Neurologic Entities of the Posterior Fossa

Roger E. Kelley and Alireza Minagar

The posterior fossa contains the brainstem and cerebellum. The brainstem houses all the cranial nerve nuclei and many efferent and afferent fiber tracts that connect the brain with the rest of the body. The cerebellum is the major organ of coordination for all motor functions. Various neurologic entities can involve posterior fossa structures. These entities can affect the cranial nerves, cerebellum, and brainstem, alone or in combination. Some of the more common neurologic entities of the posterior fossa include multiple sclerosis (MS), acute disseminated encephalomyelitis, neurosarcoidosis, progressive multifocal leukoencephalopathy, Behçet disease, neurocysticercosis, Lyme disease, Whipple’s disease, and central nervous system (CNS) vasculitis. This chapter discusses these most significant neurologic entities.

♦ Multiple Sclerosis

Multiple sclerosis is an immune-mediated disorder of the CNS that is usually characterized by a relapsing-remitting course, the presence of inflammatory lesions involving both the gray and white matter, and loss of the myelin/oligodendrocyte complex. MS is a CD4⁺ T-lymphocyte–mediated disorder that develops in genetically susceptible individuals following some as yet unidentified environmental exposure.¹ Increased permeability of the blood–brain barrier (BBB) followed by transendothelial migration of monocytes and myelin basic protein-specific CD4⁺ T lymphocytes are among the significant features of the pathogenesis of MS.²^–⁴ Indeed, disruption of the BBB has been demonstrated in vivo in acute and chronic active MS lesions using contrast-enhanced magnetic resonance imaging (MRI) (gadolinium–diethylenetriamine penta-acetic acid [Gd-DTPA] MRI),⁵ and the presence of enhancing lesions on MRI is a strong indicator of the formation of new lesions and the expansion of former inflammatory lesions in relapsing-remitting multiple sclerosis (RRMS). Correlative MRI-neuropathologic studies of acute MS lesions have shown that these focally enhanced areas consist of fresh lesions, characterized by severe inflammation, edema, perivascular cuffing, and, in many cases, infiltration of mononuclear cells. Activated monocytes and myelin basic protein-specific CD4⁺ T lymphocytes are the major cell types in the perivenular infiltrates characteristic of MS. MS lesions show a unique predilection for the cerebral hemisphere, periventricular white matter, brainstem, cerebellum, optic nerves, and spinal cord.

Posterior fossa involvement in MS occurs frequently with development of demyelinating lesions in the cerebellum and brainstem. Cerebellar lesions of MS can cause disturbances in motor control, impairment of muscle tone regulation, and loss of coordination of skilled movements. Clinically, cerebellar involvement manifests with hypotonia, ataxia, dysarthria, tremor, and ocular motor dysfunction. Hypotonia is more common with acute cerebellar hemispheric lesions and is ipsilateral to the side of the cerebellar lesion. More often, hypotonia is noticeable in the upper limbs, particularly in the proximal musculature. Hypotonic limbs show decreased resistance to passive stretching of the muscles, and frequently exhibit pendular and diminished reflexes. Ataxia in MS results from loss or impairment of timing of the sequential contractions of agonist and antagonist muscles. Cerebellar ataxia refers to failure in the smooth performance of voluntary motor acts. This failure of performance affects speed, timing, force, and range of movements. Cerebellar dysarthria is characterized by abnormalities of articulation and prosody, either independently or in combination. Dysarthria may result from hypotonia and may affect intonation rather than articulation. Tremor in MS patients usually is disabling, and it may occur in patients who have normal strength. It is not unusual to observe tremor in MS patients with moderate cognitive impairment, for which tremor is termed cerebellar-cerebral. Tremor of MS patients is usually kinetic in nature. Cerebellar lesions in MS can cause various ocular motor disorders, particularly nystagmus. Gaze-evoked nystagmus, rebound nystagmus, abnormal optokinetic nystagmus, and periodic alternating nystagmus are among the most frequent ocular abnormalities that are observed in MS. Downbeat nystagmus may also happen with posterior midline cerebellar lesions affecting vestibulocerebellum.

Other clinical manifestations of MS lesions in the posterior fossa include trigeminal neuralgia, internuclear ophthalmoplegia (INO), and vertigo. Trigeminal neuralgia (TN) (also known as tic douloureux) is characterized by a sudden, stabbing, excruciating pain of paroxysmal nature; TN is more commonly unilateral and can manifest in the distribution of one or more of the divisions of the trigeminal nerve. Paroxysms of facial pain in TN are brief and usually last less than a minute. This painful syndrome is more common with advancing age, affects more females than males, and more commonly involves the right hemiface than the left hemiface. The presence of bilateral TN at the same period of time strongly raises the possibility of MS and necessitates further investigation. In MS patients, TN is possibly due to compression or irritation of the entry zone of the trigeminal nerve root by MS demyelinating plaques. INO or medial longitudinal fasciculus (MLF) syndrome manifests with adduction weakness on the side of the MLF involvement and mono-ocular nystagmus of the abducting eye. In a young woman with INO, the first consideration in the differential diagnosis is MS. In patients with INO, unless the lesion is high enough to involve the midbrain, convergence is intact. Patients with INO may not have any complaints or may complain of diplopia or oscillopsia. INO is also commonly accompanied by skew deviation, with the higher eye on the side of the lesion. Acute vertigo is common in MS patients, and its recurrence may herald a new relapse. In severe cases, vertigo is associated with severe nausea and vomiting.

♦ Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is another immune-mediated acute inflammatory demyelinating syndrome that occurs in association with immunization, vaccination, or systemic viral infections. ADEM is characterized by multifocal white matter involvement of the brain and spinal cord and diffuse neurologic signs. ADEM differs from MS in that it is generally a monophasic disorder with no relapses and with favorable long-term prognosis. Currently, there are no definitive diagnostic criteria to differentiate ADEM from MS, and in certain cases differentiation of ADEM from the first demyelinating attack of MS may not be possible.

Acute disseminated encephalomyelitis has a broad clinical spectrum of manifestations. Acute neurologic syndromes associated with ADEM include cerebellitis, transverse myelitis, optic neuritis, and brainstem encephalitis. The neurologic manifestations usually begin 1 to 3 weeks after the time of the precipitating event (usually viral infection or vaccination) and consist of headache, fever, nausea, vomiting, confusion, obtundation, delirium, and coma. Frequently focal neurologic deficits such as hemiparesis, hemisensory loss, ataxia, visual loss, and paraparesis are superimposed on these global deficits.

Neuropathologically, ADEM is characterized by a syndrome primarily composed of perivenular inflammatory myelinopathy with massive infiltration of lymphocytes and macrophages. Other alterations consist of hyperemia, endothelial swelling, and vessel wall invasion by inflammatory cells, perivascular edema, and hemorrhage. These changes affect small blood vessels of both white and gray matter. Plasma cells and granulocytes are rarely observed in the context of ADEM. Demyelination with relative axonal preservation is the pathologic hallmark of ADEM. The infiltrating T cells in ADEM are directed against the myelin/oligodendrocyte complex, most likely myelin basic protein (MBP). A possible theory to explain targeting of MBP in ADEM is “molecular mimicry,” in which a certain peptide, carbohydrate, or lipid epitopes on an infecting virus or microorganism are similar to epitopes on myelin, and this leads to cross-reactivity.

♦ Neurosarcoidosis

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology. It involves the nervous system in 5% of patients. Although cutaneous and pulmonary systems are most commonly seen, neurologic manifestations of sarcoidosis can be potentially as disabling as other nonneurologic impairments. Neurosarcoidosis has a predilection for the base of the brain. The main clinical manifestations of neurosarcoidosis include cranial neuropathy, meningeal involvement, brain parenchymal disease, encephalopathy and seizures, myelopathy, peripheral neuropathy, and myopathy. Cranial neuropathy and meningeal involvement are the most prominent complications of neurosarcoidosis in the posterior fossa.

Single or multiple cranial neuropathies are common and the majority of patients have more than one cranial neuropathy. The facial nerve is most commonly affected. Facial nerve involvement occurs in 25 to 50% of patients with cranial nerve involvement, and this involvement is bilateral in one third of cases. The site of facial nerve involvement in neurosarcoidosis remains unknown; facial neuropathy frequently is associated with dysgeusia, which indicates that the lesion is probably proximal to the stylomastoid foramen. The next most commonly affected cranial nerve is the optic nerve. The next most common cranial neuropathy in neurosarcoidosis is eighth cranial nerve involvement, which occurs in 10 to 20% of patients and may be asymptomatic with only prolonged brainstem auditory evoked potentials, or can present with vestibular or hearing impairment. Optic neuropathy is less common in neurosarcoidosis and is observed in roughly 15% of patients. However, uveitis is a common ocular presentation of sarcoidosis. Optic neuropathy in neurosarcoidosis is usually due to local granulomatous invasion of the optic nerve or extraneural compression by a granulomatous mass. Papilledema is present in 14% of patients with ocular involvement. Olfactory nerve impairment in patients with neurosarcoidosis can manifest with anosmia or hyposmia and occurs in 2 to 17% of cases. Meningeal involvement presents with aseptic meningitis. It can manifest in 64 to 100% of patients with neurosarcoidosis and occasionally occurs as a meningeal mass lesion. Cerebrospinal fluid (CSF) examination in these patients reveals a mononuclear pleocytosis with elevated protein and occasionally hypoglycorrhachia. Meningitis can present as an acute monophasic illness or can be recurrent; it usually has a favorable outcome. Another complication of neurosarcoidosis is hydrocephalus, which can be either communicating or obstructive. Mechanisms of hydrocephalus formation include chronic basilar meningitis with obliteration of cerebrospinal flow, development of granulomatous lesions in the ventricular system causing obstruction, and compression of the cerebral aqueduct.

♦ Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is caused by a primary infection or is secondary to viral reactivation and infection of oligodendrocytes with JC virus. It almost always occurs in individuals who have underlying diseases that alter their cell-mediated immunity or who are iatrogenically immunosuppressed; currently, AIDS is the most common clinical syndrome that predisposes patients to PML. PML, in a diffuse and asymmetric distribution, typically involves, in descending order of occurrence, the cerebral hemispheres, cerebellum, brainstem, and spinal cord. PML is mainly restricted to the subcortical white matter and presents itself in a variety of neurologic syndromes. Patients are generally afebrile and without any manifestations of a systemic infection. Neurologic compromise slowly occurs over weeks to months. The well-recognized clinical triad of PML consists of visual impairment, motor weakness, and altered sensorium; prominent homonymous hemianopsia, monoparesis, or hemiparesis are among the typical initial manifestations of PML. Progressive loss of myelin in the cerebral visual centers may eventually cause cortical blindness. Subtle intellectual decline is a prominent early presentation, manifesting as personality change and progressing to blunted intellect, frank dementia, and eventually coma. Although patients usually present with cerebral symptoms, some patients present with brainstem or cerebellar involvement or seizures. The presence of ataxia in a patient with PML usually indicates the presence of lesions in the cerebellum and brainstem. Symptoms referable to both gray-and white-matter involvement can occur. JC virus, a 45-nm icosahedron, is one of the simplest of circular supercoiled double-stranded DNA viruses, which contains 5243 base pairs (bp) of DNA, and is mainly composed of VP1.

Most individuals are infected with JC virus at some point in their lives, and by age 5 at least 10% of individuals are J Cantibody–positive; by age 6, this number rises to 50% seropositive, and by age 14, 65% are seropositive. Eventually, 76% of individuals are seropositive for JC virus. Specific immunoglobulin G (IgG) antibodies to JC virus VP1 have been detected in 84.5% of adult control individuals. Initial infection with JC virus is asymptomatic, and the virus rapidly enters a latent phase in the kidney, other extraneural organs, and possibly the brain. In most individuals, the virus does not reactivate or cause problems. However, in individuals who develop diseases that suppress their cellular immunity or individuals who are iatrogenically immunosuppressed, primary viral infection or reactivation of latent virus can occur. Immunosuppressed individuals commonly shed JC virus into their urine, as do 12.9% of leukemia and renal transplant patients.

♦ Behçet Disease

Behçet disease is a chronic recurring multisystemic disorder that presents mainly with mucocutaneous and ocular manifestations. According to the work of the International Study Group,6 the major diagnostic criteria for Behçet disease include (1) oral ulcers recurring at least three times per year; (2) genital ulcers or scars; (3) eye involvement; (4) skin lesions (erythema nodosum, folliculitis, acneiform lesions); and (5) pathergy skin test⁷ observed by a physician. Minor diagnostic criteria include arthritis or arthralgia, deep venous thromboses, subcutaneous thrombophlebitis, epididymitis, family history, and gastrointestinal, CNS, or vascular involvement. Oral ulcers plus two other major criteria are required for the diagnosis.

In 4 to 49% of cases, Behçet disease involves the CNS, usually during active disease; in 5%, neurologic syndromes are the presenting manifestations. CNS involvement is usually polysymptomatic, with a relapsing-remitting or chronic progressive course with dementia, ataxia, or dysarthria, and a tendency to recur when immunosuppressive therapy is reduced. Brainstem or corticospinal tract signs (neuro-Behçet syndrome), acute confusion, increased intracranial pressure due to dural sinus thrombosis, meningoencephalitis, and isolated behavioral symptoms (psycho-Behçet syndrome) are among the most frequent neurologic manifestations. Rare cases with demyelinating lesions have been reported. Pure cerebellar or parkinsonian syndrome, peripheral neuropathy, and myelopathy are possible but uncommon. Neuropathologically, cerebral lesions of Behçet disease consist of multifocal necrotizing lesions with marked invasion of the inflammatory cells. In addition, necrosis may involve both the gray and white matter, probably secondary to vasculitis.

♦ Neurocysticercosis

Neurocysticercosis is the most common parasitic infestation of the CNS, which is caused by the larval stage of Taenia solium, the pork tapeworm. Four forms of neurocysticercosis have been reported: meningeal, parenchymal, ventricular, and mixed. Parenchymal lesions consist of small cysts, large cysts, and calcified lesions. Clinical manifestations of neurocysticercosis depend on the number of cysts, their location within the CNS, and the cyst’s state of health. Generally, cysticerci do not produce clinical symptomatology until the cysts begin to degenerate. Cyst degeneration begins from 2 to more than 10 years after the original infestation. As the cyst degenerates, cysticercal antigens leak into the adjacent brain or meninges and provoke a massive inflammatory response. The inflammatory reaction cause clinical manifestations such as seizures, headaches, altered mental status, and focal neurologic signs like hemiparesis, visual loss, and paraparesis.

♦ Lyme Disease

Lyme disease is a multisystem infectious disease caused by the closely related group of spirochetes, known originally as Borrelia burgdorferi and now referred to as Borrelia burgdorferi sensu lato. The members of the B. burgdorferi sensu lato complex are transmitted by the bite of Ixodes ticks. Three members of this genus (B. burgdorferi sensu stricto, B. garinii, and B. afzelii) are pathogenic for humans. Skin, nervous system, joints, and heart are the most commonly affected organs. Up to 90% of infected patients develop the characteristic erythematous, macular, and painless rash, which evolves over days to become many centimeters in diameter.8 Following this acute and usually localized cutaneous infection, patients may develop subacute problems secondary to bacterial dissemination. Often, this dissemination is accompanied by a flu-like syndrome with fever, malaise, and diffuse aches and pains. In some, bacterial dissemination results in a multicentric erythema migrans. About 5% of patients develop cardiac conduction abnormalities. Others may develop a mild hepatitis or myositis, whereas some develop arthralgias or frank arthritis.

In 15% of patients, Lyme disease affects the nervous system, and these patients present with lymphocytic meningitis, cranial neuritis, and painful radiculitis. Every cranial nerve may be affected; however, the facial nerve is the most commonly involved cranial nerve. The painful radiculitis may resemble a mechanical monoradiculopathy or may be more disseminated, causing plexitis or even a diffuse disorder that may clinically resemble Guillain-Barré syndrome. In rare cases, patients (probably approximately 0.1% of infected and untreated individuals) may present with encephalomyelitis with prominent white matter involvement, frequently manifesting with a myelopathic picture. Studies of experimental infection in immunosuppressed primates have shown meningeal, but not CNS, parenchymal infection.

♦ Whipple’s Disease

Whipple’s disease is an infectious multisystemic disorder that mainly involves the small bowel and causes a malabsorption syndrome.⁹ Osteoarticular, cardiac, and CNS involvements are frequently observed in the context of Whipple’s disease.^9,10 Whipple’s disease is caused by a gram-positive bacillus, Tropheryma whippelii. The pathogenesis and epidemiology, however, remain obscure. The most common neurologic manifestations of Whipple’s disease consist of cognitive decline, supranuclear gaze palsy, altered level of consciousness, psychiatric signs, and upper motor neurons signs. Postmortem studies have shown that these neurologic symptoms are associated with a granulomatous infiltration of the different levels of the CNS, particularly the brain, chiasm, pituitary gland, pons, and spinal cord.¹¹ Cerebral lesions are essentially confined to the gray matter, preferentially the basal part of the telencephalon, the hypothalamus, and the thalamus.¹²

♦ Central Nervous System Vasculitis

Vasculitis is defined as inflammation involving blood vessels with associated structural damage and usually tissue necrosis. Vasculitis primarily affecting the CNS, also known as isolated CNS angiitis, is confined to the brain, spinal cord, and their covering membranes. Isolated CNS vasculitis manifests with headache, signs of meningeal irritation, seizures, encephalopathic episodes, and hemispheric strokes. CSF examination is abnormal in more than 90% of cases, and neuroimaging of the brain and spinal cord reveals evidence of multifocal ischemic change of varying ages. Neuropathologic examination shows vasculitis of small and medium vessels of leptomeninges and underlying cortex with variable degrees of granulomatous changes. Occasionally giant cells may be present.