stocking hypoesthesia,
 Posterior column dysfunction,
 Both gloves & stocking, & posterior column dysfunction.
 Abnormal NCV may even precede clinical neuropathy.
Uremic Polyneuropathies may be:
 A nonspecific effect of uremia on nerve function.
 Potential uremic neurotoxins including:
 Urea
 Creatinine
 Parathyroid hormone
 Myoinositol
 Transketolase
 Guanidine derivatives
 Middle molecules
 Secondary demyelination of spinal cord → posterior column dysfunction.
Treatment of Uremic Polyneuropathies:
 Long-term hemodialysis → stabilization of the symptoms.
 Rapid hemodialysis may worsen the polyneuropathy.
 Peritoneal dialysis is more successful in improving polyneuropathy.
 Successful renal transplantation → complete recovery over 6-12 months, through
eliminating the causative toxins e.g. methylguanidine & myoinositol.
 Carbamazepine (Tegretol), 400-600mg/d PO in 3 doses.
 Gabapentin (Neurontin), 400-800mg tid
 Clonazepam (Rivotril), 0.5mg PO tid,  by 0.5/2-3 days up to 20mg/d.
Uremic Mnononeuropathies:
 Carpal tunnel syndrome (CTS)
 Vestibulocochlear dysfunction → deafness.
 L.M.N.facial palsy.
Uremic Mononeuropathies are attributed to:
 Hearing Loss ( Vestibulocochlear dysfunction ):
- Bleeding in the inner ear space as a consequence of heparinization.
- Cellular injury in hair cells of the cochlea as a result of edema
- Desferrioxamine neurotoxicity → Auditory toxicity.
 Carpal Tunnel Syndrome:
- A-V fistula.
- Prolonged time of dialysis.
- The uremia itself.
- Deposition of B2 - microglobulin in the carpal tunnel synovia & tendons.
 L.M.N.Facial Palsy:
- Diffuse disorder of neural conduction as a consequence uremia.
 Deterioration of vision
- Pseudotumor cerebri associated with uremia.
- Desferrioxamine neurotoxicity → visual toxicity.
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3.
Uremic Autonomic Neuropathies:
 Orthostatic hypotension,
 Impotence.
 Bowel disturbance.
Autonomic Dysfunction in Uremia is attributed to:
 Altered plasma levels of catecholamines.
 Depressed baroreceptor activity.
 Toxic sympathetic neuropathy.
 Afferent autonomic lesion .
Uremic Myopathy is attributed to:
 Vitamin D deficiency.
 Secondary to hyperparathyrodism.
 Vascular calcification.
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CEREBROVASCULAR STROKE IN RF
Ischemic Stroke:
1. Accelerated atherosclerosis.
 Endothelial damage.
 Isolated elevation of plasma triglycerides.
 Reduction in HDL.
 Accelerated diabetes mellitus
2. Arrhythmogenic events related to hemodialysis uremic cardiomyopathy:
 Abnormal catecholamine levels in plasma.
 Premature aortic & mitral annular calcification.
3.
Reduction of Protein C, Protein S. & Antithrombin III in the chronic condition.
Hemorrhagic Stroke:
1. Heparin anticoagulation in hemodialysis.
2. Coagulopathic effect of uremia.
3. The extremely prolonged half life of Prostacyclines in plasma → bleeding tendency
in uremics .
HEMODIALYSIS HEADACHE
Migraine may  by hemodialysis.
The dialysis disequilibrium syndrome → headache during & for up to 8 hrs after
dialysis.
 Persistent headache points to subdural hematoma.
Mechanism:
1. Increase Interleukin- I activity → release of Prostopeptidin E2 → alteration of
Neuropeptide release.
2. Increase activity of Renin - Angiotensin - Aldosterone system → vasodilatation →
vascular headache.
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SEIZURES IN RF
Causes:
1. Uremic encephalopathy
2. Cerebral edema, water intoxication & hyponatremia
3. Hypocalcemia
4. Hypomagnesemia
5. Hypertensive encephalopathy
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6. Dialysis disequilibrium syndrome
7. Very large doses of penicillin
8. Blood transfusion
9. Erythropoietin treatment
Treatment of Seizures:
 Correction of the underlying metabolic problem.
 Dialysis for uremic encephalopathy-induced seizures.
 AEDs:
 Phenytoin (Epanutin) in usual dosages.
 Phenobarbital (Sominal, Sominalette) in lower dosages.
 Diazepam (Valium), up to 10 mg IV, or
Lorazepam (Ativan), 2-4 mg IV.
 Valproic acid (Depakine) in usual dosages.
 Carbamazepine (Tegretol) in usual dosages.
 Ethosuximide (Zarontin) in usual dosages.
 Seizures during hemodialysis, due to the disequilibrium syndrome are controlled by:
1. The rate & duration of dialysis &  its frequency.
2. Phenytoin (Epanutin), 100 mg tid for hemodialysis pts.
Muscle Cramps
 Occur during or immediately following dialysis → pain.
 Treated by:
Quinidine sulfate, 320 mg PO at the beginning of each dialysis.
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COMPLICATIONS OF RENAL TRANSPLANTATION
Primary lymphoma of the brain may develop in immunosuppressed pts.
Immunosuppressants e.g. Cyclosporin → wide-spread cerebral edema, more
occipitally.
Systemic fungal infections (Cryptococcus, Listeria, Aspergillus, Candida, Nocardia &
Histoplasma).
Other CNS infections (Toxoplasmosis & Cytomegalic inclusion disease).
Bleeding diathesis may → Subdural or Cerebral hemorrhage.
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NEUROLOGICAL COMPLICATIONS OF
HEPATIC DISEASE
HEPATIC ENCEPHALOPATHY
Portal-Systemic Encephalopathy
Hepatic Stupor & Coma
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It affects pts. with chronic hepatic disease e.g. cirrhosis, as well as those with acute
hepatitis.
 Predisposing factors:
 Excess dietary protein.
 GI hemorrhage.
 Hypoxia.
 Hypokalemia.
 Metabolic alkalosis.
 Electrolyte depletion.
 Excessive diuresis.
 Sedative-hypnotic drugs.
 Constipation.
Clinical Features of Hepatic Encephalopathy
 Mental confusion with  psychomotor activity.
 Progressive drowsiness, stupor & coma.
 Wing-flapping tremor (asterixis).
 Fluctuating rigidity of the trunk & limbs.
 Grimacing.
 Suck & grasp reflexes.
 Hyperreflexia & Babiniski sign.
 Focal or generalized seizures.
 Concentrations of blood ammonia (NH3) > 200 µg/dL.
 EEG changes: Paroxysms of bilaterally synchronous slow or triphasic waves in the delta
range, more frontally.
Pathogenesis of Hepatic Encephalopathy
 The most accepted hypothesis relates hepatic coma to an abnormality of Nitrogen
metabolism, wherein Ammonia (NH3), which is formed in the bowel by the action of
urase-containing organisms on dietary protein, is carried to the liver in the portal
circulation but fails to be converted to urea, either because of hepatocellular disease, or
portal-systemic shunting of blood, or both → excess amounts of ammonia reach the
systemic circulation, where they interfere with cerebral metabolism.
Treatment of Hepatic Encephalopathy
General Principles:
 Restriction of dietary protein.
 Oral Neomycin or Kanamycin to reduce bowel flora.
 Enemas.
 Lactulose orally → acidification of colonic contents.
 Liver transplantation for intractable liver failure.
 Other therapies:
 Bromocriptine (Parlodel) -a dopamine agonist-enhance dopaminergic transmission.
 Keto-analogues of essential amino acids -a nitrogen-free source of essential amino
acids.
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Elimination of predisposing factors:
 Avoid sedatives, tranquilizers, & analgesics
 Correct fluid & electrolyte balance
 Correct hypokalemia & alkalosis. Avoid potassium-wasting diuretics
 Maintain intravascular volume to prevent prerenal azotemia
 Treat hyponatremia promptly but cautiously (to avoid central pontine myelinolysis)
 A careful search for occult infection; e .g. peritonitis, & treatment of any infection
 Acute inflammation (e .g pancreatitis), trauma, & surgery
Supportive measures:
 Foley’s catheter, skin care, fluid balance.
 Tracheal intubation in deeply comatose.
Dietary protein restriction:
 Protein – free diet until improvement of neurologic function;
 Feeding; oral, NGT, or parenteral.
 Enough calories (at least 500 kcal/day) to inhibit proteolysis (1500 ml of 10% D/W
→ 600 kcal).
 A mixture of 10 %or 20% D/W & lipids via NGT to give 1500 – 2000 kcal/day .
 Cathartics on admittance
Mg citrate, 200 ml, or Sorbitol, 50 gm in 200 ml water via NGT or PO
 GI bleeding may precipitate hepatic coma:
 Vigorous treatment of GI bleeding
 Aspirate bl.in stomach through a NGT
 Enemata followed by cathartics
Repeated doses of Sorbitol, 50 gm in 200ml water to  one loose motion q4 hrs.
 Adequate vit. supplementation, ê daily doses of folate, 1mg, vit.k, 10mg, &
multivitamins.
 As the pt improves, a diet of 20 gm protein/day is provided, &  daily protein intake by
10 gm every 2 – 3 days (up to 50 gm/day)
Decrease gut ammonia absorption:
 Neomycin, 1gm qid PO, or by retention enema.
It may → Hearing loss, renal impairment, colitis, candidiasis of bowel, & malabsorption.
 Lactulose, 30-50ml (0.65gm/ml) tid PO, by NGT, or by retention enema → acidify the
stool &  ammonia absorption.
 Flumazenil (Anexate), an inverse agonist of the benzodiazepine receptor, 1-3 mg by IV
infusion, may reverse some of the neurologic effects.
L–Dopa have no long-term benefit in pts ê hepatic encephalopathy.
Monitoring Therapy:
 Hepatic Encephalopathy Stages:
 Stage 1 (Precoma): Mild confusion & mental slowness. No asterixis or EEG
slowing
 Stage 2 (Impending coma): Disorientation, drowsiness, asterixis ± mild EEG
slowing
 Stage 3 (Pt is asleep most of the time, confused + asterixis + EEG slowing
 Stage 4 (Coma): Pt responds only to pain + hypotonia + marked EEG slowing
In mild stages of encephalopathy, a handwriting chart & tests of constructional
ability (e.g. drawing a clock or constructing a star ê match sticks)
 Blood ammonia levels correlates ê clinical status. Arterial levels correlate better than
venous levels.
 EEG slowing correlates ê the pt’s clinical status in deeper stages of hepatic
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encephalopathy. Abnormalities in VERs have a similar correlation
CSF glutamine concentrations correlates with the presence & degree of hepatic
encephalopathy.
Chronic Management:
 Low– protein diet (usually 50 gm/day) + Vit. supplementation.
 Pt should have at least one bowel motion each day.
 Neomycin, 500 mg PO bid – qid for a few wks or even months.
 Lactulose (Duphalac), 10 – 30 ml tid, is equally effective & safer.
 Surgical exclusion of the colon from the bowel → high mortality & morbidity.
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ACQUIRED CHRONIC HEPATOCEREBRAL DEGENERATION (ACHD)
Clinically: → dementia, dysarthria, cerebellar ataxia, tremor, spastic paraparesis, &
choreoathetosis. Often superimposed on recurrent bouts of hepatic encephalopthy.
Treatment:
 No specific treatment
 It is preventable through appropriate management of liver disease & prevention of
bouts of hepatic encephalopathy
 Choreoathetosis respond to neuroleptics.
 Behavioral abnormalities respond to protein restriction.
 Bromocriptine (Parlodel) - a dopamine receptor agonist improves mental status. It
is givenPO, 2.5 mg/day in 3 or 4 divided doses,  by 2.5 mg every 3 days up to 15
mg/day, improves mental status.
ACUTE LIVER FAILURE
Clinically → CNS dysfunction, coma & death, if not treated
Treatment:
 Bl. ammonia by protein restriction
+ neomycin or lactulose
 Mannitol 20% for  ICP
 IV dextrose to correct hypoglycemia
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HEPATOLENTICULAR DEGENERATION
(Wilson’s disease)
An autosomal recessive disorder of copper metabolism
Clinically: → liver cirrhosis & cerebral dysfunction → movement disorders, tremor, &
personality changes
Treatment: discussed in Chapter II “Movement Disorders”.
Fulminant Hepatic Failure
Acute Hepatitis → Confusion, delirium & coma
Cerebral edema is a prominent finding in all cases
Cerebral edema is detected by CT scan
Monitoring the ICP, osmotic diuresis & hyperventilation can prevent death from
cerebral edemas
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HEART & BRAIN
(NEUROCARDIOLOGY)
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Cardiac sympathetic nerves arise from cells in the dorsal root ganglia (DRG) at T1 - T5
levels & enter the sp. cord via T 1 - T5 roots.
Fibers ascending from the thoracic sp. cord toward the thalamus also project to NTS &
other cardiovascular nuclei.
Axonal projections from NTS terminate on preganglionic parasympathetic neurons in
the dorsal motor nuclei of vagus & nuclei ambiguous, on preganglionic sympathetic
neurons in the intermediolateral columns, & on cells in the ventrolateral medulla &
raphe nuclei that regulate the cardiovascular system (CVS) by modulating activity of
the sympathetic cells.
The cerebral cortex projects to NTS both directly & via limbic system, hypothalamus, or
parabrachial nuclei.
Neural Control of The Heart
Neuroanatomy of Cardiovascular Regulation
Cardiac Afferents
 Both the vagus (parasympathetic) & the sympathetic nerves carry afferent nerve fibers
from the heart.
 Mechanoreceptor & chemoreceptor endings of these nerves are located in the atria,
ventricles, coronary vessels & pericardium.
 Vagal fs → cells in the nucleus tractus solitaria (NTS) in the medulla oblongata.
 Other afferents regulating heart rate are part of arterial baroreceptor & chemoreceptor
reflexes.
 Those from aortic arch are carried in the vagus or aortic depressor nerves.
 Those from carotid sinus (baroreceptors) & carotid body (chemoreceptors) are carried
in the carotid sinus & 9th nerves.
Cardiac Efferents
 Preganglionic parasympathetic fs. originate in the nuclei ambiguus & pass via
ipsilateral cardiac vagal ns. to the heart, to terminate on neurons of the intracardiac
ganglia.
 Efferent preganglionic sympathetic fs. arise in the upper 4-5 thoracic segments of the sp.
cord.
 Pregang. vagal & postgang. sympathetic fs. combine at the base of the heart to form the
cardiac plexus.
 Parasympathetic fs. → Sinoatrial (SA) & AV node, where fs from the Rt. & Lt. vagus
overlap.
 Rt. sympathetic ns. predominantly innervate the SA node.
 Lt. sympathetic ns. innervate the AV node.
Autonomic Influences on Cardiac Function:
 Parasympatetic ns.  discharge of SA nodal pacemaker.
 Sympathetic ns. exert the opposite effect.
 Parasymp. & sympath.  contractility of atrial & ventricular myocardium.
 Parasymp. & sympath.  AV nodal conduction.
 Cardiac vagal responses are mediated by Acetylcholine (Ach).
 Cardiac sympathetic responses are mediated by Norepinephrine (NE).
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Sympath. & parasympath. outflow to the SA node is primarily influenced by arterial
baroreceptors.
Cardiac influences of the vagus & sympath. ns. are interdependent.
Ach can inhibit the release of norepinephrine from sympath. fs.
Norepinephrine can inhibit acetylcholine release from vagal fs.
Thus, autonomic NS has powerful effects on cardiac conduction & contractility.
The NS may contribute to control of coronary blood flow.
A central pathway from lateral hypothalamus to neurons in the periaqueductal gray
matter & thence to the rostral ventrolateral medulla that modulates cardiac sympathetic
activity → modulation of coronary bl. flow.
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Figure 2. Innervation of the Heart
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1.
2.
Autonomic neuropathies → cardiac denervation → fixed tachycardia.
Primary neurologic disorders may cause ECG signs of ischemia & arrhythmias.
Cardiac disease may coexist with ischemic strokes.
The incidence of ECG changes is:
 60-70% in pts. with IHD.
 40-60% in pts. with SAH.
 15-40 in pts with ischemic strokes.
Stress alone can induce arrhythmias or sudden death.
Intense release of catecholamines may be responsible for this.
ECG Changes in CNS Disease
Changes in ECG Morphology:
 LVH (evidence of chronic HTN).
 Pathologic Q waves (evidence of a prior MI).
 ST-T wave abnormalities (seen in subendocardial MI).
 QT prolongation.
 U waves.
Mechanisms for Neurally-induced ECG Abnormalities
 MI associated with CAD.
 Diffuse MI in absence of CAD, 2ry to exposure to local catecholamines.
 Changes in ventricular repolarization 2ry to activation of the sympathetic NS, or
direct stimulation of the thalamus & insula.
Disturbances of Cardiac Rate & Rhythm:
 Sinus tachycardia / bradycardia.
 AF / A. Flutter (in 1/3 of pts with acute neurologic disorders).
 Atrial tachycardia.
 Premature atrial / ventricular complexes (PVCs).
 Intermittent AV node block.
 Nonsustained / sustained ventricular tachycardia.
Neurally Induced Cardiac Damage
Neurogenic Pulmonary Edema (NPE)
Mechanism of NPE:
 Lt. atrial HTN.
 Systemic HTN.
 Pulmonary venoconstriction.
 Sympathetic overactivity.
 Sympath. n. stimulation →  pulm. capillary permeability to protein.
 Sympath. n. stimulation may → lymphatic constriction.
Pathogenesis of NS-Induced Pulmonary Edema:
 Two major causes:
(1) Elevated intravascular pr.
(2) Pulmonary capillary leak.
 Pulm. edema may follow epileptic seizures or éICP.
 The neuroeffector site for NS-induced pulm. edema is located in the caudal medulla,
where nuclei regulating systemic arterial pr. & aff. & eff. pathways to & from the lungs
are located.
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Neurogenic Heart Disease
Two categories of ECG changes are noted in neurologic disease:
1. Arrhythmias.
2. Repolarization changes.
Mechanism of the Production of Neurogenic Heart Disease:
  Catecholamines levels.
 Stress + Steroids, via the hypothalamic sympathetic NS.
 NS stimulation e.g. stim. of hypothalamus.
 Reperfusion → myofibrillar degeneration, due to entry of Ca.
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Sudden Death:
A Neurocardiologic Phenomenon
A tight relation between brain activation of unbalanced autonomic function &
arrhythmias, exists & ends in SCD.
Insular & infralimbic cortex exert direct & indirect effects on hypothalamus & other
brain stem nuclei in modulating cardiac sympathetic - parasympathetic interactions.
Sympathetic hyperactivity → life-threatening cardiac arrhythmias
Vagal activation exerts protective & antifibrillatory effects
Epileptic activation of cortical brain sites can turn this system on, &  incidence of
unexpected death in epileptics.
The role of environmental stress in arrhythmogenesis & SCD is of great importance in
the outcome of Heart disease.
Cardiac Arrhythmias & Syncope
Bradyarrhythmias That Can Cause Syncope:
 Sinus node dysfunction → inappropriate sinus bradycardia or episodic sinus pauses.
 AV conduction disturbances → symptomatic bradyarrhythmias.
Tachyarrhythmias That Can Cause Syncope:
 Supraventricular tachycardias.
 Ventricular tachyarrhythmias.
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Cardioneurogenic Syncope
(Vasovagal Syncope = Vasodepressor Syncope = Reflex Syncope)
It results from stimulation of the medullar vasodepressor region of the brain stem
→  parasympathetic tone (via vagus n.) & vasodilatation → Cardiac filling &
bradycardia à syncope
It is characterized by being:
- Situational & recurrent, occurs in younger pts.
- Preceded by prodromal symptoms (lightheadedness, ringing in ears, visual
disturbances, diaphoresis, or nausea).
- It occurs in upright position.
- It is aborted by assuming the supine position.
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Cardiac Valvular Disease & Stroke
Valvular heart disease may → Systemic embolization → Stroke.
Antithrombotic therapy can  but not eliminate this risk.
The incidence of embolism in pts with rheumatic valvular diseases is decreasing.
Mechanical & bioprosthetic valves may → thromboembolism.
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Percutaneous balloon valvuloplasty for mitral stenosis & aortic stenosis may →
embolic events.
Surgical repair of the mitral valve  the risk of embolic events.
Aortic valve disease rarely causes systemic embolization.
Emboli associated with aortic insufficiency occur in patients with endocarditis, AF, or
coexistent mitral valve disease.
Mitral valve disease frequently causes thromboembolism.
The presence of AF  the risk of thromboembolism by 3-7 times.
Recurrent emboli occur in 30-65% of cases.
The mortality rate may reach 42% in such patients.
Anticoagulants are indicated in patients with rheumatic mitral valve disease particularly
if associated with AF.
Persistance of AF after surgery or balloon valvuloplasty requires continuous
anticoagulation.
Mitral valve prolapse affects 5-7% of adult population.
It may cause cerebral ischemia by embolism of valvular thrombi.
Long - term aspirin therapy is prophylactic against TIAs.
Long - term warfarin is indicated in patients with mitral valve prolapse (MVP) & AF.
Mitral annular calcification is more in females & the elderly & is associated with
double mitral, calcific aortic stenosis, H.B., arrhythmias, endocarditis, & embolic stroke.
Prophylactic anticoagulation should be reserved to patients with AF.
Balloon valvuloplasty for mitral stenosis & aortic stenosis may → Systemic
embolization → TIAs & strokes ? by calcific emboli.
Prosthetic valves (mechanical or tissue prosthesis) may → Thromboembolism
more with mitral valve replacement than with aortic.
Life - long anticoagulation is needed in all patients.
Mitral valve repair for mitral insufficiency  the morbidity & mortality rates, &  the
risk of thromboembolism.
Coronary Artery Disease, MI
& Brain Embolism
The incidence of in - hospital stroke after acute MI is 1%.
Ischemic strokes are most common after large anterior wall MIs.
Lt. ventricular thrombi are common after anterior wall MIs.
High - dose anticoagulation prevents their formation.
Aspirin is an alternative if anticoagulants are contraindicated.
Mobile, pedunculated LV thrombi à high risk of embolization.
Thrombi in LV aneurysms, probably do not require anticoagulation.
Aspirin  the risk of stroke after MI & should be given to all MI patients.
t-PA treatment of MI → high risk of stroke than streptokinase due to excessive risk of
cerebral hemorrhages.
Neurologic Complications of
Infective Endocarditis
The overall incidence is 30%, mostly in patients with Lt-sided valvular disease.
The incidence of CNS complications is higher with more virulent organisms.
CT/MRI scanning are useful for diagnosis of CNS complications.
Cerebral angiography is used in patients with suspected I.C. mycotic aneurysms.
Appropriate antimicrobial therapy is mandatory
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Aneurysm surgery may be needed for I.C. mycotic aneurysms.
Anticoagulants should be continued in patients with prosthetic valve endocarditis, with
no evidence of I.C. hemorrhage.
They should be avoided in patients with native valve endocarditis because of the high
risk of hemorrhagic CNS complications.
Mortality rate is higher in patients with neurologic complications of infective endocarditis.
Early diagnostic & therapeutic interventions will improve the outcome.
Neurologic Complications of
Congenital Heart Disease
I. Spontaneous Neurologic Complications:
1. Rt - to - Lt Shunt Lesion:
(e.g. Tetralogy of Fallot & Transposition of the great arteries).
 CVAs occur in 17-19% of patients, due to hypoxia & polycythemia.
 Arterial or venous thrombosis.
 A prolonged hypercyanotic spell → brain hypoxia → seizures.
 Clotting abnormalities → prolongation of prothrombin & thromboplastin time
→ hemorrhagic diathesis.
 CT/MRI are useful in diagnosis.
2. Silent Atrial Septal Defect (ASD):
 May → paradoxic thromboembolism → stroke or retinal ischemia.
 Transesophageal echocardiography is helpful in diagnosis.
3. Ventricular Septal Defect (VSD):
 May → paradoxic embolization.
4. Coarctation of the Aorta:
 It may à intracranial arterial aneurysms.
 Rarely ruptured aneurysm + HTN → SAH.
 Development of collateral vessels within the sp. canal → compression of the
sp. cord → paraplegia, or may rupture → SAH.
5. Infective Endocarditis:
 May → infective emboli → stroke, more with left - sided valve affection.
 Two - dimensional echocardiography is helpful in diagnosis.
6. Brain Abscess:
 It is common with cyanotic C.H.D. with Rt.- to - Lt. shunt.
 Septic embolization from infective endocarditis & hematogenous dissemination from a nearby infection.
7. Pre-existing or Congenital Neurologic Problems:
e.g. CNS abnormalities, chromosomal abnormalities.
8. Arrhythmia
 May → Dizziness, Lightheadedness, Syncope, Seizures.
II. Neurologic Complications Related to Procedures:
1. Cardiac Catheterization:
 May → thromboembolism, air embolism, CNS hypoxia → seizures
2. Cardiac Surgery:
 May → thromboembolism, air embolism, hypoxia, metabolic derangement e.g.
azotemia, hypoglycemia, hyponatremia, or hypocalcemia.
 Neurologic problems in early years include: seizures, impaired consciousness,
hypotonia, hemiparesis, personality changes, & choreoathetosis.
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Postoperative Neurologic Complications
1. Horner’s syndrome.
2. Vocal cord palsy.
3. Phrenic nerve palsy.
4. Spinal cord injury.
5. Subclavian steal syndrome.
6. Superior vena caval syndrome.
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Cerebrovascular Complications
Associated With The Use of
Artificial Circulatory Support Services
Neurological complications are associated with the use of total artificial hearts & with
ventricular support systems.
They include thromboembolism → device - related strokes.
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Cardiac Arrhythmias & Stroke
They → hypoperfusion & cerebral hypoxia
AF → Thromboembolic strokes.
AF pts should receive Warfarin or Aspirin 325 mg/d.
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CNS Complications In Coronary Artery Bypass Graft Surgery (CABG)
CABG → CNS complications in 3.8%
(altered mental state, stroke & seizures).
Ophthalmoplegia, primitive reflexes, psychosis, depression, & brachial plexopathy may
also occur.
Minor cognitive impairment may follow CABG procedures.
CABG encephalopathy is characterized by: a delay in emerging from anesthesia,
agitation or restlessness, poor visual fixation, small reactive pupils, Babinski sign
Post-CABG stroke occurs in 0.9-5.9% of cases, due to:
- Macroemboli from the heart & atheromatous emboli from aorta.
- Stroke prone pts those with CHF, elderly, carotid stenosis/bruit, TIAs.
Hypotension:
- Peri-operative hypotension is due to LVF, arrhythmias, or blood loss.
- Operative hypotension is rare (in 2% of cases). BP of 50 mmHg is enough.
- CABG encephalopathy reflects bilateral frontal lobe damage, & is due to
hypoperfusion.
Microemboli:
- During CABG surgery, microemboli → microvascular occlusion → neurocognitive decline.
- Cerebral & retinal microemboli are detected by TCD & retinal fluoroscein
angiography.
- Using “membrane oxygenators” is safer than “bubble oxygenators”.
382
NEUROCUTANEOUS DISORDERS


Also known as Neuroectodermatoses or Phakomatoses (Phakos is the Greek word
for lentil, mole; birthmark)
The diseases customarily considered neurocutaneous syndromes are notable for their
dysplastic nature & tendency to form tumors in various organs particularly the skin
& nervous system
Common types of phakomatoses include:
1. Neurofibromatosis (Von Recklinghausen disease)
2. Tuberous Sclerosis
3. Sturge-Weber syndrome (Encephalofacial angiomatosis)
4. Von Hippel-Lindau disease
5. Ataxia-telangiectasia
6. Incontininta Pigmenta
 The six diseases are considered the major phakomatoses & except for Sturge-Weber
syndrome, all are inherited, although sporadic cases could occur.

Each of these conditions is a distinct clinical entity, although there are scattered
reports of “Double phakomatoses” or clinical overlap.
 The clinical spectrum ranges from frequent abortive forms “Formes frustes” to
severe lethal conditions.
Additional Neurocutaneous Syndromes
Autosomal- Dominant
 Hemorrhagic telangiectasia (Osler-Rendu-Weber syndrome):
Telangiectasiae of the skin & mucus membranes, particularly involving the face,
ears, fingers, conjunctiva & nasopharynx, often associated with epistaxis. The lung,
liver, GIT, bladder & brain are sometimes affected. Pulmonary arteriovenous fistulae
& polycythemia can occur.
Autosomal- Recessive
 Chediak-Hagashi syndrome:
Partial albinism, photophobia, nystagmus & hepatosplenomegaly. Mental retardation,
seizures & severe neuropathy are associated findings. Giant peroxidase-positive
granules are found in polymorphonuclear leukocytes; functional abnormalities are noted
in the platelets & leukocytes, & recurrent pyogenic infections can occur.
 Divry-Van Boegart syndrome:
Cutis marmorata, leptomeningeal angiomatosis & leukodystrophy manifested as M.R &
dementia, seizures, visual loss & spasticity.
 Meckel-Gruber syndrome (dysencephalic splachnocystica):
Craniofacial anomalies include microcephaly, encephalocele, meningocele, ocular
anomalies, & facial clefts. Associated cystic changes are found in the kidney, liver, &/or
pancreas; skeletal anomalies may occur.
 Xeroderma pigmentosum:
 Cutaneous atrophy, telangiectasiae, & ulceration + extreme photosensitivity.
 Mental retardation, seizures, dysarthria & ataxia are present.
 Endocrine abnormalities.
X-linked
 Albright syndrome (Polyostotic fibrous dysplasia):
 Short stature, brachydactyly, subcutaneous ossification, & large areas of cutaneous
hyperpigmentation.
 Mental deficiency & seizure; precocious puberty is found in female.
383

Dyskeratosis congenita (Zinsser-Cole-Engman syndrome):
 Gray skin hyperpigmentation is particularly noted in the face, neck, & chest.
 Dystrophic nails with ridging
 Oral leukoplakia & hyperhidrosis.
 Excessive lacrimation.
 Fabry`s disease
 Punctate reddish-black skin eruption is commonly found about the hips,genitalia, &
occasionally the face.
 Progressive cerebrovascular disease & renal disease & recurrent cerebral infarction.
 Sensory neuropathy with burning or shooting pains.
 Abnormal ceramide dihexosides & trihexosides.
No Inheritance Recognized
 Cobb syndrome (Cutaneomeningeal angiomatosis)
 Cutaneous angiomas are associated with spinal angiomas at the corresponding
spinal segment.
NEUROFIBROMATOSIS (NF)
(Von Recklinghausen Disease)
 Although Von Recklinghausen is credited with the initial clinical & pathological account
of this disease in 1882, he cited Tilesius (1793) for the first description of a patient with
multiple fibrous skin tumors.
 Wishart (1822) & Smith (1849) also provided clinical accounts of the disease before the
report of Von Recklinghausen .
 Neurofibromatosis (NF) is a multisystem neurocutaneous disorder involving both
neuroectodermal & mesenchymal derivatives, transmitted as autosomal-dominant trait.
NF is notable for its great variability of clinical expression.
 The expression of this disease is highly variable, even within an affected family, ranging
from mild inconvenience with normal lifespan, to serious & progressive manifestations
leading to death as early as the perinatal period.
 The disease is autosomal dominant without predilection for sex, race, or color, &
penetrance is complete
 Eight distinctive types of NF are recognized.
 At least 85% are represented by Type I (von Recklinghausen or Classic peripheral
neurofibromatosis, with a prevalence of 1:4000 live births) & an additional 10% by
Type II (Acoustic or Central neurofibromatosis, with a prevalence of 1:50000 live
births).
NF Subtypes:
 NF I: Classic or von Recklinghausen NF, Peripheral NF is an autosomal dominant
form, characterized by multiple café-au-lait spots (six or more 1.5 cm diameter lesions
in an adult), axillary freckling, numerous fibromas, & Lisch nodules or iris hamartomas.
 NF II: Acoustic or Central NF is an autosomal dominant form, characterized by an
almost 100% incidence of bilateral acoustic neuromas. Cafe-au-lait spots tend to be few,
very large, & pale. Few neurofibromas are present. Lisch nodules are absent.
 NF III: Mixed NF is an autosomal dominant form combining features of the above two
forms: few large, pale cafe-au-lait lesions & more numerous cutaneous neurofibromas
with higher frequency of CNS tumors, such as optic gliomas, neurilemomas, &
meningiomas than found in NF I.
 NF IV: Variant NF is an autosomal dominant form in which cutaneous, acoustic &
other CNS lesions may be present but that does not fit well into other groupings.
384

NF V: Segmental NF consists of unilateral localized distribution of either cafe-au-lait
spots or neurofibromas, or both. There have been 15 reported cases. A post zygotic
mutation restricted to somatic cells has been assumed to be responsible for most cases.
However, in two cases of segmental disease, genetic transmission of the generalized
disease has been reported.
 NF VI: This autosomal dominant form is characterized by cafe-au-lait spots but no
cutaneous neurofibromas.
 NF VII: Late-onset NF is a form in which no signs of the disease appear before age 20,
when neurofibromas may start developing. No cafe-au-lait spots have yet been reported.
One reported case had a maternal uncle with neurofibromatosis. No offspring have yet
been reported to develop neurofibromatosis.
 NF VIII: Unspecified NF includes those cases that do not fit into the above groupings.
Genetics
 Transmission of NF is by an autosomal dominant mode of inheritance. In about 50%,
the condition is due to a new mutation.
 Furthermore, advanced paternal age is associated with increased risk of new mutations.
 Patients born of affected mothers tend to have more severe expression of their disease
than those born of affected fathers.
 The NF-1 gene has been localized to chromosome 17 at band q11.2.
 The NF-2 gene has been localized to chromosome 22 at band q12.
Clinical symptoms & signs in NF
Café au lait spots (Fig:1)
 Present in 95% of patients with neurofibromatosis (& 10-20% of normal individuals),
are usually present at birth, but may appear up to the first year of age, often increasing
in size & number over the first decade of life.
 They vary from few millimeters to few centimeters in size & are found commonly on
the trunk than on limbs & not found on the scalp, palms or soles.
 Six or more macules are seen in 78% of NF-I patients. Pigmentation & size increase
with aging.
 The cafe-au-lait spots of patients with neurofibromatosis are distinguished by the
presence of more DOPA-positive melanocytes than surrounding normal skin, whereas
similar macules in normal individuals, & in patients with other diseases associated with
cafe-au-lait spots (such as McCune-Albright syndrome), contain fewer DOPA-positive
melanocytes per square centimeter in their cafe-au-lait macules than in surrounding skin.
Crowe's sign (Fig: 2)
 Axillary or inguinal freckling, appearing as 1-4 mm cafe-au-lait spots in the axilla or
inguinal region, occurs in 20-50% of patients with NF.
 Blue-red macules & pseudoatrophic macules
 Generally occurring around the time of puberty, these lesions are slightly elevated to
dome shaped, & may contain small blood vessels with the appearance of telangiectasia.
Neurofibromas
 The appearance of neurofibromas is often associated with puberty. They may be few or
many, & increase in size & number as the patient ages, or during pregnancy in affected
female patients. Areolar neurofibromas are particularly common in post-pubertal
females with NF. (Fig 3)
 Neurofibromas can develop at any time & at any location from the dorsal root ganglion
to the terminal nerve twigs. They vary from a few millimeters to several centimeters &
are more commonly found in trunk than limbs.
 The subcutaneous tumors, take two forms:
385
1.
2.
Firm nodules attached to a nerve,
An overgrowth of subcutaneous tissue, sometimes reaching enormous size. The
latter, is called plexiform neuromas (also pachydermatocele, elephantiasis
neuromatosis, la tumeur royale). (Fig: 4)
 When the hyperpigmentation overlies a plexiform neurofibroma & extends to the
midline, one should suspect an intraspinal tumor at that level
 Lisch nodules (Fig: 5)
 Lisch nodules are the most common clinical feature of NF I, seen in 5% of children
under 3 years of age, 55% of children 5-6 years of age, 94% of children older than 6
years, & 97 to 100% of postpubertal patients with peripheral neurofibromatosis II.
Although they are not seen in normal individuals, the absence of Lisch nodules does not
exclude the diagnosis.
Seizures & intellectual compromise
 Neurologic disease is present in over 50% of affected individuals, including seizure,
intellectual compromise, & tumors .
 Seizures occur in 8 – 13 % of patients, often associated with intracranial tumors .
 Intellectual impairment (including retardation, hyperactivity, learning disabilities, &
speech impediments) occurs in 10 – 20 % of affected individuals, often with onset prior
to school age ranging from mild to severe, but not progressive .While only 2-5% of
affected patients will have mild mental retardation, 30 – 40 % will have speech
pathologies .
Optic involvement (Fig: 6)
 Eyelid ptosis in early childhood is a harbinger of eyelid neurofibroma or plexiform
neuroma .
 Optic nerve gliomas, neurofibromas, schwannomas, & optic nerve sheath meningiomas
may involve the globe & surrounding soft tissues .
 Optic gliomas tend to appear in the first decade, show sarcomatous degeneration, &
have a perineural pattern of growth (unlike the intraneural pattern seen in similar lesions
of non-NF patients).
 Glaucoma is a rare complication.
Intracranial & spinal tumors
 The intracranial tumors associated with neurofibromatosis include optic gliomas, other
astrocytomas, neurilemmomas, acoustic neuromas, neurofibromas, & meningiomas
 Spinal tumors are usually meningiomas or neurofibromas
Malignancies (Fig: 7)
 Malignant degeneration of neurofibromas in NF may occur in 3 – 15 % of affected
individuals .These secondary tumors are most often sarcomatous, although other forms
have been reported .
 Other neoplastic entities, such as leukemia, malignant schwannoma, Wilms' tumor, &
pheochromocytoma, have also been reported in increased association with
neurofibromatosis .
Osseous defects & congenital dislocations (Fig: 8)
 50 % of individuals affected with neurofibromatosis may have osseous defects,
including focal kyphoscoliosis, in more than 10% of NF patients, pseudoarthrosis, &
dysplasia or thinning of the long bone cortex .These lesions all relate to neurofibromas
near or within the affected bone .
386
Oral Pathology
 Pathologic oral lesions may occur in up to 72% of affected individuals .
 ommon associations include: neurofibromas of oral soft tissues (27%), enlarged
fungiform papillae (32%), mandibular bony lesions (18%), widened inferior alveolar
canal (27%), & enlarged mandibular foramina (27%).
Endocrine disorders
 Early (most common) or late sexual maturation
 Menstrual abnormalities,
 Gynecomastia
 Acromegaly
 Hyper -or hypo-thyroidism
 Hyperparathyroidism
 Medullary thyroid carcinoma,
 Infertility
 Addison's disease
 Hypoglycemia
Gastrointestinal involvement
 Complications related to mucosal bleeding overlying intestinal neurofibromas are
reported in 10% of affected patients, & include dyspepsia, hematemesis, melena,
obstruction & intestinal perforation .
Hypertension
 Secondary hypertension is a frequent finding in adults with NF .
 The cause may either be renovascular, or pheochromocytoma, or both .
 In affected patients under 18 years of age, renovascular hypertension is a seven times
more likely cause of hypertension than pheochromocytoma .
 The prevalence of pheochromocytoma in NF patients is 1:223, while the prevalence of
NF in patients with pheochromocytoma is between 1:5 & 1:20 .
 Medical & endovascular treatments have, to date, had poor long-term outcomes.
 Surgical reconstruction remains the therapy of choice .
Vascular anomalies (Fig: 9)

Almost all children with NF develop vascular lesions, most commonly involving the
abdominal aorta, & the renal, internal carotid & vertebral arteries, although any artery
may be affected .

NF is the most common genetically determined renovascular disorder in children .

The renal artery stenosis, resulting from fibromuscular dysplasia of the media, often
begins at the origin of the artery from the aorta, & may extend into the intrarenal
branches.
Features Listed For NF1
(Chromosome 17;q;11)
 Macrocephaly


Macrodactyly
Lipomata

Absent or hypoplastic patella

Adrenal tumors (excluding
neuroblastoma)
387

Neurofibromas

Asymmetric arms/forelimbs

Optic atrophy

Asymmetric legs/hind limbs

Optic disc & nerve, general abnormalities 

Osteosclerosis or osteopetrosis

Bifid/fused ribs

Patchy depigmentation of skin

Brain tumors/cysts

Patchy pigment of skin/cafe au lait spots 

Pedunculated skin lesions/skin tags

Fibrous dysplasia of bones

Pigmentary abnormalities of iris

Glaucoma

Pseudoarthrosis

Hemi-hypertrophy

Ptosis of eyelids

Hypertrophy of leg/hind limb

Renal artery stenosis

Hypertrophy of arm/forelimb

Renal tumours (including Wilms')

Iris, general abnormalities
Axillary freckles
Early puberty in male
Features Listed For NF 2
(Chromosome(s) 22;q;12)
 Aplasia or dysplasia of retina
 Brain tumors/cysts
 Cataract
 Deafness, sensorineural
 Intra-cranial calcification
 Neurofibromas
 Patchy pigment of skin/cafe au lait spots
 Pedunculated skin lesions/skin tags
 Spinal tumors
Diagnostic Criteria for NF1
Criteria for the diagnosis of NF 1 are met in an individual if two or more of the following are
found:
1. Six or more cafe-au-lait macules over 5 mm in greatest diameter in prepubertal
& over 1.5 cm in postpubertal individuals .
2.
Two or more neurofibromas of any type, or one plexiform neurofibroma
3.
Multiple freckles (Crowe's sign) in the axillary or inguinal regions .
4.
A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone
cortex, with or without pseudoarthrosis
5.
Optic glioma.
6.
Two or more iris hamartomas (Lisch nodules) on slit lamp or biomicroscopy
examination.
7.
A first-degree relative (parent, sibling, or offspring) with NF-I by the above
criteria.
388
Diagnostic Criteria for NF2
1. CT or MRI evidence of bilateral internal auditory canal masses consistent with
acoustic neuromas,
2.
or
A first-degree relative with NF-II & either:
a.
Unilateral eighth nerve mass
or
b. Two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile
posterior subcapsular lenticular opacity.
Complications of NF
 Disfigurement.
 Kyphosis &/or scoliosis.
 Malignancy
 Mental retardation, speech retardation, hyperacivity & seizures
 Large heads.
 Optic gliomas
 Hypertension
 Congenital defects of bone:
 Congenital absence of the orbital wall.
 Bowing of the leg bones below the knee (tibia or fibula).
Differential diagnosis of neurofibromatosis:
Characteristic cutaneous lesions:
 Watson's syndrome – autosomal disorder characterized by cafe-au-lait macules,
pulmonary stenosis & intellectual compromise .
 Albright syndrome -polyostotic fibrous dysplasia with endocrine dysfunction &
precocious puberty & somatic development .
 Multiple mucosal neuroma syndrome
 Leopard syndrome
Characteristic tumors:
 Isolated optic glioma
 Multiple lipomatosis
 Solitary neurofibroma
 Isolated hemihypertrophy
Management of NF:
 The multi-organ occurrence of neurofibromas & their complications often requires
care from a variety of medical & surgical specialists. The physician should
coordinate such care.
 Treatment is aimed at facing the complications as they occur.
 Some of the problems, such as renal artery stenosis, if detected early, can be
managed successfully. Enlarging tumors can sometimes be managed by observation
& surgery.
 If malignancies (including leukemia) develop, treatment is the same as for children
without NF.
389
In the medical supervision of a child with NF, a number of areas require ongoing
assessment & periodic review throughout life, including the following:
 Evaluate the child for new neurofibromas & progression of lesions. Examine the
skin carefully for signs of plexiform neurofibromas that may impinge on or infiltrate
underlying structures.
 Check the child's blood pressure. Because renal disease (particularly renal artery
stenosis), aortic stenosis, pheochromocytomas (more common in adults) & adrenal
tumors may occur, regular & careful blood pressure measurements are important. A
variety of vascular hypertrophic lesions may be found.
 Evaluate neurodevelopmental progress.
 Evaluate the child for skeletal changes. Look for scoliosis, vertebral angulation, &
limb abnormalities. Sometimes localized hypertrophy of a leg, arm, or other part of
the body results from plexiform neurofibromata.
 If any complications occur or if neurocutaneous lesions appear to be rapidly
advancing, refer to the appropriate specialist.
 Recommend available resources for patients with NF (e.g, NF clinics, support
groups, & individual NF-1 families).
TUBEROUS SCLEROSIS (TS)
Bourneville & Brissaud (1880)
 First pathologic description of TS
 First to call the disease tuberous sclerosis
 First to relate cerebral sclerosis to the renal tumors
 Vogt (1908)
 Emphasized association of adenoma sebaceum & cerebral sclerosis
 Emphasized cardiac & renal tumors are constituents of TS
 Triad of: mental retardation (MR), seizures & adenoma sebaceum
Tuberous Sclerosis
 A neurocutaneous syndrome characterized by cutaneous &
manifestations (mental retardation & seizures), & tumors.
 Clinical triad is adenoma sebaceum, seizures, & mental retardation.
 Incidence: 1/30,000
 Age of onset: 1st decade

neurologic
Genetics
 Familial - autosomal dominant with variable penetrance
 Rates of spontaneous mutation have varied but have been approximated as greater
than 50%
 Genetic linkage studies of the gene for TS:
- gene 1 chromosome 9q33-34 (TSC1)
- gene 2 chromosome 11q23 (TSC 2)
- gene 3 chromosome 12q23.3 (TSC 3)
- gene 4 chromosome 16p13 (TSC 4)
 If 2 or more siblings have Tuberous Sclerosis (TS) then one parent always has at
least one skin manifestation of TS
 If both parents are normal, the TS in a child is probably a new mutation
 Sporadic rate varies from 58-77%
390
Clinical features

Clinical presentation is extremely variable depending on the age of the patient, which
organs are involved, & the severity of involvement
 Clinical variability even within the same family
Cutaneous Manifestations
1. Adenoma Sebaceum (80%)
 rarely present at birth
 usually presents between 4-6 years of age:
- present in 12 % at 1 year
- present in 33 % at 2 years
- present in 40 % at 3 years
 are angiofibromas:
- usually pink or red papules appearing in patches or in a butterfly-shaped
distribution on or about the nose, cheeks, & chin
- with time may enlarge, coalesce, & assume a fleshy appearance
2. Ash-leaf Spots (90%)
 hypopigmented oval or leaf-shaped spots
 vary in size from mm to cm
 vary in number from several to 75 or more
 found on the trunk & limbs in a linear orientation
 apparent at birth & seen prior to 2 years in 50% of patients
 visualized using a Wood's light (melanin absorbs wavelengths at 360 nm)
 represent depigmented macules in which the melanocytes are normal but the
melanosomes are reduced in number & contain less melanin
3. Shagreen Patches (35%)
 isolated "leathery" raised & thickened plaques
 have an orange-peel consistency
 may be grayish-green or light brown in colour
 found over the lumbosacral or gluteal region
 develop in late infancy or early childhood but may also be present at birth
 may be preceded by patches of grey or white hair (these hairy patches may be the
first manifestation of TS)
4. Others
 cafe-au-lait spots (7-16%)
 fibromas
 angiomas
Neurologic Manifestations
1. Seizures (90%)
 most common symptom of TS
 initially present as infantile spasms:
- 25-50% of patients with infantile spasms later develop signs of TS
- can appear as early as 1 week of age
 later develop other types of generalized seizures:
- tonic, clonic, myoclonic, akinetic, Lennox-Gastaut syndrome
2. Mental Retardation (60-70%)
 highly variable but when present is irreversible
391

may be initially normal but then deteriorate intellectually during the
latter part of the 1st decade (secondary to seizure or increased
intracranial pressure)
 The earlier the onset of seizures the greater the likelihood of mental
retardation (if seizures begin <1 year of age a 92% chance of MR)
 all who have mental retardation (MR) have had seizures
 33% of TS have normal intelligence
3. Others
 hydrocephalus: if tubers obstruct the foramina of Monro or the Sylvian
aqueduct
 developmental delay
 may develop autistic features
Tumors
1. Retinal (50-80%)
a. Mulberry Tumor
- a nodular astrocytoma of the retina on or about the optic nerve head
- refractile, yellowish, multinodular cystic lesions
b. Hamartomas
- round or oval grey-yellow glial flat patches found centrally or peripherally
- complications do not include papilledema or impaired vision
2. Renal (50-80%)
3. Heart (50%)
4. Cutaneous (20%)
5. Intracranial (15%)
6. Oral
Investigations
Imaging Studies (CT/ MRI)
1. Intracranial Calcifications (60%)
- most reliable finding in TS is calcified subependymal tubers
- also occur in the region of the foramina of Monro & periventricular regions
- multiple scattered calcium deposits may vary in size up to several cm
- occur as early as 5 months & become more prominent with time (typically around
3-4 years of age)
- tubers which project into the lateral & 3rd ventricles may appear as "candle
drippings"
2. Others
- only 5% of patients with the clinical features of TS have normal CT's
- may also identify cerebral atrophy, subependymal tumors, ventriculomegaly, &
areas of diffuse demyelination
EEG
1. Infantile Spasms
- hypsarrhythmias, can persist up to 8 years of age
2. Generalized Seizures
- generalized slow wave-&-spike activity or independent multifocal spike discharges
392
STURGE – WEBER SYNDROME (SWS)
Most cases are sporadic, but affected siblings suggest autosomal recessive
inheritance in some families.
 Most cases are sporadic, but affected siblings suggest autosomal recessive
inheritance in some families.
 Schirmer (1860) initially described a patient with a facial vascular nevus who had
associated buphthalmus but, he did not mention the CNS lesion.
 Sturge (1879) initially describe this syndrome by providing the clinical findings of 6
year-old girl with a facial nevus who also had angiomas of the lips, gingiva, palate,
floor of the mouth, uvula, & pharynx. The child had buphthalmos & was
hemiparetic, & Sturge suggested that she had a similar vascular nevus of the
underlying brain.
 Weber (1929) Associated intracranial calcification was later described.
 Sturge-Weber syndrome
 A neurocutaneous syndrome characterized by facial nevus (port-wine stain,
nevus flammeus), ipsilateral vascular anomalies & intracranial calcifications, &
contralateral hemiparesis, hemianopia, & seizures
 Incidence: 1/50,000
 Age of onset:
- nevus (birth),
- seizures (< l year)
Genetics
 Most cases are sporadic, but affected siblings suggest autosomal recessive
inheritance in some families.
 Other cases suggest an autosomal dominant pattern, with incomplete penetrance with
marked variability of the clinical manifestations.
 The gene locus has not yet been mapped.
 Although a port-wine stain on the face is a relatively common malformation,
occurring in about 3/1000, only 5% of affected infants have Sturge-Weber syndrome.

Clinical features
I.
Cutaneous Manifestations
Facial Nevus (Port Wine Stain)
 Capillary nevus that is flat & blanches on pressure, usually conforms to the
sensory distribution of the 1st & sometimes the 2nd &/or the 3rd divisions of the
trigeminal nerve.
 Some authors suggested that the distribution of facial angioma is determined by
embryologic development of a facial cleft.
 The facial angioma can extend to other facial areas including the lips, gingiva,
palate, tongue, pharynx, & larynx.
 Moreover, the neck, trunk & extremities can also be involved either ipsilaterally
or contralaterally to the facial angioma
II. Neurological Manifestations
1. Seizures
- Contralateral partial or secondarily generalized seizures usually begin in the
first year of life. Increase in frequency & severity do not correlate with the
extent of cutaneous involvement
- Recurring Todd's paralysis which requires longer periods to recover with
eventual permanent paresis occurred in one third
2. Hemiparesis
393
-
Gradually develops contralateral to the facial nevus associated with
hemiatrophy of limbs, cortical sensory deficits & hemianopia spasticity
with pyramidal signs
3. Mental Retardation
- Progressive
- ? role of seizures vs the disease process itself
4. Hemianopia
III. Ocular Manifestations
1. Fundal Choroidal Angiomas
- affected area has a dark color
- dilated retinal veins, ectopia lentis, optic atrophy
- homonymous hemianopia (33%)
2. Others
- iris heterochromia
- congenital (buphthalmos) or acquired glaucoma (25-50%)
Investigations
1.
2.
3.
4.




Skull X-Ray
Intracranial calcifications in 90% (railroad track pattern)
CT/MRI
Leptomeningeal angiomatoses, atrophy of the cortex & calcification
Cerebral angiography
PET
VON HIPPEL-LINDAU DISEASE (VHL)
A neurocutaneous syndrome characterized by hemangioblastomas (cerebellar &
retinal), visceral cysts, & tumors.
Incidence: 1/36,000
Age of onset; any but usually in the 2nd decade
Risk factors:
 familial - autosomal dominant
 chrom.#: 3p25-p26
 gene: plasma membrane calcium-transporting ATPase isoform 2 (PMCA-2)
gene
 penetrance is almost complete by age 65 with delayed & variable expression
even within the same kindred
Diagnostic criteria:
1. more than 1 hemangioblastoma in the CNS
2. one hemangioblastoma in the CNS + visceral cyst or renal carcinoma
3. any manifestation with a family history
Clinical features:
I. Neurological Manifestations
1. CNS Hemangioblastomas
- 2% of all brain tumors
- 7-10% of all posterior fossa tumors
2. Cerebellar Hemangioblastomas (83%)
- mean age of onset is 32 yrs; before age 15 is rare
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-
may present with posterior fossa signs/symptoms
associated with polycythemia in 10-50% of patients
all children presenting with cerebellar hemangioblastomas have
VHL disease
3. Spinal Cord
- 2nd most frequent site of CNS hemangioblastomas
- present with abnormalities of proprioception, gait, & bladder
dysfunction
II. Ophthalmologic Manifestations
Retinal Hemangioblastomas (46%)
 may appear as early as the 1st decade but usually in 2nd (before the
presentation of cerebellar hemangioblastomas)
 may be multiple & bilateral
 no sex predilection
 Vision unaffected (if tumor in periphery)
 Visual impairment may occur with:
- macular involvement
- intraocular hemorrhage
- retinal detachment secondary to exudation
III. Others
1. Visceral Cysts
 tend to progress & become apparent during adult life
 pancreatic (72%)
 renal (59%)
 hepatic (17%)
 epididymis (7%)
2. Other Tumors
 Pheochromocytomas (17%)
 Renal cell carcinoma (51%)
 Neurofibromatoses
 Multiple endocrine neoplasia syndrome
Investigations
CT/MRI
 Cerebellar hemangioblastomas appear as cystic lesions with a vascular mural
nodule
 For visceral cysts & tumors
Arteriography
 To visualize blood supply to hemangioblastomas
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
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ATAXIA TELANGIECTASIA (AT)
It is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia,
choreoathetosis, proclivity to pulmonary infections & immunoincompetence,
associated with underdevelopment or absence of the thymus gland &
lymphoreticular neoplasm.
Incidence 1/40,000
Gene 11q22-23 autosomal recessive inheritance
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Fig (1) Café au lait spot
Fig 2: Crowe's sign
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Fig 3:Areolar neurofibromas
Fig 4:Plexiform neuromas
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Fig 5: Lisch nodules
Fig 6: MRI of Optic nerve Glioma
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Fig 7: Sarcomatous degeneration of pelveic neurofibroma
Fig 8: Osseous defects
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Fig9: Vascular anomalies. There is middle aortic coarctation & stenosis of superior right
renal artery, left renal artery & superior mesenteric artery
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