CADASIL, small vessel disease, stroke, dementia, migraine, NOTCH3 mutation.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common and recognized genetic form of small vessel disease. In its advanced form, it leads to vascular dementia. CADASIL is caused by mutations in the NOTCH3 gene; NOTCH3 protein is expressed in vascular smooth muscle cells, whose degeneration results in progressively impaired cerebrovascular autoregulation, hypoperfusion, and ischemia.

Migraine—often beginning around age 30—is the most common initial symptom in CADASIL and is reported in up to half of CADASIL patients (but is less common in Asian patients). About 80% of CADASIL patients with migraine have migraine with aura.

Transient ischemic attacks and stroke are reported in approximately 85% of symptomatic individuals. Mean age at onset of ischemic episodes is 45 to 50 years but the range at onset is throughout adulthood. Ischemic episodes typically present as a lacunar syndrome, but strokes may occur in the brainstem, in the hemispheres, or may be lacunar syndromes. Large vessel strokes have also been reported. Stroke volume burden is associated with the manifestations of the vascular dementia which often includes gait disturbance, urinary incontinence, pseudobulbar palsy, and cognitive impairment.

Encephalopathy, cognitive impairment, and psychiatric disturbances are common in CADASIL. An acute encephalopathy evolving from a migraine attack may be a presenting symptom in about 10% of patients. It is commonly mistaken for encephalitis or other causes of acute delirium. Cognitive deficits often begin with executive dysfunction, although memory is eventually affected; cortical signs are less common and cortical infarcts can occur. Psychiatric symptoms of apathy and depression are also common.

The diagnosis of CADASIL is often suspected from the clinical presentation coupled with a brain MRI showing extensive white matter changes, with frequent involvement of the anterior temporal pole and external capsule. No abnormality is pathognomonic, but confluent bilateral anterior temporal pole T2-hyperintensities are highly suggestive. Definitive diagnosis is via genetic testing for NOTCH3 mutations. An autosomal recessive variant—cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)—has been described, mainly in Japanese families, presenting with extensive white matter changes, dementia, alopecia, and low back pain due to mutations in the serine protease HTRA1.

There are no specific treatments for CADASIL although aspirin is often used, as in typical cerebral small vessel disease. A study of Donepezil yielded no clear cognitive benefit.


DiDonato I., Bianchi S., De Stefano N., et al. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. BMC Med. 2017;15:41. doi:10.1186/s12916-017-0778-8.

Caloric testing


Caloric testing, COWS, CUWD, vestibulopathy, vestibulo-ocular reflex, coma

Caloric testing is a method of assessing the integrity of the vestibulo-ocular reflex (VOR), particularly in comatose patients. The presence of nystagmus indicates that both vestibular and cortical inputs are intact.

Water that is colder or warmer than body temperature, when applied to the tympanic membrane, changes the firing rate of the ipsilateral vestibular nerve, causing ocular deviation and nystagmus. Cold water normally induces a slow ipsilateral deviation with contralateral “corrective” fast phases. Warm water induces a slow contralateral deviation and ipsilateral fast phases. Because the direction of nystagmus is conventionally described as the direction of the fast phase, the mnemonic cold opposite, warm same indicates the direction of caloric nystagmus for cold and warm stimuli. Bilateral irrigation induces vertical nystagmus; the mnemonic cold up, warm down refers to the fast phases.

Caloric testing may be done qualitatively at the bedside or quantitatively in a laboratory. Quantitative caloric testing is used to evaluate vestibular function. Bedside caloric testing is used (1) to establish the integrity of the ocular motor system in patients with an apparent gaze paresis, and (2) to evaluate altered states of consciousness. Caloric stimulation may be used to elicit vestibular eye movements if oculocephalic maneuvers (see VOR) have negative results or when a cervical injury is suspected.

Bedside caloric testing is performed after the external auditory canal has been examined, cerumen removed, and the patency of the tympanic membrane verified. The head is elevated 30 degrees from horizontal, aligning the lateral semicircular canal in the horizontal plane and maximizing amplitude of lateral horizontal nystagmus, if elicited. Water is gently injected with a syringe through a soft catheter inserted in the external auditory canal. Usually 1 mL of ice water is sufficient in alert patients and minimizes discomfort. Up to 100 mL of ice water can be used in unresponsive patients, and several minutes should be allowed for a response. Irrigation is repeated in the opposite ear after waiting at least 5 minutes for vestibular equilibration. Warm water (44°C) may also be used. Because of the risk of thermal injury, hot water should never be used.

Eye movements elicited by vestibular stimuli, whether with passive head rotation or caloric stimulation, may allow localization of lesions within the ocular motor system. Impaired movement of both eyes to one side occurs with lesions of the ipsilateral paramedian pontine reticular formation. Impaired abduction in one eye suggests a palsy of CN VI. Impaired adduction is seen in third-nerve palsies and in the eye ipsilateral to a medial longitudinal fasciculus lesion (internuclear ophthalmoplegia). Bilateral internuclear ophthalmoplegias cause, in addition to bilateral adduction weakness, impaired vertical vestibular eye movements. Eye deviation may occur in aberrant directions in patients with drug intoxication or structural disease of central vestibular connections.

As consciousness declines, the caloric stimulus-induced eye movements relate to the integrity of brainstem structures. Tonic eye deviation indicates integrity of brainstem function but impaired cortical inputs. Asymmetrical horizontal responses are interpreted as previously described and may give localizing information. Lack of any response may result from lesions of VOR pathways in the medulla or pons, the eighth CN, or the labyrinth or from drug intoxications, such as those resulting from vestibular suppressants (barbiturates, phenytoin, tricyclic antidepressants, or major tranquilizers) and neuromuscular blockers. The presence of caloric-induced nystagmus in an unresponsive patient suggests a psychogenic etiology.


Gonçalves D.U., Felipe L., Lima T.M. Interpretation and use of caloric testing. Braz J Otorhinolaryngol. 2008;74:440–446.

Cardiopulmonary arrest (See also brain death, COMA)


Coma, CPR, prognosis, brain death

The outcome for patients with cardiac arrest remains poor despite improved resuscitation practices. Accurate prediction of neurologic outcome in comatose patients following cardiac arrest is of great importance not only to help families with decision-making but also to avoid prolonged use of health care resources in patients with invariable poor outcome.

The 2006 American Academy of Neurology (AAN) practice parameters for prediction of outcome in comatose survivors after cardiopulmonary resuscitation (CPR) provide very useful prognostication guidelines. However, these guidelines were based on studies done before the widespread use of hypothermia, and neurologists should be cautious when providing prognostication in such patients. Delay in making decisions about prognostication might be appropriate in patients undergoing hypothermia.

According to AAN practice guidelines, prognosis cannot be made based on circumstances of CPR or elevated body temperature alone. There is not enough evidence to make clinical decisions based on abnormal S100 levels, or that creatine kinase brain isoenzyme predicts poor outcome. Similarly, there is also not enough evidence that abnormal brain imaging accurately predicts poor recovery.

The prognosis is invariably poor in comatose patients with absent pupillary or corneal reflexes, or absent extensor motor responses at 3 days after cardiac arrest. Patients with myoclonic status epilepticus within the first day after cardiac arrest have a poor prognosis. There is good evidence that absent N20 component of the somatosensory evoked potential within 1 to 3 days after CPR accurately predicts poor recovery from coma.


Wijdicks E.F. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;67(2):203–210.

Carotid-Cavernous fistula


Carotid-cavernous fistula, cavernous sinus, angiography, carotid artery, embolization, shunt


A carotid-cavernous fistula (CCF) is an abnormal shunt between the carotid artery or its branches and the cavernous sinus (CS).


Classification is based on etiology (traumatic vs. spontaneous), flow rate (high vs. low flow) or vessel architecture (direct vs. indirect). Barrow classification of CCF defines four types based on arterial supply:

Type A (most common type): direct fistula from internal carotid artery (ICA) to CS. Usually high-flow and traumatic; 20% to 30% are spontaneous, mainly in older women.

Type B and C are supplied only by dural branches of the ICA and external carotid artery (ECA) respectively.

Type D: supplied by meningeal branches of both ICA and ECA.

Clinical features

Dandy’s clinical triad of pulsatile exophthalmos, chemosis, and orbital pain is common in direct, high-flow CCF. Cranial nerve (V, IV, III, and VI) deficits are common, especially double vision. Resultant ipsilateral venous hypertension may result in vision loss, and intracerebral or subarachnoid hemorrhages. Massive, even life-threatening epistaxis may also occur in 1% to 2% of cases. Indirect CCFs manifest as chronic conjunctival injection and are usually caused by sinus thrombosis.


Computed tomography angiography and magnetic resonance angiogram are used for workup, but conventional digital subtraction angiography (DSA) (Fig. 11) is essential for diagnosis, classification, and treatment planning.

Figure 11
Figure 11 Pre- (left) and post- (right) treatment.
Note retrograde flow in superior ophthalmic vein and inferior venous drainage pre-treatment (left).


Symptomatic high-flow direct CCFs are considered emergencies. First-line treatment is endovascular (stent-assisted coil embolization or flow diversion), although surgery, radiosurgery, or ICA sacrifice can be done in refractory cases. Low-flow indirect CCFs are usually treated medically, and many resolve spontaneously.

Carotid stenosis (See also ischemia)


Carotid stenosis, carotid stenting, carotid endarterectomy, carotid disease, arotid plaque, carotid atherosclerosis


As many as 20% to 30% of strokes are due to carotid artery disease. The clinical presentation of cerebral ischemia is explained in the discussion of stroke under “Ischemia.” Briefly, a stroke or transient ischemic attack (TIA) has to be related to the territory of the stenosed artery to be symptomatic, as confirmed by a neurologist. Amaurosis fugax, as well as middle cerebral artery and/or anterior cerebral artery TIAs/minor or major strokes, are common.


The gold standard is a diagnostic cerebral angiogram, followed by a computed tomography angiogram, magnetic resonance angiogram, and carotid ultrasound (its reliability in routine daily practice is not as effective as has been shown in clinical studies). However, a carotid ultrasound is routinely used for surveillance of asymptomatic carotid stenosis due to its cost-efficient and non-invasive nature.


Approaches to therapy include surgery and stenting in appropriate settings, but medical therapy is a critical component of managing carotid artery disease. Ideal medical therapy for carotid stenosis includes antiplatelet therapy with daily aspirin, angiotensin-converting enzyme inhibitor, and statin (regardless of lipid panel status). Smoking cessation and intensive treatment of diabetes are crucial aspects of therapy as well. Four randomized studies treating symptomatic carotid stenosis comparing carotid endarterectomy (CEA) to aspirin showed that patients with symptomatic severe stenosis (50%–70%) benefited from revascularization, with an absolute risk reduction of 17% over 2 years and with numbers needed to treat to achieve a benefit of 3 to 6. Patients with asymptomatic carotid stenosis less than 50% are best managed medically. Combined surgeon and surgical center perioperative morbidity and mortality rates should be below 3% in order for surgical intervention to be favorable for asymptomatic patients.

Carotid angioplasty and stenting are currently indicated for high-risk surgical patients; the most common indications are as follows:

  1. I. Anatomic indication: infraclavicular lesions in the chest, high lesion (at the angle of jaw/C2 or higher), tandem lesion with 50% or higher diameter stenosis
  2. II. Prior radiation to the neck
  3. III. Prior neck surgery and dissection
  4. IV. Prior CEA
  5. V. Contralateral high-grade stenosis or occlusion
  6. VI. Contralateral cranial nerve palsy and hoarseness from neck surgery or nerve injury
  7. VII. Co-morbidities, coronary artery disease, congestive heart failure, ejection fraction less than or equal to 30%, severe chronic obstructive pulmonary disease, poorly controlled diabetes mellitus, end-stage renal disease
  8. VIII. Patients older than 75 years of age

For low surgical risk group, it has been shown to be equivalent to CEA in the Carotid Revascularization Endarterectomy vs. Stenting Trial; however, patients younger than 70 years of age tend to do better with stenting and those older than 70 years of age tend to do better with CEA in this low surgical group. Well-trained and experienced neurointerventionalists who can address potential procedural complications, as well as surgeons experienced in CEA, are critical in achieving good procedural and surgical outcomes over medical therapy alone. The use of a distal embolic protection device is recommended.

Carpal tunnel syndrome


Carpal tunnel, pain, pregnancy, EMG, surgery, hand, Tinel’s test, Phalen’s test

Carpal tunnel syndrome (CTS) occurs as a result of compression of the median nerve as it courses beneath the transverse carpal ligament (Fig. 12). Occupational trauma from repetitive motion is a common cause. Inflammatory and infiltrative conditions like arthritis and tenosynovitis; structural lesions like ganglion and neuroma; systemic diseases like hypothyroidism, amyloidosis, and mucopolysaccharidoses; and fluid-overload states such as pregnancy and obesity can be associated with CTS. Often, no apparent cause is identified (idiopathic). Half of the cases are bilateral, and the dominant hand is affected more. Causes other than idiopathic should be considered if CTS is worse in the nondominant hand. CTS prevalence is about 276 per 100,000 person-years. More than 80% of patients are over 40 years old, and 65% to 75% are women.

Figure 12
Figure 12 Distal motor and sensory branches of the median nerve. (From Preston, D. C., & Shapiro, B. E. (2013). Median neuropathy at the wrist. In Electromyography and neuromuscular disorders, ed 3. London: Elsevier, pp. 267–288. Chapter 17, Fig. 17.3.)

Patients characteristically complain of nocturnal numbness and paresthesia or burning pain in the median distribution (but which may radiate to the forearm, elbow, or shoulder). Weakness and atrophy of the opponens pollicis, abductor pollicis brevis, and first two lumbricals and loss of two-point discrimination are late signs of long-term involvement. The symptoms may be reproduced by tapping over the median nerve at the carpal tunnel (Tinel’s sign) or by maximum flexion of the wrist for 60 seconds (Phalen’s sign). Awakening from sleep and needing to shake the affected hand is characteristic. Nerve conduction studies show prolongation of distal median sensory and motor latencies across the wrist. A difference in latencies of ≥ 0.4 ms between the distal median and ulnar nerves measured by “palmar mixed comparison study” is the most sensitive electrodiagnostic feature (Table 20). Ultrasound of median nerve or magnetic resonance imaging of wrist can reveal structural lesions.

Table 20

Electrodiagnostic features of carpal tunnel syndrome
Study Stimulation Site Recording Site Findings Significance
Median nerve sensory Wrist Index finger Slowing of conduction (prolonged latency or reduced CV), reduced SNAP amplitudes Compression at the wrist causing demyelination and/or axonal loss
Median nerve motor Wrist and elbow APB at the ball of the thumb Slowing of conduction (prolonged latency or reduced CV), reduced CMAP amplitudes Compression at the wrist causing demyelination and/or axonal loss
Median F-waves Wrist APB muscle Prolonged minimum F-waves Slowing or blocking of F-waves at the wrist
Ulnar sensory Wrist Little finger Normal Ulnar nerve is unaffected at wrist
Ulnar motor Wrist ADM muscle Normal Ulnar nerve is unaffected at wrist
Ulnar F-waves Wrist ADM muscle Normal Ulnar nerve is unaffected at wrist
Median-ulnar palmar comparison 8 cm from wrist in the palm along the ulnar sensory distribution and median sensory distribution Wrist, over the ulnar and median sides of the wrist Difference of ≥ 4 ms between median and ulnar peak latencies Median conduction through the wrist is slower than that of ulnar

Table 20

Note: Coexisting ulnar nerve neuropathy can affect these studies and should be interpreted in its context. Axonal neuropathies such as in diabetes can also confound these studies. Additional nerves are studied in cases of suspected polyneuropathy.

ADM, Abductor digiti minimi; APB, abductor pollicis brevis; CMAP, compound muscle action potential; CV, conduction velocity; SNAP, sensory nerve action potential.

Differential diagnosis includes degenerative arthritis at the wrist, more proximal median neuropathies, mononeuritis multiplex, C6 or C7 radiculopathy, brachial plexopathy, thoracic outlet syndrome, and polyneuropathies. Evaluation for underlying causes is dependent on clinical presentation and should be individualized.

Treatment consists of avoiding activities that precipitate symptoms and wearing a wrist extension splint at night. Local steroid injections with or without lidocaine may provide limited relief but may worsen symptoms. Indications for surgery are weakness, atrophy, or electromyography evidence of denervation. Surgical treatment, which can be done by either open or endoscopic approach, is usually not necessary during pregnancy as symptoms resolve spontaneously.


Ghasemi-rad M., Nosair E., Vegh A., et al. A handy review of carpal tunnel syndrome: from anatomy to diagnosis and treatment. World J Radiol. 2014;6(6):284–300.

Preston D.C., Shapiro B.E. Median neuropathy at the wrist. In: Electromyography and neuromuscular disorders: clinical-electrophysiologic correlations. London: Elsevier; 2013:267–288.

Catamenial epilepsy


Catamenial epilepsy, neurosteroids, menstrual cycle

Catamenial epilepsy is a resistant form of epilepsy during which a woman is more likely to have seizures during a particular phase of her menstrual cycle. Seizures or seizure clusters tend to occur during or immediately before menses, or around ovulation. Metabolites of steroid hormones such as progesterone enhance gamma amino butyric acid-A (GABA-A) receptor function. Fluctuation of these hormones during the menstrual cycle is thought to lead to an increase in seizure susceptibility, and a reduction in the therapeutic effect of commonly prescribed anticonvulsants.

Estimates of prevalence among women with epilepsy range from 12.5% to 78%. Three patterns have been identified (Fig. 13):

  •  Perimenstrual (C1), with more seizures during days −3 to + 3 compared with other phases. Perimenstrual is the most common form of catamenial epilepsy.
  •  Periovulatory (C2), with greater than average daily seizure frequency during days 10 to −13 in normal cycles.
  •  Luteal (C3), marked by frequent seizures within 14 days before menstruation during inadequate luteal phase cycles.

Figure 13
Figure 13 The three subtypes of catamenial epilepsy.

To diagnose catamenial epilepsy, ask the patient to keep a diary that tracks seizures in relation to menses; check progesterone level during seizures.

Treatment consists of antiepileptic drugs, acetazolamide, and hormonal therapy depending upon the subtype of catamenial pattern. Be wary of giving progesterone to those interested in becoming pregnant. Refer to Fig. 14.

Figure 14
Figure 14 Treatment algorithm for catamenial epilepsy. (From Navis, A., & Harden, C. (2016). A treatment approach to catamenial epilepsy. Curr Treat Options Neurol, 18(7), 30.)


Navis A., Harden C.A. Treatment approach to catamenial epilepsy. Curr Treat Options Neurol. 2016;18(7):30.

Reddy D.S. The neuroendocrine basis of sex differences in epilepsy. Pharmacol Biochem Behav. 2017;152:97–104.



Cerebellum, dentate nucleus, fastigial nucleus, nucleus interpositus, Purkinje cells, cerebellar cortex, ataxia, nystagmus, vertigo

General anatomy: The cerebellum makes up 10% of the brain’s total weight and volume, but contains approximately 50% of all brain neurons.

The anterior lobe, rostral to the primary fissure, is made up of the paravermian cortex and the anterosuperior vermis which receives proprioceptive information from muscle and tendons via the dorsal spinocerebellar tracts (from lower limb) and ventral spinocerebellar tracts (upper limb) to modulate posture and muscle tone.

The posterior lobe, caudal to the primary fissure, contains the middle vermis and its lateral extensions. Inputs from the cerebral cortex via the pontine nuclei and brachium pontis are processed to modulate coordination.

The flocculonodular lobe, inferiorly separated from the main cerebellum by the posterolateral fissure, receives proprioceptive input from the vestibular nuclei for control of equilibrium.

The cerebellum may also be divided into longitudinal zones which project to the deep nuclei of the cerebellum. The vermis projects to the fastigial nuclei, intermediate zone to the interpositus nuclei and lateral zone to the dentate nucleus. Refer to Fig. 15A and B.

Fig. 15
Fig. 15
Figure 15 The cerebellum has three functional components (vestibulocerebellum, spinocerebellum, and cerebrocerebellum) with different outputs (A) and inputs (B).

Deep cerebellar nuclei

The dentate nucleus receives afferent from the premotor and supplementary motor cortex via pontocerebellar system and sends efferents to the contralateral ventrolateral thalamus which projects to the motor cortex for the initiation of volitional movements.

The interpositus nucleus receives input from the pontocerebellar system as well as the spinocerebellar system (Golgi tendon organs, muscle spindles, cutaneous afferents, and spinal cord interneurons) to fine tune movement and is involved in control of physiological tremor.

The fastigial nucleus sends output to the bilateral vestibular nuclei and reticular formation as well as alpha and gamma motor neurons in the spinal cord to maintain antigravity and modulate standing and walking synergies.

Cellular anatomy: The cerebellar cortex is composed of three layers and five types of neurons.

The outermost molecular layer contains two types of inhibitory cells, stellate and basket, which are scattered among dendrites of Purkinje cells.

The middle layer is composed of Purkinje cell bodies, which as the primary output of the cerebellum, sends inhibitory signals to the deep cerebellar nuclei.

The innermost granular layer contains densely packed granule cells and larger Golgi interneurons. Axons of granule cells send excitatory output to the Purkinje cells and are the only neurons to send excitatory signals among all five cell types.

Mossy fibers carry input from axons of spinocerebellar tracts, pons, vestibular and reticular nuclei to send excitatory signals to the granule layer. Their primary neurotransmitter is aspartate.

Climbing fibers receive afferent from the crossed inferior olivary nuclei and send excitatory signal on to Purkinje as well as stellate and basket cells.

Clinical presentation of cerebellum lesions

Cerebellum lesions disturb the rate, range, and force of an action to cause undershooting or overshooting and fragmentation of smooth movements into irregular jerks. Often the velocity and force of an action is affected. Common signs seen in testing include ataxia of volitional movement, dysdiadochokinesis, and a type of intentional tremor which is composed of (increasing) horizontal oscillations when approaching target (e.g., finger to nose testing). With acute lesions, muscle tone tends to be diminished. When deep nuclei or cerebellar peduncles are affected, especially if dentate or the superior cerebellar peduncle, the clinical picture may mimic that of an extensive cerebellar hemispheric lesion. Lesion of the cerebellar cortex and subcortical white matter, on the other hand, may cause minimal if any clinical signs.

Gait: With lesion of the anterior vermis, the patient may walk with uneven steps and lurch due to misaligned foot placement. Midline anterior cerebellar lesions may present solely as gait disturbance without any other associated features, so anyone suspected of a cerebellar lesion should have gait tested if possible.

Speech: Cerebellar dysarthria is characterized by slow scanning disrupted speech, a breakdown of words into syllables, and explosive speech with various changes in intonation.

Eyes: Testing of extraocular movements may demonstrate loss of smooth pursuit with rapid repetitive saccades. Periodic alternating nystagmus is one of the few lesions associated with cerebellar lesions, in this case of the flocculonodular lobe.

Causes of cerebellar dysfunction include congenital lesions, childhood tumors (e.g., medulloblastoma), multiple sclerosis, paraneoplastic syndromes (e.g., anti-Purkinje cell antibodies), stroke and hemorrhage, metastatic lesions, medication and drug effects (e.g., alcohol, ARA-C chemotherapy, Dilantin toxicity), and Arnold-Chiari malformations and other developmental abnormalities. Cerebellar-type lesions can be caused by focal dysfunction in afferent and efferent structures and pathways in the brainstem, vestibular nuclei, and thalamus.

Cerebral aneurysms


Cerebral aneurysm, aneurysm


Cerebral aneurysms occur in approximately 5% of the general population (9% in first-degree relatives). The ratio of ruptured to unruptured is approximately 1:1, although the number of incidentally discovered aneurysms may be increasing with the widespread use of magnetic resonance imaging and computed tomography angiography. Most are believed to be acquired, with only 2% occurring during childhood. An increased incidence of cerebral aneurysms is associated with various collagen synthesis disorders, such as Ehlers-Danlos syndrome, Marfan syndrome, autosomal dominant polycystic kidney disease (15%), α1-antitrypsin deficiency, and neurofibromatosis type 1.


Saccular aneurysms are responsible for most subarachnoid hemorrhages. Fusiform aneurysms and mycotic aneurysms are less common. Fusiform aneurysms consist of dilation of the entire involved vessel. Atherosclerosis can lead to fusiform aneurysm. Mycotic aneurysm is formed as a result of infected embolus usually due to ineffective endocarditis. Saccular aneurysms occur along bends in the artery, or at arterial branch points, in direct line with the blood flow. The underlying defect appears to be fragmentation of the internal elastic lamina and absent muscularis at the aneurysm neck; the aneurysm wall is composed of a thin adventitia with or without an inner endothelium.

Eighty-five percent occur in the anterior circulation, and 15% in the posterior circulation. They are evenly divided among midline, right, and left. The most common locations are the anterior or posterior communicating artery (25%–30% each, depending on the study), middle cerebral artery (20%), and basilar artery (10%). Multiple aneurysms occur in 20%, usually at mirror locations.

Clinical presentation

The overall risk of aneurysm rupture is 0.5% to 1% per year. This risk is dependent on size, history of prior ruptured aneurysm, and location. The risk is 0.5% to 1% per year if less than 7 mm in diameter and 1% to 2% per year if greater than 7 mm in diameter; the risk then increases with increasing size. Previous subarachnoid hemorrhage from another aneurysm is associated with 1% to 2% per year, regardless of size, and an 8- to 10-fold relative risk increase in posterior circulation and posterior communicating artery. Tobacco smoking is associated with a 3- to 10-fold increased risk of rupture and is the only environmental factor definitively linked with rupture.


Treatment involves a team approach with the neurologist, neurointerventionalist, and neurosurgeon to consider potential aneurysm clipping versus endovascular coiling or observation.

Cerebral cortex


Allocortex, mesocortex, isocortex, Broadman areas, insular lobe

The cerebral cortex (from the Latin word for bark) is made up of a total of six lobes, five of which are exposed on the surface of the cerebral hemispheres, and are named according to the respective abutting skull bones. The sixth lobe (insular) is located internal to the lateral sulcus mantle of gray matter on the cerebral surface. Based on the difference in number of cell layers, the cerebral cortex can be divided into allocortex (three layers), mesocortex (three to six layers), and isocortex (six layers). The isocortex can further be divided into functionally relevant areas (Brodmann areas) based on cytoarchitectonics. Fig. 16 shows Brodmann areas in lateral and medial views.

Figure 16
Figure 16 Brodmann’s cytoarchitectural map of cerebral cortex, indicating major functional areas. 4, Primary motor strip; 3, 1, and 2, sensory strip; 17, primary visual cortex; 18 and 19, visual association cortex; 8, frontal eye fields; 6, premotor cortex; 41 and 42, auditory cortex; 5 and 7, somesthetic association cortex. Areas 13 to 16 (not shown) make up the insula. Labeling is from anterior to posterior. (A) Lateral view of brain. (B) Medial view of brain. (From Carpenter, M. B. (1991). Core text of neuroanatomy, ed 4. Baltimore: Williams & Wilkins.)


Simić G., Hof P.R. In search of the definitive Brodmann’s map of cortical areas in human. J Comp Neurol. 2015;523(1):5–14.

Cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage


Intracerebral hemorrhage, aneurysm, subdural hemorrhage, epidural hemorrhage, aneurysm, neurosurgery, putamen, thalamus, brainstem, cerebellum, trauma, amyloid angiopathy


Primary intracranial hemorrhage (ICH) accounts for 10% to 15% of all strokes. The annual incidence is 10 to 20 cases per 100,000 people with a prevalence of 37,000 to 52,000 cases per year in the United States. ICH is more common in persons older than 55 years of age, men, African-Americans, and Japanese. Chronic hypertension is a common cause, often due to lipohyalinosis of the small intraparenchymal arteries, resulting in arteriolar wall weakness and subsequent rupture. Locations of hemorrhage in order of frequency are as follows: putamen (35%–50%), subcortical white matter (30%), cerebellum (15%), thalamus (10%–15%), and pons (5%–12%). The active bleeding usually lasts only a short time, and later clinical deterioration is most often ascribed to surrounding edema and ischemia, rather than continued hemorrhage; however, up to 25% of patients have hematoma expansion.

Intracranial hemorrhage risk factors

Risk factors are hypertension, excessive use of alcohol, low serum cholesterol (< 160 mg/dL), amphetamine and cocaine use, and genetic predilection (mutation of a subunit of factor XIII, β amyloid deposition in blood vessels, and presence of e2 and e4 alleles of apolipoprotein E) and cerebral amyloidosis.

Clinical features

The clinical presentation correlates with anatomic location, size, and degree of associated mass effect (Table 22). Headache is a frequent accompanying symptom. Classic symptoms vary by location:

  1. 1. Putamenal hemorrhage is associated with dense ipsilateral hemiplegia, hemianesthesia, and homonymous hemianopsia with aphasia or neglect (depending on which hemisphere is involved). There is also decreased level of consciousness (disproportionate to the weakness), ipsilateral eye deviation, and normal pupils.
  2. 2. Thalamic hemorrhage can be highly variable and may produce dense contralateral hemisensory loss with variable hemiparesis, contralateral homonymous hemianopia, vertical or lateral-gaze palsies (including “wrong way” deviation), and occasionally, nystagmus.
  3. 3. Cerebellar hemorrhage is associated with severe occipital headache, sudden nausea and vomiting, gait changes, and truncal ataxia. It is a potential neurosurgical emergency when brainstem compression is imminent or for lesions greater than 3 cm in diameter. Emergency decompressive surgery may be indicated to relieve signs of brainstem compression or acute hydrocephalus.
  4. 4. Pontine hemorrhage causes coma, pinpoint pupils (reactive to light), bilateral extensor posturing, and impaired ocular motility.


  1. I. The size is estimated based on the computed tomography (CT) findings using the simple volumetric formula: ABC/2 (A = width, B = length, C = height). Angiography may be necessary to exclude underlying vascular malformation or tumor.


Immediate attention must be directed at the ABCs: airway, breathing, and circulation. Patients with a Glasgow coma score (GCS) of 8 or less or an impaired gag reflex need rapid sequence intubation. Sedation with short-acting drugs (midazolam) prevents the intracranial pressure (ICP) spikes and allows frequent neurologic checks.

  1. I. Blood pressure management is critical. Judicious lowering of the BP is indicated, although the BP goals and agents to use are controversial. Many authors favor the calcium channel blocker nicardipine starting at 3 to 5 mg/hour to keep systolic BP 140 to 160 mm Hg or mean arterial pressure (MAP) around 100 mm Hg to keep cerebral perfusion pressure above 60 mm Hg. Other agents that are easily titratable with limited ICP changes have been used: labetalol, enalapril, and hydralazine. Patients with chronic severe hypertension with autoregulation curve shifted to the right require higher MAP.
  2. II. Adequate ventilation, oxygenation, and pulmonary/pharyngeal toilet must be maintained.
  3. III. Antiedema agents (osmotic diuretics or hypertonic saline) may be used. Mass effect may be managed medically with hyperosmolar therapy, typically only for up to three days. Patients who are not clinically improving or holding stable may require surgical decompression.
  4. IV. Intraventricular instillation of thrombolytic agents to aid dissolution of mainly intraventricular clot remains controversial.
  5. V. Procoagulants such as factor VII (rFVIIa) have not yielded favorable clinical results that can be reproduced.
  6. VI. Neurosurgical evaluation should be obtained for superficially located cerebral hemorrhages and all cerebellar hemorrhages, for placing ICP monitors, external ventricular drainage for obstructive hydrocephalus and intraventricular hemorrhage and possibility of intraventricular recombinant tissue plasminogen activator.
  7. VII. Other supportive measures: Prophylactic use of anticonvulsant agents is no longer recommended in the treatment of patients with ICH. Clinical seizures should be treated, and patients for whom subclinical seizures are suspected should be evaluated with continuous electroencephalogram monitoring for at least 48 hours, if available. Maintain adequate fluid and electrolyte balance. Raise the head of the patient’s bed 30 degrees, barring contraindications due to spinal injury. Correct underlying coagulopathy if present. Prophylaxis for stress ulcer involves proton pump inhibitor, and for deep vein thrombosis pneumatic sequential compression devices are needed.

Prognosis and complications

Death from ICH is usually due to mass effect with herniation or brainstem compression and brainstem hemorrhages. Common ICH complications are hematoma expansion (20%–40% within the first 24 hours, 25% within the first hour), intraventricular extension, and edema with shift, obstructive hydrocephalus, and increased ICP. ICH has the highest mortality rate of all strokes (23%–58% at 6 months). The main predictors of fatality are (1) GCS at presentation; (2) hematoma volume; and (3) intraventricular extension. Mortality rate varies from 17% (GCS > 9 and hematoma volume < 30 mL) to 90% (GCS < 9 and hematoma volume > 60 mL). A survivor’s long-term functional prognosis may be better than for infarction because there is more reversible injury. The 2015 American Heart Association/American Stroke Association (AHA/ASA) guideline recommends not discussing new do not resuscitate (DNR) status on ICH patients until, at the earliest, hospital day 2. They specify, “Current prognostic models for individual patients early after ICH are biased by failure to account for the influence of withdrawal of support and early DNR orders.”

Other causes of intraparenchymal hemorrhage (Table 23) include the following:

  1. I. Trauma (accounts for up to 50% of nonhypertensive cerebral hemorrhage)
  2. II. Ruptured arteriovenous malformation
  3. III. Ruptured aneurysm with parenchymal extension
  4. IV. Metastatic carcinoma, especially lung, choriocarcinoma, melanoma, and renal adenocarcinoma
  5. V. Primary neoplasms (glioblastoma multiforme, pituitary adenoma)
  6. VI. Embolic infarction with secondary hemorrhage (up to one third of embolic infarcts)
  7. VII. Hematologic disorders, including leukemia, lymphoma, thrombocytopenic purpura, aplastic anemia, sickle cell anemia, hemophilia, hypoprothrombinemia, afibrinogenemia, and Waldenström macroglobulinemia
  8. VIII. Anticoagulant therapy
  9. IX. Cerebral amyloid angiopathy. This usually presents as multiple, recurrent hemorrhages in the white matter or cortex, sparing deep gray matter (as opposed to hypertensive hemorrhages). Amyloid angiopathy may be the cause in 5% to 10% of sporadic intracerebral hemorrhages. It is associated with dementia in about 30% of cases; familial cases are associated with mutations in the amyloid precursor protein on chromosome 21 (Dutch and Icelandic forms). Attempts at surgical evacuation are usually futile because the vessels are very fragile, bleeding is very difficult to control, and there is a high incidence of recurrent hemorrhages.
  10. X. Vasculopathies such as lupus, polyarteritis nodosa, and granulomatous arteritis
  11. XI. Cortical vein thrombosis with secondary hemorrhage
  12. XII. Drugs, including methamphetamine, amphetamine, pseudoephedrine, phenylpropanolamine, and cocaine

Other forms of ICH

Subarachnoid hemorrhage occurs with an incidence of 15:100,000 with peak incidence at 55 to 60 years of age. The majority of cases are due to rupture of cerebral aneurysm or trauma (see Aneurysm for further discussion).

Subdural hemorrhage (SDH) may be acute or chronic. Acute SDH is usually due to trauma with tearing of bridging veins in the subdural space. There may be an initial loss of consciousness with regaining of consciousness (lucid interval) followed in several hours by progressive deterioration of mental status and headache. Lateralizing signs may be present. Diagnosis is based on clinical course, emergency CT (appears as hyperdensity over cortex), and if necessary, angiography. Treatment consists of neurosurgical evacuation and correction of underlying coagulopathies (if present). Dialysis patients and alcoholics are particularly prone to develop SDH.

Chronic SDH is less clearly related to trauma and may follow minor head trauma in the elderly and in patients on anticoagulants. Symptoms and signs resemble those in acute SDH but develop gradually over several days to months. Lateralizing signs are common. Mental status changes may suggest dementia. Diagnosis is as for acute SDH, although the lesion on CT is usually hypo- or isodense. Treatment is neurosurgical evacuation. The prognosis for survival and recovery in surgically treated patients is generally good, but SDH may recur.

Acute epidural hemorrhage results from skull fracture with laceration of the middle meningeal artery and vein. The clinical course is similar to acute SDH but is more rapidly progressive. Rapid herniation, respiratory depression, and death may ensue. The diagnosis is established emergently as for acute SDH. The CT appearance is a convex hyperdensity. This hemorrhage is a neurosurgical emergency and is treated by immediate evacuation.

Cerebral palsy


Cerebral palsy, spasticity, seizures, disability

Cerebral palsy (CP) refers to a heterogenous group of early-onset nonprogressive disorders of the central nervous system manifested primarily by neuromotor impairment. It is the most common cause of physical impairment in children. CP shares a significant overlap with many developmental conditions, and is thus a diagnosis of exclusion with five key elements: (1) a group of disorders with (2) abnormality in fetal/infant brain, which is (3) permanent, although not unchanging, (4) nonprogressive, and (5) affecting movement/motor function. It is often accompanied by multiple comorbidities (particularly its severe forms), e.g., cognitive impairment, epilepsy (30%), hearing (20%) or vision loss (25%–30%), feeding difficulty, and behavioral disturbances.

Risk factors for development of CP include probable genetic disorders (up to one-third), prematurity, intrauterine growth restriction, maldevelopment, placental abnormalities, intrauterine infections, perinatal stroke, tight nuchal cord, multiple gestations, prolonged shoulder dystocia, and intrapartum hypoxia.

CP classification has been traditionally based on neurologic examination into different forms, including spastic, dyskinetic, ataxic, hypotonic, and atonic. The more recent Gross Motor Function Classification System is based on differences in ambulation, from level I (most able) to level V (least able).

The mainstay of treatment is physical therapy and orthoses. Surgery involves tendon release and transfer. Spasticity is treated with baclofen, diazepam, clonidine, tizanidine, or botulinum toxin injections. Dyskinesia treatment is challenging, but trihexyphenidyl and intrathecal baclofen can be tried. Seizure treatment must account for higher sensitivity to sedative and cognitive effects or antiepileptic drugs in CP patients.

Prognosis depends on the severity of the disease; however, improved medical care has extended the quality of life for even the most affected patients.


Smithers-Sheedy H., Badawi N., Blair E., et al. What constitutes cerebral palsy in the twenty-first century?. Dev Med Child Neurol. 2014;56(4):323–328. doi:10.1111/dmcn.12262.

MacLennan A.H., Thompson S.C., Gecz J. Cerebral palsy: causes, pathways, and the role of genetic variants. Am J Obstet Gynecol. 2015;213(6):779–788. doi:10.1016/j.ajog.2015.05.034.

Cerebral salt-wasting syndrome


Cerebral salt-wasting syndrome (CSW), subarachnoid hemorrhage (SAH), syndrome of inappropriate ADH secretion (SIADH)

Cerebral salt-wasting syndrome (CSW) is defined as renal sodium wasting leading to hyponatremia and a decrease in extracellular fluid volume.

Not all patients with hyponatremia have syndrome of inappropriate ADH secretion (SIADH) with resultant free water retention; instead, they have inappropriate natriuresis.

CSW is associated with numerous intracranial pathologies, such as primary cerebral tumors, carcinomatous meningitis, head trauma following intracranial surgery, and pituitary surgery, but it has most commonly been studied as subarachnoid hemorrhage. The mechanism underlying this association has not yet been clearly identified. The following mechanisms have been proposed: renin–angiotensin–aldosterone system, sympathetic nervous system hypothesis, and natriuretic peptide theory, including atrial natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide, and dendroaspis natriuretic peptide.

It is important to recognize this syndrome as CSW is one of the most commonly encountered electrolyte disturbances in the neurologic intensive care unit, and the treatment is different from SIADH. It is not possible to distinguish CSW from SIADH based on serum and urine laboratory findings alone. Differentiation is done by careful assessment of volume status (Table 24).

Classical signs and symptoms of hypovolemia include hypotension, orthostatism, lassitude, increased thirst, and muscle cramps but all lack specificity. If there is any doubt regarding the diagnosis, fluid restriction should be instituted. Then, if the natriuresis persists, cerebral salt-wasting should be suspected and treated appropriately. The syndrome responds to vigorous sodium and water replacement. Other therapies such as vasopressin antagonists have recently been suggested with promising results, although long-term studies will be needed.


Cerdà-Esteve M., Cuadrado-Godia E., Chillaron J.J., et al. Cerebral salt wasting syndrome: review. Eur J Int Med. 2008;19:249–254.

Yee A.H., Burns J.D., Wijdicks E.F.M. Cerebral salt wasting: pathophysiology, diagnosis, and treatment. Neurosurg Clin N Am. 2010;21:339–352.

Cerebrospinal fluid


CSF, oligoclonal bands, lumbar puncture, LP, post LP headache, glucose, protein, xanthochromia, meningitis, subarachnoid hemorrhage


Cerebrospinal fluid (CSF) is produced mainly by the choroid plexuses (95%) but also in the interstitial space and ependyma (5%). The rate of CSF formation is about 500 mL/day, and total CSF volume is 150 mL (50% intracranial, 50% spinal). Secretion is an energy-requiring process related to ion exchange (Na/K). Production is also dependent on the cytosolic enzyme carbonic anhydrase. Therefore carbonic anhydrase inhibitors (e.g., acetazolamide, furosemide, topiramate) substantially reduce CSF formation. CSF is absorbed primarily by arachnoid villi extending into the dural venous sinuses. Normal CSF opening pressure during lumbar puncture (LP) should be less than 20 cm H2O (Table 25).


Normal CSF is clear and colorless (specific gravity 1.007, pH 7.33–7.35); when cell counts reach approximately 200 white blood cells (WBCs)/mm3 or 400 red blood cells (RBCs)/mm3, it may become cloudy. Viscous CSF can result from large numbers of cryptococci within the CSF, secondary to their polysaccharide capsules. Clot or pellicle formation occurs with elevated protein. Froin syndrome refers to clot formation in the setting of complete spinal block and very high protein. CSF is perceived as grossly bloody with cell counts greater than 6000 RBC/mm3, and at cell counts of more than 500, xanthochromia appears, which refers to the yellow, pink, or orange coloration of the CSF corresponding to the breakdown products of RBCs. Oxyhemoglobin released from RBCs can be detected within the supernatant fluid within 2 to 4 hours after the release of blood into the subarachnoid space; it reaches a maximum at about 36 hours and disappears in about 7 to 10 days. Supernatant fluid may, however, remain clear for up to 12 hours after a subarachnoid bleed. CSF can be analyzed with spectrophotometry or by visual inspection to rule out xanthochromia. The differential diagnosis of xanthochromia includes hyperbilirubinemia, hyperproteinemia, hypercarotenemia, and drugs (e.g., rifampin), though if there is clinical suspicion for subarachnoid hemorrhage (SAH) in the setting of a possible sentinel bleed or thunderclap headache, management should be directed toward a hemorrhagic cause such as a ruptured aneurysm.


Cytologic analysis must be done soon after LP. Prompt refrigeration is necessary. Lymphocytes are the predominant leukocyte forms in normal CSF. An occasional granulocyte is seen in normal fluid and is not necessarily pathologic if the total WBC count is normal (0–3 cells/mm3). A few or moderate numbers of granulocytes may occur following spinal anesthesia, myelography, or other intrathecal injections, or with trauma, hemorrhage, or infarct in the absence of infection.

No RBCs should be present in normal CSF. In a traumatic spinal tap, it is important to differentiate whether the WBCs are truly elevated or whether they are present in the same WBC/RBC ratio as in the peripheral blood. In a nonanemic patient, as an approximation, subtract 1 WBC for every 700 RBCs. Fishman’s formula can be used for correction of WBC counts in the presence of significant anemia or peripheral leukocytosis. It estimates the WBC count in the CSF before the LP (actual WBCCSF = WBCCSF ∞ RBCCSF/RBCblood). Detection of tumor cells is enhanced by collection of large volumes of CSF (20 mL), repeated CSF examination, and cisternal taps in suspected basilar meningitis.

Cerebrospinal fluid protein

CSF protein is a nonspecific indicator of disease. Normally, the blood-brain barrier keeps serum proteins out of the CSF (normal adult, 15–45 mg/dL). Many central nervous system (CNS) diseases disrupt the barrier, allowing entrance of serum protein and consequently elevation of CSF protein (see Table 21). Increases greater than 500 mg/dL are rare and occur mainly in spinal block, meningitis, arachnoiditis, and SAH. Metabolic conditions such as myxedema and diabetic neuropathy and Guillain-Barre syndrome may cause an increase in protein levels.

The major immunoglobulin in normal CSF is IgG. The IgG index and synthesis rate correct for serum IgG. Elevated levels may result from production within the CNS in various immune response disorders. Oligoclonal bands are not specific to one diagnosis and may indicate the presence of an immune-mediated pathologic process such as multiple sclerosis or, very rarely, subacute sclerosing panencephalitis. Serum should be drawn in conjunction with CSF collection to confirm that the oligoclonal banding is unique to the CSF. Oligoclonal bands occur in 80% to 90% of patients with clinically definite multiple sclerosis, but oligoclonal bands are less important than the clinical history and imaging findings in making the diagnosis. Myelin basic protein, a product of oligodendroglia, may be increased by any processes that result in myelin breakdown, such as stroke or anoxia; elevated levels are not a specific marker of demyelinating disease. Low CSF protein may occur with dural leaks and in benign intracranial hypertension. Protein in cisternal CSF is 50% of the lumbar value and is even lower (25%) within the lateral ventricles.


Glucose is derived from serum and is a reflection of the previous 4 hours of systemic glucose levels. Normal CSF to blood ratio is 0.6 with a usual value of 40 to 80 mg/dL. Simultaneous serum glucose level should be done. Hypoglycorrhachia occurs in bacterial, fungal, or tuberculosis meningitis, and inflammatory processes such as sarcoidosis, carcinomatous meningitis, and SAH. The mechanism of hypoglycorrhachia in meningeal disorders is related to an increase in anaerobic glycolysis in brain and spinal cord and, to a variable degree, polymorphonuclear leukocytes (PMNs) as well as an inhibition of glucose entry from altered glucose membrane transport across the blood brain barrier.

Complications of lumbar puncture


Headache may occur immediately after LP or with persistent dural CSF leak, and occurs in about 5% to 10% of LP procedures. Onset is 5 minutes to 4 days after LP. Pain is related to positioning and may be diminished or relieved when the head is lowered and exacerbated by sitting up. Post-LP headache usually resolves spontaneously, the majority within 1 week, but may persist up to several months. These headaches are more common in women and younger patients. Provoking factors are related to larger needle size, use of the traditional beveled spinal needles, larger amounts of CSF obtained, and failing to replace the stylet before removing the needle. Preventive measures include use of the smallest gauge needle, insertion of the needle bevel parallel to the dural fibers of the posterior longitudinal ligament, and the use of nontraumatic needles.

Treatment of an established post-LP headache involves bed rest, adequate hydration (particularly if nausea and vomiting occur), and analgesics. Caffeine 300 to 500 mg PO and theophylline may be used. Intractable cases often respond (> 80%) with an epidural blood patch by injection of 10 mL of the patient’s freshly drawn blood into the epidural space, where it can clot. There is no evidence that extended bedrest after an LP prevents post-LP headache, contrary to popular belief.

Brain Herniation

Brain herniation may occur immediately or up to 12 hours after an LP in patients with supratentorial mass lesions and midline shift or obstructing posterior fossa tumors.


Spinal subdural, epidural, and SAH may occur in patients treated with anticoagulants or those with thrombocytopenia or bleeding diatheses.


Rare transient unilateral or bilateral abducens palsy can cause diplopia.


Radicular irritation, meningitis, and implantation of epidermoid tumor cells are also complications of LP.

Lumbar Puncture Contraindications

Contraindications include infection over the site of entry, coagulopathy, presence of a known or suspected intracranial mass especially with midline shift, and noncommunicating hydrocephalus (always try to obtain computed tomography [CT] before procedure). For patients with elevated intracranial pressure due to pseudotumor cerebri, CSF drainage via LP can be both diagnostic and therapeutic. In patients for whom the diagnosis of bacterial meningitis is suspected, the Infectious Disease Society of America guidelines recommend performing a CT brain prior to LP in patients with focal neurologic deficits, new onset seizures, suspicion for mass lesions, papilledema, alterations in consciousness, or immunocompromised states. Obtaining a CT prior to LP in patients without the above red flags should not delay prompt antibiotic therapy and worsens outcomes if bacterial meningitis goes untreated.

Aug 12, 2020 | Posted by in NEUROLOGY | Comments Off on C
Premium Wordpress Themes by UFO Themes