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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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 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.

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 WBC_CSF = WBC_CSF ∞ RBC_CSF/RBC_blood). 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.

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.