http://www.nejm.org/doi/full/10.1056/NEJMra1404489

http://www.nejm.org/doi/full/10.1056/NEJMra1404489

Nocturnal Frontal lobe epilepsy (Autosomal Dominant)

Disease characteristics. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (5 seconds to 5 minutes). They vary from simple arousals from sleep to dramatic, often bizarre, hyperkinetic events with tonic or dystonic features. Affected individuals may experience aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Onset ranges from infancy to adulthood. About 80% of individuals develop ADNFLE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidity, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent.

Clinical Diagnosis

The clinical diagnostic features of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) include the following:

• Clusters of seizures with a frontal semiology*
• Occurrence of seizures predominantly during sleep*
• Normal clinical neurologic examination
• Preserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidity may occur
• Normal findings on neuroimaging
• Ictal EEG that may be normal or obscured by movement artifact
• Interictal EEG that shows infrequent epileptiform discharges
• Presence of the same disorder in other family members with evidence of an autosomal dominant mode of inheritance [Tassinari & Michelucci 1997, Provini et al 1999, Combi et al 2004]

* History of clusters of brief (5 seconds to 5 minutes) nocturnal motor seizures which are often stereotyped and may include nightmares, verbalizations, sudden limb movements, or other parasomnias (undesirable phenomena that occur mainly or only during sleep). The history may be obtained from the affected individual and witnesses, and supplemented if necessary by video-electroencephalogram (EEG) monitoring.

The diagnosis of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is established in individuals with the above clinical features and/or a disease-causing mutation in CHRNA4, CHRNB2, or CHRNA2.

Ictal EEG recordings may be normal or may be obscured by movement artifact. Ictal rhythms, if present, are usually sharp waves or repetitive 8-11 Hz spikes. Recruiting patterns and rhythmic theta (bifrontal, unilateral frontal, or with diffuse desynchronization) are occasionally seen [Steinlein et al 1997, Oldani et al 1998, Provini et al 1999, Picard et al 2000]. El Helou et al [2008] suggest that seizures may be initiated by K-complexes.

Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals.

Interictal sleep EEG may show infrequent epileptiform discharges.

Note: The clinical features of ADNFLE are indistinguishable from those of nonfamilial nocturnal frontal lobe epilepsy [Hayman et al 1997, Tenchini et al 1999, Steinlein et al 2000]. The term ADNFLE should only be applied if the family history is positive for other affected individuals and/or if a disease-causing mutation has been identified in either CHRNA4, CHRNB2, or CHRNA2.

Natural History

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures with a range of manifestations. Within a family, the manifestations of the disorder may vary considerably [Hayman et al 1997]; individuals with subtle manifestations may not present for medical attention. Magnusson et al [2003] reported an increase in psychiatric symptoms in families with ADNFLE. A high incidence of true parasomnias (undesirable phenomena that occur mainly or only during sleep) has been reported in relatives of those with ADNFLE [Provini et al 1999].

Seizures may occur in any stage of sleep [Oldani et al 1996, Steinlein et al 1997, Provini et al 1999], although typically in clusters in non-REM sleep, most commonly in stage two sleep [Oldani et al 1998, Provini et al 1999]. Theaffected individual often goes back to sleep rapidly after a seizure, only to be awakened by another event. A minority of individuals experience daytime seizures, typically during a period of poor seizure control.

The seizures are often stereotyped and brief (5 seconds to 5 minutes) [Oldani et al 1996, Thomas et al 1998, Nakken et al 1999, Provini et al 1999, Ito et al 2000, Picard et al 2000]. They vary from simple arousals from sleep to dramatic hyperkinetic events with tonic or dystonic features. The hyperkinetic manifestations may appear bizarre, sometimes with ambulation, bicycling movements, ballism (flinging or throwing arm movements), and pelvic thrusting movements.

Retained awareness during seizures is common and may cause affected individuals to fear falling asleep. A sense of difficulty breathing and hyperventilation may occur, as well as vocalization, clonic features, urinary incontinence, and secondary generalization.

Some individuals experience an aura, which may be nonspecific or may consist of fear, a shiver, vertigo, or a feeling of falling or being pushed.

The three distinct sub-classifications of seizure types based on clinical features of the seizures (semiology) and their duration [Oldani et al 1998, Provini et al 1999] are “paroxysmal arousals,” “paroxysmal dystonia,” and “episodic wandering.”

ADNFLE is lifelong but not progressive. Onset ranges from infancy to adulthood. About 80% of affected individuals develop ADNFLE in the first two decades of life [Oldani et al 1998, Picard et al 2000]; mean age of onset is ten years. As an individual reaches middle age, attacks may become milder and less frequent. Seizures may vary over time; for example, tonic attacks appearing in early childhood may evolve into seizures with dystonic or hyperkinetic components in later childhood.

Clinical neurologic examination is normal and intellect is usually preserved [Oldani et al 1996, Nakken et al 1999]; however, in some individuals neuropsychological assessment reveals reduced intellect, cognitive deficits, or psychiatric comorbidity [Khatami et al 1998, Provini et al 1999, Picard et al 2000, Cho et al 2003, Wood et al 2010].Picard et al [2009] found below-normal general intellect in 45% of 11 subjects with special difficulty in executive tasks and concluded that cognitive dysfunction is an integral part of ADNFLE with nicotinic receptor mutations. It is suggested that certain nAChR mutations could be associated with an increased risk for such symptoms [Steinlein et al 2012].

Imaging in acute stroke

The principal purpose of MRI in the evaluation of a patient with acute stroke is to determine the extent of tissue damage and to identify additional tissue at risk that is potentially salvageable. The combination of diffusion- and perfusion-weighted MRI is a frequently used protocol for this purpose. The evaluation is based on the premise that DWI would delineate the tissue that suffered permanent damage whereas the areas that do not cause signal change on DWI but have abnormal signal on perfusion-weighted images represent tissue at risk, the so-called ischemic penumbra (Hakim, 1998; Srinivasan et al, 2006). If a mismatch occurs between the extent of DWI changes and perfusion deficits (Sorensen et al, 1999), the latter being larger, reperfusion treatment with IV, or, beyond 3 hours, intraarterial thrombolytics or other intravascular techniques is justified to salvage the brain tissue at risk (Warach, 2002). If the extent of diffusion and perfusion abnormalities is similar or the same, the tissue is thought to be irreversibly injured with no penumbra; therefore, the benefit from reperfusion treatment is low or none.

These are useful guiding principles in general; however, several caveats must be kept in mind. Restriction of diffusion, DWI positivity, is not an infarct (ie, definite, permanent damage or loss of tissue) but is an ongoing ischemia. Once seen on DWI, the damage is most often irreversible, but not in every case, and there is chance for rescuing some tissue in the DWI-positive region as well. With regard to the perfusion images, a few words of caution need to be said. While DWI, are easy to read and the extent of deficit is usually very clear, perfusion MRIs are often more difficult to judge. Significant noise problems on calculated transit time, blood volume and blood flow images, the variable blood flow around stroke lesions, and artifact from large vessels may interfere with interpretation (de Crespigny, 2003). In one study, poor interobserver reliability was found in estimating diffusion-perfusion mismatch by visual inspection (Coutts et al, 2003). This may lead to underestimation or overestimation of the amount of tissue at risk. Another difficulty is that no standard perfusion measurements are available with which to compare the obtained data, although in human and animal stroke models PET and SPECT data have been used for validation (de Crespigny, 2003). Repeated measurements in human volunteers using PET and MRI perfusion, however, still showed the superiority of PET (Carroll et al, 2002).

Having said all this, the MR diffusion/perfusion protocols in acute stroke imaging are very useful in clinical decision making, and with further improvements in imaging methodology and image interpretation they will be essential for state-of-the-art acute stroke imaging.

Duchenne Muscular Dystrophy

To rise from a sitting position, he first flexes his trunk at the hips, puts his hands on his knees, and pushes the trunk upward by working the hands up the thighs. (Adams and Victor)

Duchenne Timeline

http://www.youtube.com/watch?v=KA8W5UfE4ts

Localization of Nystagmus.

Vestibular nystagmus

Vestibular nystagmus may be central or peripheral. Important differentiating features between central and peripheral nystagmus include the following: peripheral nystagmus is unidirectional with the fast phase opposite the lesion; central nystagmus may be unidirectional or bidirectional; purely vertical or torsional nystagmus suggests a central location; central vestibular nystagmus is not dampened or inhibited by visual fixation; tinnitus or deafness often is present in peripheral vestibular nystagmus, but it usually is absent in central vestibular nystagmus. According to Alexander's law, the nystagmus associated with peripheral lesions becomes more pronounced with gaze toward the side of the fast-beating component; with central nystagmus, the direction of the fast component is directed toward the side of gaze (eg, left-beating in left gaze, right-beating in right gaze, up-beating in upgaze).

Downbeat nystagmus

Downbeat nystagmus is defined as nystagmus with the fast phase beating in a downward direction.The nystagmus usually is of maximal intensity when the eyes are deviated temporally and slightly inferiorly. With the eyes in this position, the nystagmus is directed obliquely downward. In most patients, removal of fixation (eg, by Frenzel goggles) does not influence slow phase velocity to a considerable extent; however, the frequency of saccades may diminish.

The presence of downbeat nystagmus is highly suggestive of disorders of the craniocervical junction (eg, Arnold-Chiari malformation). This condition also may occur with bilateral lesions of the cerebellar flocculus and bilateral lesions of the medial longitudinal fasciculus, which carries optokinetic input from the posterior semicircular canals to the third nerve nuclei. It may also occur when the tone within pathways from the anterior semicircular canals is relatively higher than the tone within the posterior semicircular canals. Under such circumstances, the relatively unopposed neural activity from the anterior semicircular canals causes a slow upward pursuit movement of the eyes with a fast, corrective downward saccade.

Upbeat nystagmus

Upbeat nystagmus is defined as nystagmus with the fast phase beating in an upward direction. Daroff and Troost described 2 distinct types.The first type consists of a large amplitude nystagmus that increases in intensity with upward gaze. This type is suggestive of a lesion of the anterior vermis of the cerebellum. The second type consists of a small amplitude nystagmus that decreases in intensity with upward gaze and increases in intensity with downward gaze. This type is suggestive of lesions of the medulla.

This condition may occur when the tone within the pathways of the posterior semicircular canals is relatively higher than the tone within the anterior semicircular canals, and it can occur from lesions of the ventral tegmental tract or the brachium conjunctivum, which carry optokinetic input from the anterior semicircular canals to the third nerve nuclei.

Torsional (rotary) nystagmus

Torsional (rotary) nystagmus refers to a rotary movement of the globe about its anteroposterior axis. Torsional nystagmus is accentuated on lateral gaze. Most nystagmus resulting from dysfunction of the vestibular system has a torsional component superimposed on a horizontal or vertical nystagmus.

This condition occurs with lesions of the anterior and posterior semicircular canals on the same side (eg, lateral medullary syndrome). Lesions of the lateral medulla may produce a torsional nystagmus with the fast phase directed away from the side of the lesion. This type of nystagmus can be accentuated by otolithic stimulation by placing the patient on their side with the intact side down (eg, if the lesion is on the left, the nystagmus is accentuated when the patient is placed on his right side).

Pendular nystagmus

Pendular nystagmus is a multivectorial nystagmus (ie, horizontal, vertical, circular, elliptical) with an equal velocity in each direction that may reflect brain stem or cerebellar dysfunction. Often, there is marked asymmetry and dissociation between the eyes. The amplitude of the nystagmus may vary in different positions of gaze.

Horizontal nystagmus

Horizontal nystagmus is a well-recognized finding in patients with a unilateral disease of the cerebral hemispheres, especially with large, posterior lesions. It often is of low amplitude. Such patients show a constant velocity drift of the eyes toward the intact hemisphere with fast saccade directed toward the side of the lesion.

Seesaw nystagmus

Seesaw nystagmus is a pendular oscillation that consists of elevation and intorsion of one eye and depression and extorsion of the fellow eye that alternates every half cycle. This striking and unusual form of nystagmus may be seen in patients with chiasmal lesions, suggesting loss of the crossed visual inputs from the decussating fibers of the optic nerve at the level of the chiasm as the cause or lesions in the rostral midbrain. This type of nystagmus is not affected by otolithic stimulation.

Gaze-evoked nystagmus

Gaze-evoked nystagmus is produced by the attempted maintenance of an extreme eye position. It is the most common form of nystagmus. Gaze-evoked nystagmus is due to a deficient eye position signal in the neural integrator network. Thus, the eyes cannot be maintained at an eccentric orbital position and are pulled back toward primary position by the elastic forces of the orbital fascia. Then, corrective saccade moves the eyes back toward the eccentric position in the orbit.

Gaze-evoked nystagmus may be caused by structural lesions that involve the neural integrator network, which is dispersed between the vestibulocerebellum, the medulla (region of the nucleus prepositus hypoglossi and adjacent medial vestibular nucleus [NPH/MVN]), and the interstitial nucleus of Cajal (INC). Patients recovering from a gaze palsy go through a period where they are able to gaze in the direction of the previous palsy, but they are unable to sustain gaze in that direction; therefore, the eyes drift slowly back toward primary position followed by a corrective saccade. When this is repeated, a gaze-evoked or gaze-paretic nystagmus results.

Gaze-evoked nystagmus often is encountered in healthy patients; in which case, it is called end-point nystagmus. End-point nystagmus usually can be differentiated from gaze-evoked nystagmus caused by disease, in that the former has lower intensity and, more importantly, is not associated with other ocular motor abnormalities.

Spasmus nutans

Spasmus nutans is a rare condition with the clinical triad of nystagmus, head nodding, and torticollis. Onset is from age 3-15 months with disappearance by 3 or 4 years. Rarely, it may be present to age 5-6 years. The nystagmus typically consists of small-amplitude, high frequency oscillations and usually is bilateral, but it can be monocular, asymmetric, and variable in different positions of gaze.

Periodic alternating nystagmus

Periodic alternating nystagmus is a conjugate, horizontal jerk nystagmus with the fast phase beating in one direction for a period of approximately 1-2 minutes. The nystagmus has an intervening neutral phase lasting 10-20 seconds; the nystagmus begins to beat in the opposite direction for 1-2 minutes; then, the process repeats itself. The presumed mechanism is disruption of the vestibulo-ocular tracts at the pontomedullary junction.

Abducting nystagmus of internuclear ophthalmoplegia

Abducting nystagmus of internuclear ophthalmoplegia (INO) is, as the name implies, nystagmus in the abducting eye contralateral to a medial longitudinal fasciculus (MLF) lesion.

Ref : medscape /emedicine ( Christopher M Bardorf, MD, MS; Chief Editor: Hampton Roy Sr, MD  et al)

Progressive Multifocal leukoencephalopathy (PML)

PML continues be a nemesis for the antibody based therapies. The new CD30 antibody, Brentuximab, has been associated with PML.

http://www.ncbi.nlm.nih.gov/pubmed/22472351

Cerebellopontine Angle Masses

Vestibular schwannoma 75%
Meningioma 10%
Epidermoid 5%
Facial nerve schwannoma 4%
Aneurysm (vertebral,basilar,PICA)
Brain stem glioma
Arachnoid cyst
Paraganglioma
Hematogenous metastatis
Subarachnoid spread of tumors
Lipoma
Hemangioma
Choroid plexus papilloma
Ependymoma
Desmoplastic medulloblastoma


Ref :Yousem and Grossman Neuroradiology