and Gunhild Waldemar1
Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Following the history and bedside examination, the anatomic localization of the lesion should have been identified, and the neurologist can proceed with a differential diagnosis. This is usually straightforward by taking into account information related to epidemiology, comorbidities, hereditary predispositions, and occupation, as well as the time course of the disorder. For instance, hyperacute onset of deficits is characteristic for cerebrovascular disease, subacute onset for infectious and inflammatory disorders, and prolonged onset over weeks or months for malignancy. A chronic progressive course over years is indicative of neurodegenerative diseases. However, occasionally, a slowly progressing illness comes rather suddenly to the attention of the patient because the declining level of function has been exposed by an unusual activity or event. If important data are unavailable, early fixation on a single differential diagnosis should be avoided due to the risk of overlooking important details. This chapter provides a simple yet comprehensive differential diagnosis of most of the disorders encountered in neurological practice. Further, it makes extensive use of mind maps in order to enable the reader to approach and visualize the differential diagnosis of each neurological field in a structured and intuitive manner.
KeywordsAtaxiaCognitive impairmentComaDementiaDemyelinating diseasesDifferential diagnosisEncephalopathyEpilepsyHeadacheHead injuryInfectious diseasesMalignancyMotor neuron diseaseMovement disordersMyelopathyMyopathyNeuromuscular junction disordersPeripheral nerve disordersSleep disordersStrokeSyncopeVertigo
4.1 Introduction to Heuristic Neurological Reasoning
When the anatomic localization of a lesion has been identified, it is often straightforward to deduce its etiology using the available data on the time course, epidemiology, comorbidity, and genetic predispositions, including:
Hyperacute and acute onset of deficits points toward a cerebrovascular cause.
Subacute onset over hours or days is characteristic for infectious and inflammatory disorders.
Prolonged onset over several weeks or months may suggest malignancy.
A chronic progressive course over many years is indicative of neurodegenerative diseases. A complete family history can be crucial.
Relapsing-remitting deficits are seen with autoimmune and inflammatory diseases.
Short-lived phenomena of acute onset with “positive” signs that leave no residual deficits and that may reappear after hours, days, weeks, or even longer periods can be due to epilepsy, migraine, narcolepsy, and other paroxysmal disorders.
The setting in which the illness developed is often as important as the mode of onset and the clinical course. A good rule is to ask the patient precisely what he was doing the exact moment he noticed his symptoms for the first time. However, it is important to be aware of the fact that a slowly progressing illness occasionally comes rather suddenly to the attention of the patient because he has not noticed the declining level of function until it is exposed by an unusual activity or event. Such a “decompensation artifact” (Oluf Andersen, Gothenburg, Sweden, personal communication) might occur, for instance, when a patient with mild cognitive impairment (MCI) due to AD develops a postsurgical delirium or when a patient with a compressive myelopathy due to a thoracic meningioma falls while running for the bus. In both instances, a careful history is crucial in order to avoid believing that symptom onset was sudden and to avoid attributing the cause to an external event. Also, some patients with a chronic, stable deficit present to the neurologist complaining of progressive impairment, but a careful history may reveal that they have simply begun to worry more.
The following rules help to avoid diagnostic confusion:
The differential diagnoses should be ranked according to their pretest probability, severity, and associated treatment options (“Which diagnosis is most likely?”; “Which diagnoses are particularly serious, and which are treatable?”).
Most diagnostic errors are made not because of limited medical knowledge but because of failure to acquire and correctly analyze basic clinical information. Definitive data from the history and clinical examination should not be diluted by unclear data. In other words, localization and diagnosis should be based on what is reasonably certain.
When several typical features of a disease are lacking, it is likely that the diagnosis is wrong. Yet, rare manifestations of common diseases are more often encountered than common manifestations of rare diseases. (This is one of the most rephrased statements in clinical medicine but still remains true nonetheless.)
Overreliance on isolated ancillary investigations, in particular when these are interpreted outside of the clinical context, is another common source of diagnostic error (Case 4.1).
When all investigations have failed to identify the diagnosis, the tool most likely to help is a better history. In the case that not all necessary data are available, avoid early fixation on a single diagnosis; otherwise, important details may be missed. Time will solve many mysteries.
Finally, familiarity with Occam’s razor, Hickam’s dictum, and Crabtree’s bludgeon is helpful for neurological differential diagnosis.1
Occam’s razor (“entities must not be multiplied beyond necessity”; Splade 1999). When evaluating a patient with multiple symptoms, a single diagnosis explaining all features should be sought rather than several unrelated diagnoses. For instance, in a young male with gait ataxia, dysarthria, scoliosis, diabetes, and deafness, a diagnosis of Friedreich’s ataxia would elegantly explain the combination of absent tendon reflexes in the lower extremities (suggesting a peripheral lesion) and extensor plantar responses (suggesting a central lesion).
Hickam’s dictum (“a man can have as many diseases as he damn well pleases”; Hilliard et al. 2004). Frequently, patients do not respect Occam’s razor and have multiple diagnoses. Hickam’s dictum becomes particularly relevant with increasing age of the patient. Thus, upgoing toes combined with loss of Achilles tendon reflexes in an elderly patient might very well be due to degenerative spine disease leading to a cervical compressive myelopathy and a diagnosis of diabetic polyneuropathy. Hickam’s dictum, however, should be applied only infrequently in younger patients.
Crabtree’s bludgeon (“no set of mutually inconsistent observations can exist for which some human intellect cannot conceive a coherent explanation, however complicated”; Mani et al. 2011). The clinical value of Crabtree’s bludgeon is that it cautions against overelaborate explanations. Crabtree’s bludgeon is important in those relatively rare situations when patients have several well-established diagnoses that could explain various clinical features, but they suffer from yet another condition, which might easily be overlooked. For instance, in an elderly diabetic patient with a history of degenerative spine disease, who develops subacute progressive extremity weakness, an elevated CSF protein level would not be a surprising finding. But the identification of conduction blocks and significantly reduced nerve conduction velocities on neurophysiological examination would be hard to explain unless the clinician considers a diagnosis of co-occurring CIDP.
Herpes simplex encephalitis misdiagnosed as stroke, stroke misdiagnosed as herpes simplex encephalitis. A 32-year-old female with an unremarkable previous medical history was found unconscious in her apartment and brought to the hospital. A CT showed a right-sided hypodensity which was interpreted as a right MCA stroke by the radiologist. MRI seemingly confirmed this notion as it showed a large area of hyperintense signal change related to the right temporal lobe (a, DWI). However, the neurologist on-call correctly noted that the signal change also involved the right anterior lobe (b, FLAIR) and that the history of a young patient with no cardiovascular risk factors but with headache and influenza-like symptoms was highly suggestive of herpes simplex encephalitis. Treatment with IV acyclovir was started. A few days later, CSF PCR analysis turned out positive for HSV I. Next, a 82-year-old woman with atrial fibrillation, diabetes mellitus, and a previous stroke resulting in right-sided hemianopia was admitted with acute onset of left hemiplegia and hemineglect. CT of the brain 2 h after ictus was read as normal except for a previous left occipital infarction. A week later, the patient developed a urinary tract infection and her level of consciousness decreased. An MRI was performed which showed a large area of DWI signal change involving the right temporal lobe (c), including some hemosiderin deposits revealed by gradient-echo sequences (d). When a lumbar puncture revealed more than 500 cells and 5 g protein, the patient was transferred with a working diagnosis of herpes simplex encephalitis to the department of infectious diseases. The neurology team reviewing the patient a few days later suggested that the inflammatory CSF changes were fully compatible with massive cerebral tissue damage due to brain infarction. Indeed, all blood and CSF cultures turned out to be negative
Establishing a neurological differential diagnosis can be a most satisfying intellectual delight. There is arguably no other medical specialty with a more extensive differential diagnosis than neurology. This also means that frustration is common in the new beginner. The purpose of the following pages is to provide a simple yet strategic overview of the most important areas in neurology. This chapter will enable the reader to break down the differential diagnosis of each neurological field into manageable entities.
4.2 The Differential Diagnosis of Coma
Wakefulness (or arousal) is mediated by structures in the brainstem, midbrain, and diencephalon, notably the ascending reticular activating system (ARAS) and the rostral dorsolateral pontine tegmentum. Consciousness (or awareness), in contrast, is an exclusive product of higher cerebral activity and therefore depends on the cerebral cortex and its connecting pathways in the subcortical white matter. As a rule, consciousness will be preserved with lesions that only affect one hemisphere. It follows that coma can be due to:
Structural damage of:
The cerebral cortex in both hemispheres
Diffuse brain dysfunction of metabolic-toxic or hypoxic origin
As stated earlier, coma may be defined as a state of non-arousal and unresponsiveness in which the patient is not aware of his surroundings and his own person. Thus, coma must be differentiated from:
Locked-in syndrome (see Chap. 2)
Psychogenic coma (see Chap. 3)
Impairment of consciousness that does not fulfill the criteria of coma, including:
Stupor. This is a vague term for patients who are arousable by vigorous and repeated stimulation only.
Akinetic mutism. The patient is unresponsive and apparently without any cognitive or spontaneous motor activity despite the fact that the eyes may be open and vocalization present during short periods. Also, the patient with akinetic mutism may occasionally look at the examiner; however, there is no interaction. The sleep-wake cycle is intact. Akinetic mutism may be due to large bifrontal lesions, hydrocephalus, and severe cortical damage.
The vegetative state. This is one possible outcome of coma. Coma per se almost never lasts more than a few days or weeks—most patients die, regain their consciousness, or enter a minimal conscious or the vegetative state. In the vegetative state, the patient is arousable to some degree; most of the brainstem and diencephalic functions are intact, including the sleep-wake cycle; thus, eyes are open during periods of wakefulness. However, the patient is not aware of his surroundings or his own person, and therefore, there is lack of any meaningful communication or motor activity. As stated below, chances are high that numerous patients believed to be in the vegetative state indeed are in a minimal conscious state.
The minimal conscious state. Striking functional magnetic resonance imaging (fMRI) experiments have shown that many apparently vegetative patients indeed have some degree of preserved consciousness and higher cortical function. In a landmark study, Owen et al. provided auditory cues to a young woman fulfilling the established criteria for a persistent vegetative state following a traumatic brain injury and studied her brain activity in response to these cues using fMRI. The cues were verbal instructions to imagine performing one of three tasks: playing tennis, going through the rooms of a house, or simply relaxing. Compared to the “relaxed” state, fMRI showed instruction-dependent brain activation akin to that seen in healthy volunteers following the same instructions. The authors concluded that the patient was consciously imagining playing tennis and exploring a house in much the same way control participants did (Owen et al. 2006). This and similar studies are likely to fundamentally change our perception of diagnosis and therapy of patients with chronically decreased consciousness.
When coma or another state of disordered consciousness has been confirmed, the etiology needs to be defined (Fig. 4.1). The following list, although not complete, may help as guidance. Impairment of consciousness and arousal may be due to:
Differential diagnosis of coma
4.2.1 Structural Causes of Coma
° Infectious, e.g., abscess, HSV-1 encephalitis, and bacterial meningitis
° Postinfectious, e.g., acute demyelinating encephalomyelitis (ADEM)
° Traumatic, e.g., diffuse axonal injury (DAI) with closed head trauma, penetrating skull trauma, and multiple contusions
° Vascular, e.g., bilateral thalamic infarctions, multiple cortical infarctions, malignant MCA infarction, intracranial hemorrhage, infectious or noninfectious vasculitis, pituitary apoplexy, anoxic-ischemic encephalopathy, and cerebral venous sinus thrombosis (in particular thrombosis of the straight sinus and deep cerebral veins leading to bilateral thalamic venous congestion) (Case 4.2)
° Tumors, primary or secondary CNS malignancies
° Hydrocephalus, obstructive or communicating
Cerebral venous sinus thrombosis and hyperthyroidism. A 28-year-old female developed subacute onset of headache and visual disturbances, followed a few days later by focal epileptic seizures, abulia, tetraparesis, and decreased consciousness. Sagittal T1-weighted MRI (a) and MR venography (b) showed thrombosis of the superior sagittal sinus and straight sinus. The etiology of the CVST was unknown; apparently, the patient did not have any risk factors for a prothrombotic state. Despite immediate administration of IV heparin, her level of consciousness declined, and, therefore, she was treated with local infusion of 60 mg recombinant tissue plasminogen activator for 48 h (figure shows microcatheter in the straight sinus; c). After the procedure, MR venography showed that both the superior sagittal sinus and the straight sinus were open again (d). Only 3 days later, awake, orientated, and ambulatory, the patient had made a near-complete recovery. However, 10 days after admission, she developed tachycardia, flushing, sweating, and anxiety. Blood results confirmed a thyrotoxicosis and also showed a reactive thrombocytosis. The role of hyperthyroidism as the predisposing factor for CVST is well described in the medical literature, although still not widely acknowledged (Digital subtraction angiography images courtesy of Aase Wagner, Department of Neuroradiology, Rigshospitalet, Copenhagen)
Basilar artery thrombosis and other posterior circulation strokes
Central pontine myelinolysis
Cerebellum (cerebellar mass lesions affecting the brainstem)
4.2.2 Nonstructural Causes of Coma
Electrolyte disturbances, e.g., hyponatremia (the reversion of which may lead to central pontine myelinolysis, if performed too quickly) and hypercalcemia
Hypoglycemia and hyperglycemia
Endocrinological disturbances, e.g., severe hypocortisolism (Addisonian crisis)
Poisoning, e.g., illicit and prescription drugs, carbon monoxide, cyanide, and other gases
Derangement of body temperature (hypothermia, hyperthermia)
Status epilepticus, convulsive or nonconvulsive
Malignant neuroleptic and serotonergic syndrome
When Plum and Posner (Posner et al. 2007) listed the final diagnoses of 500 patients admitted to the emergency department due to “coma of unknown origin,”2 drug poisoning was by far the most common cause, followed by, in decreasing frequency, anoxia/ischemia, intracerebral hematoma, brainstem infarction, subdural supratentorial hematoma, hepatic encephalopathy, encephalomyelitis and encephalitis, subarachnoid hemorrhage, and endocrinological disturbances, including diabetes, acid-base disorders, pontine hemorrhage, temperature deregulation, cerebral infarct, uremic encephalopathy, supratentorial brain tumor, supratentorial brain abscess, cerebellar hemorrhage, and supratentorial epidural hematoma.
4.3 The Differential Diagnosis of Traumatic Brain Injury
Head injury leading to penetration of the skull is usually the domain of the neurosurgeon and will therefore not be considered here.
Closed head injury can manifest as or be associated with:
Minor blows against the head without loss of consciousness, amnesia, or focal neurological signs.
Skull fracture (with or without CSF fistula).
Brain concussion. This is a closed head injury that leads to acute loss of consciousness (usually <5 min) and/or amnesia but not to focal neurological deficits.
Brain contusion. This can be defined as closed head injury with brain tissue damage (“brain bruise”) and can lead to impaired consciousness and/or focal deficits, depending on the site and the severity of the injury.
Diffuse axonal injury (DAI)
Cerebral traumatic edema/hyperemia
Dissection, typically involving the extracranial and/or (less commonly) intracranial parts of the carotid and vertebral arteries
Dural arteriovenous (AV) fistula, e.g., carotid-cavernous sinus fistula
A lucid interval (“talk and die”) classically occurs with epidural hematoma but is also frequently associated with other intracranial hemorrhages, e.g., in warfarin-treated patients with subdural or intracerebral hemorrhage. In contrast, DAI typically leads to continuing impairment of consciousness even though the initial CT of the brain may have been interpreted as unremarkable. MRI sequences sensitive to hemosiderin (SWI, T2*) show traumatic microbleeds due to DAI. Unexpected neurological deficits despite an initially normal CT of the brain may also occur with cerebral infarction due to cerebral vascular dissections.
4.3.1 Assessing the Need for Observation and Imaging in Closed Head Injury
The necessity for observation and imaging of the patient with closed head injury depends on the severity of the trauma and the presence or absence of risk factors. Loss of consiousness, length of (anterograde) amnesia, and the GCS are the best indices of the severity of the injury.
The following rules apply for adults (≥18 years) presenting within 24 h after a closed head injury (Undén et al. 2013):
Minimal head trauma (no loss of consciousness, GCS 15): A patient with a simple blow to the head without loss of consciousness, prolonged amnesia, or focal neurological deficits can be discharged without CT scan or observation; oral and written information must be provided. Friends or relatives should be present for subsequent observation.
Mild head trauma, low risk (GCS 14 or GCS 15 with either short-lasting loss of consciousness or vomiting): These patients should be assessed by measuring serum levels of S100B. They can be discharged with written and oral information, if S100B levels are <0.10 μg/L (assessed within 6 h after the injury) and there is no evidence of significant extracranial injuries. If S100B is ≥0.10 μg/L, a CT scan must be ordered (or, alternatively, the patient is admitted for observation for at least 12 h). The patient can be discharged as outlined above, if CT is normal. Otherwise he or she is admitted for observation for ≥24 h, including neurosurgical consultation if appropriate. The CT scan should be repeated immediately if the patient’s level of consciousness decreases (GCS increase ≥2 points) and/or in case of deteriorating neurological deficits.
Mild head trauma, moderate risk (GCS 14–15 plus age ≥65 years and treatment with platelet inhibitors): These patients require a CT scan (or, alternatively, observation for at least 12 h); they can be discharged home, if the CT of the brain is normal, or must be admitted to the ward as outlined above.
Mild head trauma, high risk (GCS 14–15; and at least one of the following: treatment with anticoagulation or known coagulation disorder; clinical signs of skull fracture, e.g., crepitations, periorbital hematoma, liquorrhea, bleeding from the nose or ears, or mastoid ecchymosis; focal neurological deficits; seizures; presence of an intracranial shunt, e.g., ventriculoperitoneal): These patients need a CT scan and admission for observation as outlined above.
Moderate head trauma (GCS 9–13): These patients need a CT scan and admission for observation as stated.
Severe head trauma (GCS 3–8): These patients must be transferred to a trauma center with neurosurgical expertise available 24/7.
Obviously, patients require also admission to the ward in case of significant comorbid medical illness or any other factors that the examiner believes are putting the patient at risk.
If a CT of the brain is performed, it should be evaluated for signs of:
Epidural, subdural, subarachnoidal, intraventricular, and parenchymal hemorrhage
Brain tissue contusion
Effacement of perimesencephalic cisterns
Midline shift and brain incarceration
In case of intracranial hemorrhage, skull fracture, and mass edema or other signs of increased ICP, a neurosurgeon should be contacted without delay.
4.4 The Differential Diagnosis of Headache
The differential diagnosis of headache can be divided into:
Primary headache syndromes
The two most common primary headache syndromes are migraine and tension-type headache (Fig. 4.2). The annual sex-adjusted prevalence rate of the former has been estimated at 38% and of the latter at 35%. In comparison, the figure for the third most common primary headache syndrome, cluster headache, is only 0.15% (Evers et al. 2007; Steiner et al. 2014). Thus, the odds are very high that the patient with headache seeking medical advice either has migraine or tension-type headache. However, co-occurring medication-overuse headache should not be missed.
4.4.1 Primary Headache Syndromes
Primary headache syndromes include:
Migraine. This is a throbbing headache with features such as nausea, vomiting, phonophobia, and photophobia. Headache episodes can be preceded by a prodrome (e.g., hunger, agitation, depression, or elevated mood for several hours or up to 3 days prior to a migraine headache) and/or aura (seen in roughly 30% of migraineurs, this is an episode of focal, transitory neurologic dysfunction in the preheadache phase of a migraine attack, usually developing gradually over 5–20 min and lasting less than 60). There are many migraine variants, e.g., abdominal migraine in children and cyclical or menstrual migraine in young females. Migraine can lead to a number of complications (e.g., chronic migraine, medication-overuse headache, status migrainosus, persistent aura with and without infarction, migraine triggered seizures). The diagnostic criteria of the International Headache Society for migraine without aura include:
At least five headache attacks lasting 4–72 h (untreated or unsuccessfully treated), which have at least two of the four following characteristics: unilateral location, pulsating quality, moderate or severe intensity interfering with daily activities, and aggravation by walking on stairs or similar routine physical activity.
During headache episodes at least one of the two following symptoms must occur: phonophobia and photophobia, and nausea and/or vomiting.
The headache is not attributable to another disorder.
The diagnostic criteria of the International Headache Society for migraine with aura include at least two attacks with headache not attributable to another disorder and accompanied by symptoms fulfilling at least three of the following characteristics:
One or more fully reversible aura symptoms indicating focal cerebral cortical and/or brainstem dysfunction. Symptoms can be positive (e.g., flickering lights, spots, or lines; pins and needles) and/or negative (e.g., loss of vision, numbness). Typical auras are homonymous visual disturbance, unilateral paresthesias and/or numbness, unilateral weakness, aphasia, or unclassifiable speech difficulties.
At least one aura symptom develops gradually over ≥5 min, or two or more symptoms occur in succession.
The aura lasts less than 60 min (if more than one aura symptom is present, the accepted duration is proportionally increased).
The aura is followed by headache with a free interval lasting less than 1 h.
The headache may begin before or simultaneously with the aura.
Observe that the headache symptoms in migraine with aura do not need to meet the criteria necessary in migraine without aura; thus, headache episodes may lack migrainous features. Headache usually follows the aura symptoms but, as stated above, may begin simultaneously or precede the aura. Less commonly, headache is completely absent.
Several screening tests have been developed for migraine. One of the most practical is “PIN the diagnosis of migraine” (Lipton and Bigal 2007), which is said to have a 93% positive predictive value with two positive questions and 98% positive predictive value with three positive questions out of the following:
Photophobia: “Does light bother you a lot more than when you don’t have headaches?”
Impairment: “Does the headache limit your ability to study, work, or do whatever you need to do for at least one day?”
Nausea: “Do you feel nauseated or sick to your stomach?”
Tension-type headache. Together with migraine, this is the most common primary headache syndrome. In contrast to migraine, it is featureless, which means that apart from a squeezing headache, there are no other significant symptoms. Typically, physical activity does not worsen the pain. New-onset daily persistent headache, as suggested by its name, is de novo chronic headache that clinically resembles tension headache. However, it is necessary to exclude secondary headache forms before this diagnosis can be made.
Headache associated with abuse of painkillers (medication-overuse headache). This is probably the third most common type of headache in the general practice. With time, excessive consumption of triptans, NSAID, and opioids (≥10 days/month) obscures the original headache type. The only acceptable treatment is detoxification combined with correct treatment of the underlying headache syndrome and, if necessary, pain prophylaxis.
Trigeminal autonomic cephalalgias (TAC). These headaches are characterized by autonomic symptoms such as ipsilateral miosis, ptosis, and nasal discharge that occur together with intense, usually periorbital pain. TAC include:
Cluster headache (Horton’s headache). A typical patient is a middle-aged man (male-to-female ratio 5–10:1) waking in the early morning hours because of exceptionally severe, sharp, orbital, or periorbital pain with localized autonomic features. Attacks typically (but not always) occur in clusters lasting for a few weeks, usually with one to three headache episodes per day. The headache is always unilateral, usually reaches its peak within 15 min, and most episodes are relatively short, often between 30 and 45 min, although they may last for 3 h (or even longer). A useful rule is that the pain is so excruciating that a patient who sits or lies calmly during an attack is not having cluster headache. Indeed, almost all sufferers complain that this is the worst pain they have ever experienced. In roughly 90% of patients, onset of cluster headache is before the age of 50 years. The diagnostic criteria of the International Headache Society include:
1. Severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15–180 min if untreated.
2. Headache is accompanied by at least one of the following: ipsilateral conjunctival injection and/or lacrimation, ipsilateral nasal congestion and/or rhinorrhea, ipsilateral eyelid edema, ipsilateral forehead and facial sweating, ipsilateral miosis and/or ptosis, and a sense of restlessness or agitation.
3. Attacks have a frequency from one every other day to eight per day during most of the cluster period.
Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache with cranial autonomic symptoms (SUNA).
Other primary headache syndromes, e.g., hemicrania continua, primary cough headache, primary exertional headache, primary headache associated with sexual activity, primary stabbing headache, primary thunderclap headache, and hypnic headache. Hypnic headache is also called alarm clock headache because it starts suddenly during the morning hours and wakes the patient. It is therefore an important differential diagnostic to cluster headache, yet hypnic headache is milder and bilateral and tends to occur later in life (mean age of onset is 62 years). Also, trigeminal autonomic symptoms and remission periods are lacking.
When thunderclap headache associated with physical exertion and sexual activity occurs for the first time, subarachnoidal hemorrhage, arterial dissection, and arterial hypertension must be excluded.
Indomethacin-responsive headaches. This category overlaps with the last two. Indomethacin-responsive headaches include hemicrania continua and paroxysmal hemicrania. If in doubt, performing an indomethacin test is always advisable; see Chap. 6.
4.4.2 Symptomatic Headaches
Secondary headache syndromes (Fig. 4.2) may be due to:
Vascular disorders, including:
Cerebral venous sinus thrombosis.
Intracranial artery dissection.
Excessively high blood pressure, with or without posterior reversible encephalopathy syndrome (PRES).
Reversible cerebral vasoconstriction syndrome (RCVS). Due to improved neuroimaging, RCVS has become a common vascular headache diagnosis. Thunderclap headaches with or without physical activity occur repetitively during days or weeks. CT or MR angiograms reveal generalized cerebral vasospasm, and other causes such as primary CNS angiitis and systemic vasculitides are ruled out (e.g., CSF analysis is normal). Usually this condition is self-limiting and the prognosis good (see Chap. 6 for treatment); although rarely, vasospasms can lead to ischemic and hemorrhagic infarctions, usually borderzone infarcts, as well as cortical subarachnoidal hemorrhage (Case 4.3). Fatal cases are uncommon but well described (Case 4.4).
Reversible cerebral vasoconstriction syndrome (RCVS). A 60-year-old female presented with a 5-day history of multiple episodes of thunderclap headache. A CT of the brain showed a small cortical area with hyperintense signal change (arrow) (a), and gradient-echo MRI (SWI) revealed hemosiderin deposits consistent with a gyral SAB (b). CTA revealed spasms of multiple cerebral vessels, including the ACA (arrows; c). CSF analysis was normal. The patient was diagnosed with RCVS. Treatment with nimodipine was initiated, the headaches vanished, and 3 months later on the follow-up angiography, spasms were no longer seen
Reversible cerebral vasoconstriction syndrome (RCVS) with fatal outcome. A 58-year-old male with chronic obstructive pulmonary disease and alcoholic neuropathy was admitted with repeating thunderclap headaches over a period of 48 h. Neurological examination was normal. Non-contrast head CT and lumbar puncture, including CSF analysis for xanthochromia, were unremarkable. CT angiography revealed widespread vasospasms in the anterior and posterior intracranial circulation. A working diagnosis of RCVS was made, and treatment with 60 mg oral nimodipine six times daily was started. Over the next 2 days, episodes of confusion, blurred vision, and speech problems occurred and subsequently, the patient became obtunded (GCS 9: e2, m5, v2; FOUR 12: e1, m3, b4, r4). The patient developed a right-sided hemiparesis with bilaterally extensive toes. A second CT angiography showed progressive vasospasms (above). Treatment with epoprostenol 1 ng/kg/min in a central IV line was started 3 days after admission. However, there was no change in the clinical condition. MRI of the brain revealed widespread infarctions in both hemispheres (below). The patient died on day 7. The significance of this case is twofold. First, it shows that RCVS can be fatal despite the “R” in its name (“R” stands for “reversible”). Second, the posterior location of the infarctions is well in line with recent data indicating that RCVS and PRES are manifestations of similar underlying pathophysiologic mechanisms and that both conditions frequently coexist in a given patient (adapted with permission from Thydén et al. (2016))
Idiopathic intracranial hypertension (pseudotumor cerebri), usually encountered in obese young women.
Spontaneous CSF fistula. Note that with long-standing hypoliquorrhea, the characteristic orthostatic feature of the headache (better in the supine position) may be replaced by constant headache that is independent of the position of the body (Case 4.5).
Post-lumbar puncture headache. Risk factors include younger age, female sex, lean body shape, and a history of migraine. Using atraumatic spinal needles decreases the risk of post-lumbar puncture headache. Although the evidence is weak, performing the lumbar puncture in the lateral decubitus position may also be associated with less frequent headaches. Normohydration is important, but hyperhydration and bed rest after the procedure can no longer be recommended. If invasive treatment of the headache is warranted, an epidural blood patch may be helpful.
Spontaneous intracranial hypotension and spinal CSF leak. This 43-year-old male presented with a 6-month history of dull headache of moderate severity. The pain was consistent with an orthostatic headache, as it improved in the supine position, although the patient had noticed that lying flat did no longer alleviate symptoms to the same degree. His medical history was unremarkable, but he had suffered moderate back pain following a traffic accident 2 years prior to admission. MRI of the brain showed findings suggestive of intracranial hypotension (“brain sagging”), including bihemispheric subdural effusions (a, T2 weighted), pachymeningeal and pituitary gland contrast enhancement, a downward drooping splenium of the corpus callosum, distortion of the upper brainstem structures, and cerebellar tonsillar herniation (b, T1 weighted, gadolinium enhanced). An MRI of the spinal column revealed a fluid collection around the right pulmonary apex consistent with a cervicothoracic spinal CSF leak (c). Two blood patches were ineffective. Following discussions with the spinal surgery team, it was decided to opt for a conservative approach. Amitriptyline was slowly titrated to 75 mg once daily at bedtime with excellent clinical response
Infectious processes (e.g., abscess, cerebritis, meningitis, meningoencephalitis).
Headache with neurological deficits and CSF lymphocytosis (HaNDL), also called pseudomigraine with pleocytosis. This condition is discussed in more detail with the differential diagnosis of transitory ischemic attack (TIA)/stroke.
Trauma (e.g., post-commotio headache; typically, the severity of the pain is not proportional to the degree of the trauma)
Vascular disorders (e.g., giant cell or temporal arteritis, extracranial artery dissection)
Disorders involving the face, eyes, and oral cavity (e.g., acute glaucoma, dental pain, sinusitis, atypical facial pain, mandibular joint dysfunction). Atypical facial pain is a relatively common condition with a recognizable clinical presentation; it most often occurs in middle-aged women following dental procedures. The pain is more or less constant, moderately intense, and described as deep, aching, or boring. Typically, multiple visits to the dentist and ENT specialist have been unrewarding, neuroimaging is normal, the pain has been resistant to various analgesics, and the patient feels very distressed. Treatment consists of antidepressants and counseling, including possibly behavioral therapy, but is often unsatisfactory.
Hypercapnia. This typically leads to generalized moderate to severe throbbing headaches in the morning. Hypercapnia is often associated with sleep apnea; thus, the sleep partner should be inquired about snoring, gasping, or choking sounds and whether breathing appears interrupted; daytime sleepiness is frequent. Also, it is important to take complaints of headache in a patient with a primary myopathy such as Pompe’s disease or myotonic dystrophy very seriously. Such complaints may point to hypercapnia because of respiratory muscle failure. Does the patient need continuous positive airway pressure (CPAP) at night?
Metabolic-toxic causes, e.g., use of prescription drugs (dipyridamole, many others), use or withdrawal of illicit drugs, dehydration, caffeine withdrawal, carbon monoxide poisoning, and other causes of hypoxia.
CN neuralgias (e.g., CN V, CN IX, occipital neuralgia).
Depressive and other psychiatric disorders.
Differential diagnosis of headache
Red flags suggesting that a headache is not due to a benign cause include focal neurological deficits, worst-ever headaches, new-onset headaches, new onset of unusual headache features, migrainous headache that is always unilateral and never occurs on the other side, systemic features (meningism, weight loss, fever, diarrhea, skin rash), general malaise, and prior history of malignancy.
It is crucial not to miss the following conditions associated with acute or subacute headache:
Brain tumors, metastasis, and other mass lesions.
Parenchymal hemorrhagic stroke.
Subarachnoidal hemorrhage, including warning leaks and growing aneurysms.
Ischemic stroke, when leading to headache, is usually due to arterial dissection and/or posterior circulation infarction.
Cerebral sinus venous thrombosis.
Posterior fossa processes, e.g., cerebellar hemorrhage and Arnold-Chiari malformation (downward displacement of the cerebellar vermis and medulla through the foramen magnum).
CSF outflow obstruction, which occasionally may be intermittent, e.g., due to a colloid cyst at the foramen of Monro.
Lymphomatous or carcinomatous meningitis.
HSV type I encephalitis.
Other meningoencephalitic syndromes.
Giant cell arteritis (temporal arteritis).
Hypercapnia (see above).
Importantly, except for the first two, all of the conditions listed above may be associated with a CT that has been read as unremarkable (“CT-negative headaches”).
4.5 The Differential Diagnosis of Cognitive Impairment and Dementia
Dementia is usually defined as acquired cognitive decline that involves memory and at least one other cognitive domain that is severe enough to affect social or occupational functioning. A diagnosis of dementia cannot be established in patients with disturbed consciousness. With the increased awareness of dementia in the population and the advent of techniques for early diagnosis, patients with very mild subjective symptoms are often referred to the neurologist, and to wait for dementia criteria to be fulfilled is no longer appropriate. However, some patients presenting with mild cognitive complaints represent the “well and worried,” often young or middle-aged individuals complaining of unspecific episodes of memory slips that are described in a highly detailed manner. Characteristically, these episodes have not had any impact on performance in professional or private life except for the fact that the patient feels rather embarrassed. These patients are usually very thankful for clear reassurance that they do not fulfill the criteria of dementia or other any other cognitive impairment and that there are no findings suggesting an underlying cerebral disease. However, in some patients, a program with thorough cognitive tests, ancillary examinations, and follow-up is the only way to make sure that subtle symptoms do not represent the initial phase of a degenerative brain disorder.
When examining patients with cognitive impairment, it is important to identify and treat psychiatric conditions, by differentiating between the three “Ds”:
The differentiation may be challenging, and sometimes a treatment trial with antidepressant therapy and follow-up are needed to separate depression with cognitive symptoms from early-phase AD or FTD with prominent affective symptoms. Delirium, more common in patients with dementia, is potentially fatal and should be identified and treated immediately. Clarify and treat the underlying cause (e.g., urinary tract infection), and treat the symptoms of delirium appropriately.
Only when the “mimics” of dementia—depression and delirium—have been excluded, is it safe to diagnose the patient with dementia, but it is important to remember that dementia is a syndrome, not a diagnosis, which is why the underlying etiology must be defined (Fig. 4.3). Furthermore, patients with cognitive impairment not meeting the criteria for dementia often present to the neurologist and should be examined as thoroughly as patients with dementia. MCI is defined as impairment in memory or in a single non-memory cognitive domain, which does not (yet) impair social functioning (Petersen et al. 1999). In fact, many of the systemic conditions that may cause cognitive impairment are most often associated with mild cognitive dysfunction rather than dementia. With the advent of biomarkers, it may be possible to establish a diagnosis of a neurodegenerative disorder, e.g., Alzheimer’s disease, in the pre-dementia (MCI) stage. Of note, in their new edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the American Psychiatric Association recently introduced the terms “major neurocognitive disorder” and “minor neurocognitive disorder” as alternatives to “dementia” and “MCI” (American Psychiatric Association 2013).
Differential diagnosis of cognitive impairment and dementia
4.5.1 Potentially Reversible Conditions
In the differential diagnosis of cognitive impairment, pay particular attention to identifying potentially reversible conditions before considering a diagnosis of a (irreversible) neurodegenerative disorder, including:
Drug or alcohol abuse.
Side effects of drugs (most CNS active drugs may impair cognition, but other drugs, such as aspirin (high doses), may also give rise to cognitive symptoms).
Partial complex seizures leading to episodic impairment of cognition in a patient with unidentified epilepsy.
Chronic infections (e.g., Borrelia, neurosyphilis).
Inflammatory brain diseases (autoimmune encephalitis, sarcoidosis, vasculitis, Hashimoto’s disease).
NPH, characterized by a triad of gait ataxia, mental slowing, and urinary incontinence.
Subdural hemorrhage in a patient with a (unrecognized) head trauma, a frontal meningioma, or other space-occupying lesions may occasionally present with cognitive impairment or personality change.
Metabolic impairment, including hyper- and hypothyroidism, vitamin deficiencies (B12, B1, and B6), hyponatremia, hyperparathyroidism, hypercalcemia, Cushing disease, Addison disease, and chronic hepatic and renal failure.
Chronic sleep apnea syndrome.
4.5.2 The Amnestic Syndrome
Because neurologists often see patients with amnesia, who do not meet criteria for dementia, it is helpful to know the potential underlying causes. When isolated amnesia is thought to be a precedent to AD, it is named amnestic MCI, MCI due to AD, or prodromal AD. Amnesia may also be seen early in the course of other neurodegenerative disorders. However, there are several other causes of amnesia (Fig. 4.3):
Transient global amnesia
Concussion of the brain
Alcohol and drugs
Traumatic brain injury
Anoxic brain damage
AD (and other neurodegenerative disorders)
Ruptured AComA aneurysm
Infarcts, tumor, and hemorrhage
4.5.3 Chronic Dementia Disorders
The term dementia disorder usually refers to the chronic and progressive degenerative brain disorders, where dementia is one of the main symptoms. Few other fields in neurology are presently undergoing such rapid changes in classification as cognitive neurology. New pathophysiological insights change the way dementias are being understood and categorized. For instance, based on different abnormal protein aggregations found in the brain, neurodegenerative disorders associated with parkinsonism and dementia can be broadly classified into tauopathies (FTD, AD, PSP, CBD) and synucleinopathies (Parkinson’s disease, DLB, multiple system atrophy, neurodegeneration with brain iron accumulation (NBIA) type I). With the application of neuroimaging (MRI with assessment of total brain and hippocampal volumes, FDG PET, DAT-SPECT, and amyloid PET) and CSF biomarkers for AD, it is possible to differentiate the most common neurodegenerative disorders and to establish an accurate diagnosis early in the course of the disease, even before dementia evolves. The most commonly used current clinical criteria for the neurodegenerative dementia disorders are listed in Table 4.1.
Clinical criteria for dementia disorders
Dementia (as a syndrome)
World Health Organization (2010)
Major neurocognitive disorder
American Psychiatric Association (2013)
Mild cognitive impairment (MCI)
Petersen et al. (1999)
Minor neurocognitive disorder
American Psychiatric Association (2013)
MCI due to Alzheimer’s disease (AD)
Albert et al. (2011)
Alzheimer’s disease (prodromal)
International Working Group
Dementia due to AD
McKhann et al. (2011)
Posterior cortical atrophy
International Working Group
Crutch et al. (2013)
Román et al. (1993)
Vascular cognitive impairment
Sachdev et al. (2014)
Dementia with Lewy bodies (DLB)
McKeith et al. (2005)
Behavioral variant FTD (bvFTD)
International bvFTD consortium
Rascovsky et al. (2011)
Semantic dementia (SD)
International primary progressive aphasia working group
Gorno-Tempini et al. (2011)
Progressive nonfluent aphasia (PNFA)
International primary progressive aphasia working group
Gorno-Tempini et al. (2011)
Chronic dementias may be further divided into:
Primary cortical dementias
Primary subcortical dementias
Dementias that are both cortical and subcortical from the onset
Primary cortical dementias are those that, at least in the beginning, tend to affect either higher cognitive domains such as memory, language function, visuospatial orientation, praxis, gnosis (e.g., AD), and/or personality (e.g., FTD). As a rule of thumb, early in the course of the disease, there are little or no noncognitive neurological deficits. Primary cortical dementias include AD and FTD.
Primary subcortical dementias, in contrast, tend to leave higher cortical functioning relatively spared early in its course, but there is characteristic psychomotor retardation and often depressive symptoms. Moreover, patients with primary subcortical dementias tend to have more focal neurological deficits revealed during bedside examination. These dementias include, for instance, subcortical vascular dementia and NPH.
However, most dementias have elements of both cortical and subcortical symptoms with a mixture of cognitive and noncognitive neurological and psychiatric symptoms.
The most common dementia disorders are:
Alzheimer’s disease. Its cognitive deficits are prominent, whereas personality is largely preserved until the late stages (Albert et al. 2011; McKhann et al. 2011). Episodic memory impairment is very characteristic in the early phase, but atypical presentations with specific deficits in other non-memory cognitive domains are also seen (Case 3.1). Familial autosomal dominant AD is rare, as compared to sporadic AD, and is associated with mutations in the amyloid precursor (APP), presenilin (PSEN)-1 or PSEN-2 genes. Posterior cortical atrophy is a variant of AD, with isolated disruption of visual processing but reasonable day-to-day memory. Patients with posterior cortical atrophy may have partial Balint’s syndrome, simultanagnosia, visual inattention, topographical disorientation, impaired face and object recognition, or isolated deficits in writing, reading, and praxis (Crutch et al. 2013) (See Case 5.5).
Frontotemporal dementias. The categorization of FTD syndromes and underlying pathologies is rather complex. Specific syndromes are associated with the familial autosomal dominant FTDs: FTD with mutation in the MAPT, progranulin, chromosome 9 open reading frame 72 (C9ORF72), and CHMP2B (FTD-3) genes. Some of these patients develop FTD in combination with MND or PD. The general neurologist should be able to identify the most common syndromes because counseling and rehabilitation differ:
Behavioral variant frontotemporal dementia (bvFTD, sometimes still known as Pick dementia). It is characterized by striking personality and behavioral changes, executive dysfunction, impaired sympathy and empathy, perseverate, stereotypic or compulsive behavior, apathy or disinhibition, and lack of insight but relatively intact memory early in the course of the disease (Cases 2.15 and 4.6) (Rascovsky et al. 2011).
Primary progressive aphasia is often used as a term for degenerative disorders with aphasia at onset, which comprise progressive nonfluent aphasia (PNFA), semantic dementia (SD), and logopenic aphasia (Gorno-Tempini et al. 2011).
Progressive nonfluent aphasia (PNFA). Personality and cognitive domains other than expressive language function are usually spared until late in its course. Characterized by effortful halting speech, phonological errors, and agrammatism, PNFA is often associated with impaired comprehension of complex sentences (but spared comprehension of words, object knowledge and repetition, and relatively intact insight) (Case 4.7).
Semantic dementia (SD). This is a condition of primarily severe fluent aphasia with relatively intact episodic memory function. Characterized by impaired confrontation naming and single-word comprehension, often associated with impaired object knowledge and surface dyslexia but with spared repetition and speech production. Patients with SD may have bizarre delusions and hyper-religious thoughts. Recent studies indicate that their semantic deficits may improve with training (Case 2.17).
Characterized by hesitant speech and anomia, logopenic aphasia is a language disorder which is sometimes seen in early-phase AD.
Behavioral variant frontotemporal dementia (bvFTD). A 68-year-old female was referred to the memory clinic for evaluation of behavioral changes and functional decline during the past 2 years. She had gradually withdrawn from social activities, had developed a preference for candy, was apathetic, and lacked empathy. There were no focal deficits, but she had difficulties cooperating during the neurological examination. Neuropsychological testing revealed lack of insight, pronounced apathy, and impaired naming, abstraction, and executive functions, but no amnesia. CSF and EEG were normal. CT of the brain showed bilateral frontotemporal atrophy (a), and FDG PET revealed hypometabolism in the same area (b). She was diagnosed with bvFTD (PET images courtesy of Ian Law, Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet, Copenhagen)
Progressive nonfluent aphasia (PNFA). A 64-year-old male complained of increasing word-finding and pronunciation difficulties over the previous 2–3 years. He was still able to work as a carpenter. The MMSE score was 26/30. The neurological examination was unremarkable except for disturbed word fluency and naming, as well as mildly impaired psychomotor speed and executive functions. CSF analysis and EEG were normal. MRI demonstrated global cortical atrophy, which was most severe in the left frontal and anterior temporal lobe (a). FDG PET showed frontotemporal-parietal hypometabolism, which was most pronounced on the left side (b). He was diagnosed with PNFA (PET images courtesy of Ian Law, Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet, Copenhagen)
Vascular dementias. Cognitive disorders of vascular etiology are a heterogeneous group of disorders with diverse pathologies (e.g., dementia following strategic infarctions, small vessel disease, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)) and clinical manifestations (e.g., acute onset, a stepwise progression, or a gradual progression). For a diagnosis of vascular dementia to be made, there must be neuroradiological evidence of significant vascular disease. The vascular lesions must be related in terms of localization to the extent and severity of cognitive impairment (Román et al. 1993). For patients with strategic infarcts, the vascular lesions must be related to the onset of dementia. Patients with cognitive impairment due to cerebrovascular disease have a characteristic clinical profile and may not always meet criteria for dementia (or major neurocognitive disorder), which was taken into account by the International Society for Vascular Behavioral and Cognitive Disorders in their recently published clinical criteria for vascular cognitive impairment (Sachdev et al. 2014).
Note that many elderly patients with AD also have small subcortical vascular lesions (and these patients may be classified as having mixed AD dementia).
Dementia with Lewy bodies (DLB) is characterized by fluctuations of wakefulness and cognitive impairment, prominent visuospatial deficits (and less prominent memory impairment) in the early phase of the disease, vivid visual hallucinations, REM sleep disorders, parkinsonism, and sensitivity for antipsychotic drugs (which should be avoided or prescribed with minimal doses and short duration) (McKeith et al. 2005).
Parkinson’s disease with dementia. Up to 70% of patients with PD develop cognitive impairment with a similar profile to DLB during the course of their disease. The distinction between DLB and PD with dementia is somewhat arbitrary. When cognitive impairment occurs at least 1 year prior to parkinsonism, the diagnosis is DLB; otherwise, it is classified as PD with dementia (Emre et al. 2007).
The so–called Parkinson plus disorders such as MSA, CBD, PSP, and DLB. CBD is characterized by a combination of frontal dysfunction (e.g., personality change, impaired reasoning), speech and language impairment, and asymmetric motor features with alien limb, myoclonus, limb apraxia, rigidity, and/or akinesia. PSP is associated with cognitive impairment in combination with frequent falls and (vertical) gaze palsy, often with axial rigidity, gait disorder, and retropulsion. For more information, see Sect. 4.14.
Huntington’s disease (HD). This is an autosomal dominant trinucleotide repeat disorder with characteristic neuropsychiatric symptoms, dementia, and chorea leading inevitably to death. HD may present with cognitive impairment, personality change, or psychiatric symptoms years before chorea (Case 4.8).
Huntington’s disease. A 45-year-old female had been dismissed from her job because of inappropriate sexual behavior. Her family history was noticeable insofar as her father had developed late life chorea. Examination showed subtle choreiform movements of her hands and feet. Genetic testing revealed that the patient carried the gene mutation for HD with 47 CAG repeats on the expanded allele. CT of the brain showed marked bilateral caudate atrophy (a). An image of a normal brain is shown for comparison (b)
Other causes of cognitive impairment or dementia (see also potentially reversible dementias above):
Chronic psychiatric diseases:
Heavy metal poisoning
Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS)
Lysosomal and peroxisomal storage diseases
Chronic CNS infections:
HIV dementia, associated with a low CD4+ T-cell count and long duration of immunosuppression
CJD, the most common prion disease characterized by rapidly progressive dementia, ataxia, and myoclonus
Progressive multifocal leukoencephalopathy (PML), due to John Cunningham (JC) virus (Case 4.9)
Subacute sclerosing panencephalitis (SSPE)
Progressive multifocal leukoencephalopathy (PML). A 61-year-old female presented with a 6-week history of progressive aphasia, right-sided hemiplegia, gait ataxia, and focal epileptic seizures. She was receiving immunosuppressive therapy for a kidney transplantation undertaken 10 years earlier. MRI with axial T2-weighted sequences and coronal FLAIR showed confluating white matter signal changes in the left frontal lobe (a, b). Cerebrospinal fluid PCR was positive for JC virus, and a diagnosis of PML was made. An MRI 2 months later showed progressive white matter involvement (c, d), and the patient died 4 months later
Korsakoff’s syndrome and Wernicke’s encephalopathy. Acute thiamine deficiency that is not immediately reversed may lead to permanent anterograde and retrograde amnesia with confabulation (Korsakoff’s syndrome). Although other cognitive domains remain relatively spared, this is a devastating condition.
Decreased cognitive performance related to long-term alcohol abuse and brain atrophy on neuroimaging may be partially reversible (but represents a controversial entity).
4.5.4 Rapidly Progressive Dementias
As stated above, cognitive impairment of acute or subacute onset must be differentiated from chronic dementias. Rapidly progressive dementias may develop within a few months, weeks, or even days. Compared to chronic dementias, the spectrum of rapidly progressive dementias is quite different. Many of these disorders are fatal, but some are treatable, which is why it is of the utmost importance to evaluate patients presenting with fast cognitive decline without delay. Although far from being complete, the following section is useful as a diagnostic guideline for the assessment of rapidly progressive dementias when the preliminary diagnostic procedures have been unrewarding. When initial diagnostic procedures, including neuroimaging, CSF exam, routine blood tests, and medication review, have been without obvious explanation, the most common rapidly progressive dementia is CJD (Case 4.10).
Creutzfeldt-Jakob disease. A 59-year-old female complained of visual disturbances with altered color perception, stating, for example, that the sky was no longer blue but greenish. During the following 2 months, she developed progressive cognitive deficits, aphasia, and confusion. In addition, neurological examination revealed lead pipe rigidity in the limbs, dystonic posturing of the right arm, and gait ataxia. CSF analysis showed normal cell count and protein levels but highly increased total tau protein and CSF 14-3-3 protein levels. Serial EEG revealed increasing abnormalities and, finally, typical periodic triphasic sharp wave complexes (not shown). MRI of the brain included normal T1- and T2-weighted images, but there were bilateral hyperintense signal changes in the cortex and in the basal ganglia on DWI (a). Because of slightly increased thyroid antibodies levels, the patient was treated with high-dose steroids for 10 days but, as anticipated, subsequently became mutistic and developed generalized myoclonus. She died 1 month after admission. Autopsy confirmed the diagnosis of CJD. Isolated visual impairment at onset, including blurred vision, visual field restriction, metamorphopsia, cortical blindness, and/or hallucinations, is seen in roughly 20% of CJD patients and reflects neuronal loss and gliosis in the occipital lobes (Heidenhain variant) (adapted with permission from Kondziella et al. (2012)). Figures (b) and (c) show the serial EEG of another patient, also ultimately diagnosed with CJD. Six weeks after onset of depressive mood symptoms, confusion, and word-finding difficulties, EEG showed regional slowing of background activity and sharp waves in the left temporal region (b). In the following 2 weeks, he became mutistic and bedridden, and EEG revealed generalized periodic epileptiform discharge activity (c). He died 2 days later (EEG images courtesy of Hans Høgenhaven, Department of Clinical Neurophysiology, Rigshospitalet, Copenhagen)
Of 178 patients referred to a tertiary center in the USA with a working diagnosis of suspected prion disease or rapidly progressive dementias, 62% had CJD (75% sporadic CJD, 22% familial CJD, 3% vCJD or iatrogenic CJD) (Geschwind et al. 2008).
Thirty-eight percent had a non-prion disease:
Neurodegenerative disorders (in order of frequency: CBD, FTD, AD, DLB, PSP)
Autoimmune disorders (steroid-sensitive encephalopathy with antithyroid autoantibodies, also known as Hashimoto’s encephalopathy; antibody-mediated autoimmune encephalitis, including paraneoplastic and non-paraneoplastic; MS; neurosarcoidosis)
Infectious causes (viral meningoencephalitis of unknown origin)
Malignancy (including primary cerebral lymphoma and antibody-negative paraneoplastic syndromes)
Toxic-metabolic reasons (ethanol, methotrexate)
Vascular findings not further specified
Obviously, this list is biased insofar as the referring institutions had excluded most of the malignant, infectious, vascular, and drug-induced causes for rapidly progressive dementias prior to referral. Diagnoses that are not reported by Geschwind et al. but by others who have performed similar studies at tertiary referral centers include:
PML (see Case 4.9).
Neuronal ceroid lipofuscinosis.
MELAS (see Case 4.26).
In the young, Wilson’s disease and Niemann-Pick’s disease should always be excluded.
Elderly men with GI symptoms, weight loss, ataxia, and dementia may have Whipple’s disease.
Valproate encephalopathy, which usually develops in the elderly after prolonged valproate use, is reversible upon discontinuation of valproate.
Hereditary storage diseases may occasionally first manifest during adulthood.
It is mandatory not to miss the treatable mimics of CJD. In particular, Hashimoto’s encephalitis and certain forms of antibody-mediated limbic encephalitis can imitate CJD and respond within days to corticosteroids or plasma separation. A steroid trial seems reasonable in any very rapidly progressive dementia patient with the slightest diagnostic uncertainty.
Brain biopsy may be useful in rare and atypical cases of (rapidly) progressive dementia (see Chap. 5).
4.6 The Differential Diagnosis of Encephalopathy
Encephalopathy is a state of global brain dysfunction with acute or subacute onset, and it has a variety of underlying etiologies (Fig. 4.4). Most of these were discussed previously or will be discussed in the following chapters in the sections on coma, dementia, epilepsy, infections, and malignancies. As a result, no further comments will be made here, apart from a short review of autoimmune encephalitis and posterior reversible encephalopathy syndrome (PRES).
Differential diagnosis of encephalopathy
Autoimmune encephalitis (AIE) is a group of inflammatory antibody-mediated CNS diseases with neurological and psychiatric symptoms. Patients often have deficits compatible with affection of the limbic system (e.g., amnesia, confusion, and epileptic seizures), but the inflammatory process frequently involves extra-limbic brain structures as well. Symptom onset is usually subacute, ranging from days to weeks. A more insidious onset with depression or hallucinations may lead to a misdiagnosis of psychiatric illness. Previously, AIE was considered a very rare paraneoplastic condition associated with intracellular antibodies and a very poor prognosis (e.g., anti-Hu syndrome). However, during the last two decades, it has become evident that AIE is much more frequently associated with antibodies directed against synaptic/cell membrane proteins and that, more often than not, an underlying malignancy is absent. The two most frequent conditions are AIE with antibodies against glutamate receptors of the N-methyl-d-aspartate (NMDA) type and AIE with antibodies against a protein associated with the voltage-dependent potassium channel (leucine-rich glioma-inactivated 1; LGI1). The former is typically seen in children and young adults, whereas the latter occurs more frequently in the elderly. Of note, prognosis in AIE with synaptic surface protein antibodies can be good, if aggressive immunomodulatory treatment is initiated early. Treatment (see Chap. 6) consists of high-dose steroids plus IVIG or plasmapheresis, occasionally followed by treatment escalation using rituximab or cyclophosphamide, and tumor removal where appropriate. However, chronic cognitive deficits are frequent.
AIE associated with intracellular paraneoplastic antibodies. These conditions are rare. The diagnosis of paraneoplastic AIE requires the demonstration of cancer within 5 years of the diagnostic neurological symptoms or the detection of well-characterized onconeuronal, intracellular antibodies, e.g.:
Ri (breast, small cell lung cancer, (SCLC))
Yo (breast, ovarian)
Amphiphysin (breast, lung)
CV2 (SCLC, thymoma)
Antibodies against glutamic acid decarboxylase (GAD), which is also an intracellular protein, are only occasionally associated with paraneoplastic limbic encephalitis, and their pathogenic properties remain unclear. Of note, anti-GAD antibodies are seen with stiff person syndrome.
AIE associated with antibodies against neuronal surface or synaptic antigens. These conditions are relatively common. They occur more often than not without malignancy, although searching for an underlying neoplastic process is always mandatory.
Voltage-gated potassium channel (VGKC) complex:
Leucine-rich glioma-inactivated 1 (LGI1). This is one of the two most frequent AIE. It is typically seen in middle-aged people and the elderly (>40 years). Men are twice as often affected as women. Less than 5% of cases are associated with malignancies. Characteristically, anti-LGI1 encephalitis is associated with hyponatremia and faciobrachial dystonic seizures, an epileptic syndrome preceding the onset of limbic encephalitis. Anti-LGI1 encephalitis is a classical limbic encephalitis, leading to mesial temporal lobe inflammation and related neurological symptoms, including amnesia, neuropsychiatric features, and epilepsy. Increased signal activity on MR T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences may be seen in the temporal lobes corresponding to inflammatory infiltrates (although these imaging changes can be subtle or even missing in the early and late stages of the disease), and FDG PET of the brain typically shows focal hypermetabolism in one or both temporal lobes. EEG reveals focal slowing and/or epileptic activity involving the temporal lobes. CSF is usually slightly inflamed with pleocytosis, increased protein levels and/or oligoclonal bands, and IgG index, but occasionally can be normal (Case 4.11).
Contactin-associated protein-like 2 (CASPR2). This antibody is associated with Morvan’s syndrome, consisting of neuromyotonia, autonomic dysfunction, hallucinations, and severe insomnia.
Limbic encephalitis with anti-LGI1 antibodies. A 69-year-old previously healthy male presented with a 2-week history of behavioral disturbances, including anxiety, hypochondriac complaints, and motor hyperactivity. The neurological examination was unremarkable except for slight motor agitation. Over the next few days, the patient had several episodes of sudden onset of unresponsiveness and orofacial automatisms, including frequent jerks of the right side of the face and ipsilateral arm (faciobrachial dystonic seizures). The episodes lasted for 30–60 s. Routine blood tests showed hyponatremia. An EEG revealed epileptic spike-and-wave activity bilaterally with predominance in the left prefrontal lead (a; asterisk). MR of the brain revealed slight hyperintense signal change on FLAIR sequences in the left mesial temporal lobe (b). FDG PET showed an area of increased metabolism in the same area (c). Analysis of CSF was notable for slightly increased protein (0.66 g/L) but was otherwise normal. A whole-body PET CT did not reveal signs of systemic malignancy. When CSF analysis revealed anti-LGI1 antibodies, the patient was diagnosed as having limbic encephalitis associated with anti-LGI1 antibodies. Treatment with high-dose steroids, IVIG, and lamotrigine resulted in significant clinical improvement, although moderate neuropsychiatric disturbance and memory deficits remained (EEG image courtesy of Hans Høgenhaven, Department of Clinical Neurophysiology, Rigshospitalet, Copenhagen)
N-Methyl-d-aspartate (NMDA) receptor. This is the other of the two most frequent AIE. It typically affects children and young adults who present with sudden neuropsychiatric features followed by seizures, encephalopathy, and oral automatisms. A prodromal phase with fever and headache often occurs a few days to 2 weeks before manifestation of neurological symptoms. The majority of patients are female, and 20–50% of cases are associated with ovarian teratoma. Anti-NMDA encephalitis may be fatal because of autonomic failure including central hypoventilation, catatonia, and cardiac arrhythmia. In contrast to other AIE, NMDA receptor encephalitis may be associated with a relatively high CSF cell count (up to 200 cells/mm3) and a characteristic EEG pattern termed extreme delta brush (Case 4.12). Cases of NMDA receptor encephalitis following herpes simplex encephalitis are increasingly recognized (Case 4.13).
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.
mGluR5, associated with Ophelia syndrome (a form of limbic encephalitis occurring together with Hodgkin’s lymphoma).
GABAa receptor and GABAb receptor.
Glycine receptor and many others.
N-Methyl-d-Aspartate receptor (NMDAr) encephalitis. A 26-year-old previously healthy woman had a 2-week history with progressive signs of disorientation, disorganized speech, altered behavior, and disturbances of sleep and memory. She was admitted to a psychiatric department where she stayed for a total of 3 weeks. Upon admission, she presented with varying and fluctuating behavioral symptoms (screaming, aggression, inappropriate sexual behavior), formal thought disturbance (vague or incoherent speech), and delusions (e.g., paranoia and somatic delusions). She also had prominent perceptual disturbances (arms felt like clay, the consistency of food felt altered) and auditory hallucinations (rhythms), as well as fluctuating catatonic symptoms (e.g., staring, verbal stereotypies, bizarre movements and actions, waxy flexibility, mutism, and stupor). She was treated with atypical (olanzapine) and typical (haloperidol) neuroleptics as well as benzodiazepines (oxazepam), with no or very limited response. She then received six electroconvulsive treatments (ECT). Due to the lack of treatment response, development of convulsive seizures, increasing catatonia, and autonomic dysfunction (central hypoventilation), she was transferred to the department of neurology with a working diagnosis of autoimmune encephalitis. EEG showed an encephalopathic pattern with excess of delta activity, including “brief ictal rhythmic discharges” (BIRD; but no “extreme delta brushes”). MR FLAIR revealed a cortical parietal lesion on the right. Empirical treatment with high-dose steroids and plasmapheresis was initiated with excellent response, both with respect to the psychiatric and the neurological symptoms. Her lesion had vanished on follow-up MRI 2 weeks later. CSF analysis showed a mild lymphocytic pleocytosis (45 cells) and a strong IgG anti-NMDAr antibody titer, confirming the diagnosis of NMDAr encephalitis. Screening for malignancy, including ovarian teratoma, was negative. The patient was put on maintenance prednisolone which was slowly tapered, while azathioprine was commenced as a steroid-sparing agent. Three years later, when it was decided that withdrawal of immunosuppressive treatment was safe, she was fully independent in her activities of daily living. Yet she suffered from cognitive sequelae, including decreased levels of concentration and short-term memory deficits, which had forced her to abandon her job as a nurse
Post-herpetic NMDAr encephalitis. A 44-year-old male, the owner of a large chain of stores with several hundred employees, developed headache and tiredness but did not seek medical advice. After 5 days, he appeared confused during a business meeting and his colleagues called an ambulance. On admission, he had a focal seizure, starting with a blank facial expression and lip smacking, evolving into twitching of the left corner of his mouth and finally leading to generalized tonic-clonic convulsions. His body temperature was elevated. CT showed a right temporal hypodensity. CSF analysis revealed a lymphocytic pleocytosis (500 cells, 0.91 g protein). Treatment with intravenous aciclovir was commenced immediately. Herpes simplex type 1 DNA was identified by polymerase chain reaction (PCR), thereby confirming the diagnosis of herpes simplex encephalitis. MRI showed severe inflammatory edema primarily involving the right temporal lobe; minor lesions were seen affecting the left insula, the left mesial temporal lobe, as well as the cingulate cortex (a; FLAIR). His condition improved during the next 4 weeks and he was discharged home, albeit with moderately severe amnestic dysfunction. Back at work, he felt unable to fulfill the requirements of his former position as CEO and started as a sales assistant in one of his own stores. Two weeks later, he experienced an episode of paranoid hallucinations and agitation, leading to admission to a psychiatric department. Although his agitation quickly subsided, visual and auditory pseudohallucinations (i.e., he was able to recognize that these vivid sensory experiences were not real) persisted which were both pleasant and unpleasant. For instance, on one occasion, he saw his little son lying in bed next to him involving him in a friendly chat, while on another occasion, he saw black thick hair growing from the walls and the ceiling. The patient was fully awake and responsive; his MMSE was 26/30. There was no suspicion of subclinical seizure activity, and no paroxystic activity was noted during EEG. MRI showed moderately severe atrophy and hippocampal sclerosis, predominantly involving the right hemisphere (b). Lumbar puncture revealed six cells and normal protein; HSV DNA was negative. However, CSF IgG anti-NMDAr antibody titer was strongly positive. A diagnosis of post-herpes NMDAr encephalitis was made. Following treatment with high-dose steroids and IVIG, pseudohallucinations ceased within a few days. The patient was put on oral prednisolone maintenance therapy. He was back to baseline with moderate cognitive deficits within 2 weeks, fully able to cope with his activities of daily living but unable to take responsibility for the management of his business (mRS 2)
Seronegative. In seronegative AIE no antibodies can be detected, but new antibodies are described at an astonishing pace, and many of these patients will probably harbor antibodies that are yet to be isolated. As stated above, in all patients with AIE, including those who are seronegative, it is crucial to look for a systemic malignancy.
PRES is characterized by subacute onset of seizures, headache, confusion, and visual disturbances, often even cortical blindness. Arterial hypertension plays a role in two-thirds of all patients, but other causative factors include pregnancy (preeclampsia/eclampsia), allogenic or solid organ transplantation, autoimmune disorders, cytotoxic medication, and sepsis. The posterior circulation has relatively poorer sympathetic innervation than the anterior circulation, probably because it is phylogenetically much older. Thus, harmful stimuli such as severe hypertension may lead to breakdown in cerebral autoregulation, predominantly in the parietal and occipital lobes (and infratentorially), which explains the clinical symptoms. The diagnosis is based on clinical presentation and T2-weighted or FLAIR MR. The treatment includes blood pressure treatment, withdrawal of offending agents, and treatment of sepsis and other causes and usually requires admission to a neuro-ICU. PRES is largely reversible, although infarcts and intracerebral hemorrhages (ICH) do occur. Of note, PRES can be associated with RCVS, and vice versa. Prognosis is mainly related to the underlying disease (Case 4.14).
Posterior reversible encephalopathy syndrome (PRES). A 35-year-old female with SLE and chronic renal failure complained of severe headache and cloudy vision. Three hours later she became unconscious with eyes and head deviating to the left and upward, followed by generalized tonic-clonic convulsions, urinary incontinence, and lateral tongue biting. Her blood pressure was 243/134 mmHg. T2-weighted MRI showed hyperintense signal involving the occipital and parietal lobes bilaterally, consistent with severe vasogenic edema and a diagnosis of PRES (a, b). Following aggressive blood pressure control and symptomatic treatment, she made a full recovery within a few days. MRI 2 months later showed complete resolution of the white matter abnormalities (c, d)
4.7 The Differential Diagnosis of Epilepsy
It is mandatory to clearly distinguish between the terms epilepsy, epileptic seizures, epileptic syndromes, and status epilepticus. The epilepsy community, under the framework of the International League Against Epilepsy (ILAE), is continually reviewing and revising definitions, according to the latest developments in the field. This effort is particularly admirable as every community member is invited to make their voice heard, and all comments are posted openly on the ILAE’s website.5 Admittedly, for the non-epileptologist neurologist, these rapidly changing definitions can sometimes appear somewhat confusing. However, it is important to understand that this is work in progress with the final vision of providing clinically practical classifications that reflect current pathophysiological knowledge and that are endorsed by the entire epilepsy community.
4.7.1 Practical Clinical Definition of Epilepsy
According to an official report published by the International League Against Epilepsy (ILAE) in 2014, epilepsy is “a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome.”
The report specifies further that “epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years” (Fisher et al. 2014).
The perhaps most significant clinical implication of this revised definition (as opposed to the traditional definition, which required a mandatory number of at least two unprovoked seizures) is the fact that epilepsy now can be diagnosed (and treated!) in a patient presenting with a first-time focal seizure due to an acquired brain lesion.
4.7.2 Epileptic Seizures
An epileptic seizure is the clinical manifestation of abnormal and excessive hypersynchronous electrical discharge of a population of cortical neurons. The semiology of the epileptic seizure reflects the cortical representation and possible seizure spread to other brain regions, including the contralateral hemisphere. Depending on the involved cortical areas, an epileptic seizure leads to motor, sensory, autonomic, and/or psychic symptoms. Sensory and psychological symptoms can only be experienced and described by the patient and are called aura. It is important to understand that the aura represents epileptic cortical activity; its presence suggests a defined cortical lesion; thus, when occurring unprovoked and repeated, the patient is having partial (or focal) epilepsy. Although structural lesions account for <50% of all cases of epilepsy, this proportion is much higher in patients with partial epilepsies and in those with a later onset, in particular those over the age of 60. As a result, the etiology is structural in most new-onset epilepsies.
Epileptic seizures must be distinguished from syncope, psychogenic nonepileptic attacks, and other causes of paroxysmal events (Fig. 4.5). Epilepsy is suggested by unprovoked stereotyped and repeated events occurring with (or without) aura, automatisms, convulsions, lateral tongue biting, posturing, incontinence, postictal confusion, and muscle soreness. As stated above, it is mandatory to assess whether a generalized tonic-clonic seizure has a focal start or not; this is done by asking the patient and witnesses about a possible focal seizure onset and if there have been prior episodes consistent with partial seizures. The latter is particularly important because the patient may not volunteer this information, believing that these episodes are not related to the present event. Most epileptic seizures last no longer than 2–3 min. If a patient describes intermittent spells of symptoms lasting for more than 30 min, it is unlikely that these are epileptic seizures.
Differential diagnosis of blackouts, seizures, and drop attacks
In 1981, the ILAE put forward a classification scheme for seizures, and in 1989, it introduced a classification scheme for epilepsies and epileptic syndromes. Both classifications remain in common use. Yet, modern neuroimaging, genomic technologies, and molecular biology are providing new insight into the pathophysiology of seizures and epilepsies. As a result, the ILAE Commission on Classification and Terminology issued a revised classification called ILAE Proposal for Revised Terminology for Organization of Seizures and Epilepsies 2010, which is shown in Table 4.2. However, because this update is once again under revision, many general neurologists still rely on the classifications from 1981 for seizures and from 1989 for epilepsies and epileptic syndromes. According to these, seizures are categorized as generalized, focal, or unclassified based on clinical grounds and EEG evaluation.
Partial (focal, local) seizures
Simple partial seizures (seizures without impairment of consciousness).
Complex partial seizures (seizures with impairment of consciousness).
Focal seizures may generalize secondarily. This is usually the case when epileptic activity in one hemisphere spreads to the other hemisphere.
Atypical absence seizures
Secondary tonic-clonic generalized seizures
Unclassifiable seizures, usually due to lack of clinical data
International League Against Epilepsy (ILAE) Proposal for Revised Terminology for Organization of Seizures and Epilepsies 2010
Classification of seizures
Absences with special features (myoclonic absence, eyelid myoclonia)
Myoclonic (myoclonic, myoclonic-atonic, myoclonic-tonic)
Focal seizures are characterized according to one or more features:
Aura, motor, autonomic, and altered or retained awareness/responsiveness
Focal seizures may evolve to bilateral convulsive seizures (previously termed “secondarily generalized”)
Unknown (insufficient evidence to classify as generalized, focal, or both)
Classification of seizure etiology
Electroclinical syndromes and other epilepsies grouped by specificity of diagnosis
Electroclinical syndromes; they may be arranged by, for example, age of onset: benign neonatal seizures (neonatal period), Dravet syndrome (infancy), CAE (childhood), JME (adolescence-adulthood)
Distinctive constellations/surgical syndromes, e.g., mesial temporal lobe epilepsy with hippocampal sclerosis
Nonsyndromic epilepsies; they do not meet criteria for specific syndromes or constellations and are attributed to and organized by structural-metabolic causes, e.g., due to tumor, infections, and vascular malformations
Epilepsies of unknown cause
Most generalized convulsions starting in adulthood are secondarily generalized. Convulsions in sleep are mostly secondarily generalized, whereas convulsions following awakening are usually primary generalized.
Figure 4.5 provides a diagram of the differential diagnosis of epileptic seizures.
4.7.3 Epileptic Syndromes
After classifying seizures as described above, the neurologist attempts to define the epilepsy syndrome. This is done by analyzing the following:
Site of seizure onset (focal, generalized, or unclassifiable)
Symptomatic, a structural or metabolic cause is known.
Cryptogenic, likely to be symptomatic; a structural cause is assumed but not identified.
Idiopathic, implies a presumed genetic cause with age-specific seizure onset, normal brain imaging, and usually responds well to AED therapy.
Table 4.2 shows the classification of epileptic syndromes as suggested in the ILAE Proposal for Revised Terminology for Organization of Seizures and Epilepsies 2010.
There are dozens of epilepsy syndromes, too many to list them all here. Localization-related epilepsy syndromes in adults may be caused by, e.g., trauma, hippocampal sclerosis, brain tumors, cortical dysplasias, and vascular CNS malformations. Some of these syndromes include:
Temporal lobe seizures. Can be very frequent and may occur several times per day. Hippocampal sclerosis is the most common cause of adult epilepsy. Chapter 2 discusses the semiology of mesial and cortical/lateral temporal lobe epilepsy.
Frontal lobe seizures. Since the frontal lobes are large, the semiology of frontal lobe seizures is varied. The so-called Jacksonian “march of convulsion” is the spreading of seizure activity along the primary motor cortex with characteristic sequence of motor phenomena in the arm and face. Occasionally, postictal transient focal weakness may occur (Todd’s phenomenon). Supplementary motor area seizures are characteristically adverse seizures characterized by head and eyes turning away from the seizure focus and jerking or elevation of the arm contralateral to the focus (fencing, the sign of four). Frontal lobe epileptic seizures associated with sleep tend to be short-lasting (<1 min), are secondarily generalized, and postictal confusion is generally lacking. There is bizarre motor activity such as cycling, punching, running, and shouting (hypermotor seizures). Frontal lobe seizures are therefore often mislabeled as psychogenic. Speech arrest or dysphasia suggests focus in the dominant hemisphere; the opposite is true if speech is rather unaffected during ictus.
Occipital seizures. Often provoke contralateral visual (pseudo-) hallucinations and ipsilateral eye deviation to the side of the focus (see Chap. 2).
Idiopathic generalized epilepsies include, among others:
Juvenile myoclonic epilepsy (JME). This epilepsy syndrome is associated with myoclonus in the early morning hours, generalized tonic-clonic seizures on awakening, and (to a lesser degree) absences and photosensitivity. Seizures occur particularly often following sleep deprivation and alcohol withdrawal. JME usually manifests in teenage years and, despite its name, is usually a lifelong disorder. Only one-third or less of all JME patients are seizure-free after 25 years and no longer need AED treatment (Cramfield and Cramfield 2009).
Juvenile absence epilepsy (JAE). There is clinical overlap with JME. Absences are characterized by sudden onset and offset of impaired consciousness, sometimes accompanied by eyelid myoclonus or automatisms, and brief duration (5–10 s). Absences may be mild or severe and may occur several hundred times per day. They can be distinguished from complex partial seizures by their short duration, lack of postictal confusion, and their characteristic EEG pattern (sudden onset and termination of generalized 3 Hz spike-and-wave activity). Also, a typical absence seizure can often be reproduced by 1 or 2 min of hyperventilation, whereas a complex partial seizure cannot. Occasionally, absence status epilepticus leads to a “twilight” state in which patients are amnestic and not interacting normally but may remain able to perform basic activities.
Childhood absence epilepsy (CAE), also known as pyknolepsy, is differentiated from JAE mainly by the age of onset.
Generalized tonic-clonic seizures on awakening, without absence or myoclonus, also belong to the so-called idiopathic generalized epilepsies.
Idiopathic focal epilepsies are predominantly encountered in children:
Benign epilepsies of childhood, such as benign childhood epilepsy with centrotemporal spikes, are usually self-limiting and do not always require treatment.
Monogenic focal epilepsies. Although representing only a tiny proportion of all epileptic syndromes, more and more monogenic focal epilepsies are recognized, examples being autosomal dominant nocturnal frontal lobe epilepsy (NFLE) and epilepsy associated with glucose transporter type 1 (GLUT1) deficiency syndrome.
Symptomatic and cryptogenic generalized epilepsies are typically severe epilepsies with childhood onset and associated with intellectual disability, e.g.:
Myoclonic astatic epilepsy
For differential diagnosis of myoclonic epilepsies, please consult Sect. 4.15.2.
4.7.4 Status Epilepticus
Status epilepticus occurs because of failure of cellular mechanisms to terminate seizures. Ongoing seizure activity promotes drug resistance, neuronal energy failure, and accumulation of reactive oxygen metabolites, subsequently leading to neuronal death. Convulsive status epilepticus is associated with a high morbidity and mortality; the three most important prognostic factors are age, etiology, and seizure duration. Long-term consequences may include chronic epilepsy (because of enhanced epileptogenesis) and cognitive decline.
Traditionally, status epilepticus has been defined as a period of 30 min of continuous epileptic activity or repeated epileptic seizures without regaining of consciousness in between. Again, the ILAE has recently published revised criteria. According to these, status epilepticus is
“a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t1) beyond which the seizure should be regarded as ‘continuous seizure activity.’ The second time point (t2) is the time of ongoing seizure activity after which there is a risk of long-term consequences. In the case of convulsive (tonic–clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research” (Trinka et al. 2015).
For all practical purposes, since most epileptic seizures terminate within a few minutes, prolonged seizure activity exceeding 5 min should be regarded as status epilepticus and treated as such. Further, it is important to note that in many instances, status epilepticus is an acute symptomatic event occurring in patients without a previous diagnosis of epilepsy.
A generalized tonic-clonic status epilepticus is always life-threatening. Its recognition is usually easy, but difficulties can arise in patients with prolonged status epilepticus. These patients may no longer have generalized convulsions but may exhibit only subtle signs of seizure activity such as twitching of the eyelids or corners of the mouth, as well as impaired consciousness. Also psychogenic (nonepileptic) convulsions may provide diagnostic difficulties, but typically, there are no signs of cardiorespiratory distress such as cyanosis or lactic acidosis, and EEG and serum levels of myoglobin and creatine kinase are normal. (Importantly, the rise of serum prolactin peaks at 20 min postictally and remains elevated for 60 min following a single generalized tonic-clonic seizure, but serum prolactin levels are normal in generalized tonic-clonic status epilepticus and, therefore, cannot be used to distinguish status epilepticus from prolonged psychogenic nonepileptic convulsions.)
Nonconvulsive status epilepticus may follow a generalized tonic-clonic seizure or may arise by itself; it can be nonconvulsive generalized or focal. In nonconvulsive generalized status epilepticus, the patient typically exhibits bizarre behavior and has impaired consciousness. Focal nonconvulsive status epilepticus (sometimes termed epilepsia partialis continua) is a condition in which a patient has continuous focal motor seizures such as twitching in the face and the ipsilateral arm; it can be especially resistant to antiepileptic treatment and is always due to an underlying structural pathology, e.g., a brain tumor.
Absence status epilepticus is a complication of absence epilepsy and affects children, only very occasionally adults.
All forms of status epilepticus are medical emergencies and require immediate antiepileptic therapy (Chap. 6) as well as evaluation and treatment of the underlying cause.
4.8 The Differential Diagnosis of Nonepileptic Seizures, Blackouts, and Drop Attacks
As stated in the previous chapter, the primary aim of the neurologist evaluating a seizure is to distinguish epileptic seizures from nonepileptic events (Fig. 4.5), including:
Psychogenic nonepileptic attacks
Other causes (Case 4.15)
Moyamoya disease. Within a year, a 25-year-old female experienced up to 100 spells of sensorimotor symptoms involving the left side of her body. These spells lasted only a few seconds. Sensory symptoms (“pins and needles”) were roughly three times as frequent as motor spells (“funny twitches”). In addition, she had roughly one episode per month during which she suddenly felt close to fainting, although she never did. Neurological examination was normal. MRI showed a few scattered lesions within the territory of the right MCA, consistent with small infarcts (a, coronal FLAIR to the left and in the middle, axial T2 to the right). MR angiography revealed bilateral proximal MCA stenosis (observe that this was even more pronounced on the asymptomatic left MCA). Digital subtraction angiography (DSA) revealed a fine network of small collateral vessels (b). The patient was diagnosed with Moyamoya disease (which is a cryptogenic condition and requires exclusion of secondary factors such as sickle cell anemia; see also Case 4.23, Moyamoya phenomenon associated with Fanconi’s anemia). She was referred for bilateral IC-EC bypass (d, DSA shows the bypass graft on the right). Following surgery, the frequency of her symptoms decreased dramatically (roughly 1–2 sensory spells per year)
Generations of physicians have remembered the differential diagnosis of epileptic seizures, syncope, and psychogenic attacks by using the mnemonic “fits, faints, and funny turns.” As a rule, the likelihood of psychogenic attacks is higher in young patients, while syncope and TIA are common in the elderly. A good history, preferentially from both the patient and witnesses, as soon after the event as possible, is the best initial tool to settle the differential diagnosis. When evaluating a patient with a first-time seizure in the emergency room, it is advisable to ask for mobile phone numbers to call witnesses. Unprovoked events, aura, automatisms, convulsions, lateral tongue biting, posturing, incontinence, and postictal confusion all point toward epilepsy. If the diagnosis is uncertain, ex juvantibus prescription of AED is never a good idea as it exposes the patient to potentially dangerous and unnecessary medication. The chance is also very high that the problem will remain unsettled. Video-EEG monitoring, if available, is especially helpful in this situation.
Syncope is usually characterized by a specific history, as outlined below. In contrast to a generalized epileptic seizure, syncope is typically not associated with postictal confusion. Consequently, patients with syncope tend to wake up before the ambulance arrives, whereas following an epileptic seizure patients often regain full consciousness only in the ambulance or upon arrival at the hospital. Bear in mind that, due to temporary cortical hypoxia, syncope can lead to short-lasting myoclonic paroxysms in the extremities (convulsive syncope) and bladder emptying. A convulsive syncope is release of brainstem activity from cortical influence rather than an electrocortical seizure, but this is easily misinterpreted by the layman as signs of an epileptic seizure. Also, a minor tongue bite at the tip of the tongue may occasionally occur with syncope but not lateral tongue biting. (The explanation for this is that with syncope, sudden loss of muscle tone leads to protrusion of the tongue, and when the patient falls, the front teeth hit the tip of the tongue. In contrast, patients with a generalized tonic-clonic seizure “chew” on their tongue leading to the typical injuries of the lateral aspects of the tongue.)
Syncope can be divided into:
Vasovagal syncope. This diagnosis is normally suggested by the situation (e.g., bathroom, public transport, and hot summer days), prodrome (sensation of blackout, pallor, tachycardia, sweating, and tremor), and short unconsciousness with or without random muscle twitching and occasionally urinary incontinence (both of which can be mistaken as signs of epileptic seizure), followed by fast reorientation and a feeling of general exhaustion. Vasovagal syncope variants are cough and micturition syncope; the latter typically occurs in men who urinate at night while standing.
Cardiac syncope comes suddenly and usually lacks a prodromal phase, although sometimes the patient may report cardiac palpitations, chest pain, and shortness of breath. Brief unconsciousness is followed by rapid recovery as in other forms of syncope. Often arrhythmias and other abnormal ECG signs are present. Cardiac monitoring, including telemetry/Holter ECG and echocardiography, is mandatory. Syncope and near-syncope due to the long QT syndrome tends to be misdiagnosed as epilepsy, often with fatal consequences for the patient—and his relatives who may suffer from the same condition.
Orthostatic syncope. This is the typical syncope associated with dizziness and blackout after sudden change from the supine to the upright position. It occurs especially often in the young and the elderly and in those on antiparkinsonian medications and beta-blockers.
Carotid sinus syncope. When due to hypersensitivity of the carotid sinus, it occurs in the elderly. Shaving, wearing a tight collar, or turning the head can trigger a sudden syncope.
Psychogenic nonepileptic seizures (PNES) and other attacks of unresponsiveness due to psychological reasons can be very difficult to distinguish from true epileptic seizures, but much of what has been said about the patient with functional palsy and psychogenic coma (see Sect. 3.11) is also true for the patient with PNES. Patients with functional seizures often have a characteristic way of presenting their history; they may refer extensively to their “seizures,” but when the examiner inquires about the nature of these phenomena, they try to avoid giving detailed descriptions.
PNES, or dissociative convulsions, may account for about 20% of referrals to epilepsy clinics. Seizure duration longer than 5 min, gradual seizure onset with fluctuating course, closure of eyes and the mouth, resistance to passive eye opening, violent movements with trashing of the head from side to side, opisthotonus and pelvic thrusting, hyperventilation, exclusive occurrence of witnessed seizures, and recall of the period of unresponsiveness are all common features in dissociative seizures but are rare to exceptional in epileptic seizures.6
Panic attacks are suggested by the circumstances (e.g., shops, crowds, and claustrophobic situations), slow buildup with increasing anxiety, breathlessness, tingling, blurred vision, long duration, and tearfulness.
Other, usually far less common causes of acute unresponsiveness and paroxysmal motor phenomena include:
Hypoglycemia. This is usually encountered in patients with diabetes mellitus. An unusual cause of hypoglycemic attacks is insulinoma, which often remains unrecognized for a long time.
Neurocardiogenic syncope due to primary autonomic insufficiency, acute inflammatory demyelinating polyneuropathy, adrenal insufficiency, basilar migraine, cerebrovascular insufficiency (dominant vertebral artery and/or basilar artery stenosis, vertebral artery compression, subclavian steal), CSF flow obstruction (including ventriculoperitoneal shunt malfunction), multiple system atrophy (MSA) (in particular, MSA with predominantly autonomic features), postganglionic insufficiency, and syringomyelia.
Parasomnias such as REM sleep behavior disorder and sleep walking.
Other neuroendocrine tumors (besides insulinoma) with paroxystic systemic symptoms include pheochromocytoma and carcinoid (Case 4.16).
Pheochromocytoma. A 30-year-old previously healthy woman in the 26th week of her first pregnancy was referred from her gynecologist because of new-onset episodic frontal throbbing headaches of moderate to severe intensity, accompanied by nausea, vomiting, and hyperventilation. Episodes occurred up to five times daily and lasted from a few minutes to 1 h. On two occasions, the patient had noted a scintillating scotoma in her left visual field. She had no history of migraine. Since proteinuria and edema were absent, preeclampsia had been ruled out by her gynecologist prior to referral. Neurological examination, including fundoscopy, was unremarkable. The patient had no fever and blood pressure was 130/85 mmHg in both arms. MRI of the head including MR angiography and a lumbar puncture were normal. However, on day 3 after admission, the patient was observed during a severe headache with marked tachycardia, sweating, pallor, tremor, and anxiety. Blood pressure was 220/110 mmHg, pulse rate 115 beats/min. A working diagnosis of pheochromocytoma was made. Repeated 24 h urinary catecholamine testing revealed increased levels of norepinephrine, epinephrine, metanephrines, and vanillylmandelic acid. MRI of the abdomen showed a 6 × 6 cm solid right adrenal mass (a, b). Genetic testing for mutations in the RET, VHL, SDHB, and SDHD genes was negative. Using a multidisciplinary approach involving endocrinologists, anesthesiologists, surgeons, and neonatologists, it was decided to treat the patient with phenoxybenzamine (α-adrenoceptor antagonist) and await fetal maturity. Headaches vanished completely. In the 31st week of pregnancy, the patient underwent an uncomplicated cesarean section combined with removal of the adrenal mass. Release of catecholamines from a pheochromocytoma is related to changes in blood flow or necrosis within the tumor and to any activity that mechanically compresses it. Thus, pregnancy may uncover a pheochromocytoma due to fetal movement, uterine growth, or delivery. Undiagnosed pheochromocytoma is associated with maternal and fetal mortality of up to 58% and 56%, respectively. With an established antenatal diagnosis, maternal mortality decreases to 2% and fetal mortality to 15% (adapted with permission from Kondziella et al. (2007a, b))
The following phenomena, sometimes confused with epileptic seizures, occur by definition without loss of consciousness:
Drop attacks. These may be due to vertebrobasilar ischemia (either due to stenosis of the basilar/vertebral arteries or associated with a subclavian steal syndrome), posterior fossa lesions (including Arnold-Chiari malformations), hydrocephalus, intraventricular tumors, inner ear disorders (e.g., Ménière’s disease, migrainous vertigo), and intermittent cervical cord compression. Cryptogenic drop attacks are relatively frequent and mainly affect middle-aged women.7
Cataplexy is triggered most often by laughter, although any emotional stimulus can induce it. Occasionally, cataplexy may also occur in situations devoid of any specific emotional content but associated with certain postures such as bending forward. Loss of muscular tone may be complete or discrete and unremarkable to anyone other than the patient. A patient with narcolepsy may suffer from cataplexy several times a day or only once or twice during a lifetime, and therefore, a careful history is crucial to detect the presence of mild cataplexy. The duration of hypotonia in cataplexy ranges from several seconds to a few minutes (rarely longer), followed by complete recovery. It is useful to check tendon reflexes when observing a possible cataplexy attack; reflexes are absent during an attack but present in between. Status cataplecticus (“limp man syndrome”) is excessive daytime sleepiness associated with frequent episodes of sudden buckling of the knees without falls. It is a rare, but important, differential diagnosis because it may be confused with a functional gait disorder. For all practical purposes, cataplexy is pathognomic for narcolepsy, although there have been case reports of cataplexy in Niemann-Pick type C disease. (See also Sect. 4.10.)
Some paroxysmal symptoms in the young are highly characteristic for MS; these include brief (seconds-minutes) and very frequent (50–100/day) paroxysms of dysarthria and/or ataxia or unilateral dystonia responding to carbamazepine. The paroxysms are due to ephaptic transmission at sites of demyelination, often at the brainstem level.
TGA, although frightening for the patient, is usually harmless, and there is no increased risk of developing stroke. When a reliable account from a witness is available, TGA is easy to diagnose (see Case 2.18).
Transient ischemic symptoms, including, for instance, the rare syndrome of limb-shaking TIA (usually seen with high-grade contralateral ICA stenosis) and the capsular warning syndrome (transient lacunar ischemia that typically precedes a capsular infarction).
Transient sensorimotor symptoms associated with cerebral amyloid angiopathy (“amyloid spells”) (Case 4.17).
Amyloid spells: Jacksonian sensory march due to cerebral amyloid angiopathy (CAA). A 71-year-old male with a history of hypertension and chronic obstructive lung disease had sudden onset of bizarre behavior and headache. CT of the brain revealed a right frontal lobar hematoma (a). The patient made an uneventful recovery. Four years later, he presented with complaints of sensory spells starting in the fingers of his left hand, progressing to the arm and finally spreading to the left side of his face within 10 min. He had had nine such episodes within the previous 8 days. Neurological examination was unremarkable except for slight spasticity in both legs. In addition, despite a normal Mini-Mental State Examination score (29/30), he showed the “head-turning sign,” that is, he frequently addressed his wife when being asked questions, suggestive of a mild cognitive deficit. CT of the brain showed a right post-central sulcal hemorrhage, compatible with his Jacksonian sensory marches (b). Apart from the previous lobar hemorrhage, T2-weighted magnetic resonance imaging revealed multiple atraumatic convexal hemosiderin deposits, confluent white matter hyperintensities (c) and microbleeds (not shown). According to the modified Boston criteria, the patient was diagnosed with probable cerebral amyloid angiopathy (“definitive” CAA requires a full postmortem examination). The pathophysiology of recurrent paresthesias or “amyloid spells” remains not fully understood, but cortical spreading depolarizations (as opposed to focal epileptic seizure activity) are a likely mechanism
4.9 The Differential Diagnosis of Vertigo and Dizziness
Although many patients use the terms vertigo and dizziness synonymously, the neurologist should carefully distinguish between vertigo on one hand and dizziness or light-headedness on the other. Vertigo is best defined as an illusion of motion, the false sensation of movement (Chap. 2), and it is either of central (brainstem, cerebellopontine angle, cerebellum) or peripheral origin (inner ear, vestibular system) (Fig. 4.6). Dizziness or light-headedness, in contrast, is far more unspecific, and the patient may use these terms to describe problems of gait and balance, an experience of presyncope, a feeling of being unwell, visual impairment, or even a state of depressed mood.
Differential diagnosis of vertigo
4.9.1 Vertigo of Central Origin
As described earlier (Chaps. 2 and 3):
A patient with vertigo due to a brainstem lesion will almost always have other signs and symptoms of impaired CN and sensorimotor pathway function.
Likewise, a patient with vertigo due to a cerebellopontine lesion (e.g., a vestibular schwannoma) will typically have signs and symptoms referable to the cerebellum and/or the adjacent CNs (e.g., decreased corneal sensation, peripheral facial palsy, sensory hearing loss).
However, a patient with a cerebellar lesion may occasionally exhibit monosymptomatic vertigo, and then, the key to the correct diagnosis is careful examination of the eye movements as outlined in Chap. 3 (“three-step oculomotor bedside examination”).
Monosymptomatic vertigo has also been described with certain supratentorial lesions, including the anterior insula and the parietal lobes, and of course, it may reflect a focal seizure in patients with temporal lobe epilepsy.
Vertigo may also occur with migraine, MS, and other neurological disorders, as well as due to medication side effects and intoxications.
Rupture of an intracranial demoid cyst is another differential diagnosis of acute vertigo of central origin (Case 4.18).
Ruptured intracranial dermoid cyst. A 51-year-old male with a history of anxiety was admitted because of sudden onset of vertigo and headache. The ENT team had reviewed the patient and had not found evidence of a peripheral vertigo. Neurological examination revealed saccadic pursuit, difficulties with finger-nose and heel-shin tests, and moderate gait ataxia. The attending neurologist ordered an MRI, suspecting an acute cerebrovascular event from the posterior circulation. However, MR angiography and DWI were normal. Instead, T1-weighted imaging revealed a midline cystic lesion at the level of the midbrain and scattered bright signal in several cerebellar sulci (a). Whereas the cystic lesion was enhancing with gadolinium contrast, the cerebellar lesions were spontaneously hyperintense. On CT, the latter lesions appeared very dark (−100 Hounsfield units), which was consistent with fat (b). The patient made an uneventful recovery. Intracranial dermoid cysts are benign congenital lesions of ectodermal origin and comprise less than 1% of all intracranial tumors. They typically occur in the midline, often in the sellar/parasellar region, but may also be found in the posterior fossa. With the accumulation of epithelial desquamation and glandular secretion, they may gradually enlarge and suddenly rupture. Their material is spread around adjacent brain regions and appears as fat on MRI (spontaneous bright signal on T1) and CT (very dark signal). Most patients present with acute neurological complaints. Imaging reveals the ruptured cyst, but a previous scan showing the intact cyst is usually not available. The diagnosis is therefore based on the history, the typical neuroradiological appearance, and the exclusion of other conditions. Prognosis is excellent, although some patients may develop aseptic chemical meningitis due to inflammation related to lipid contents circulating in the CSF
4.9.2 Vertigo of Peripheral Origin
The hallmark of peripheral vertigo is the distinct sensation of relative motion with the visual world (Fig. 4.6). Peripheral vertigo typically comes in spells and usually lasts seconds as benign positional vertigo, minutes as in Ménière’s disease, or hours as in vestibular neuritis. Frequent accompanying symptoms are hearing loss, tinnitus, and aural fullness. A diagnosis of benign positional vertigo, for instance, is very likely in patients with short vertigo brought on by a change of position such as rolling over in bed. The onset is sudden, while the offset is usually less well defined.
The most common associated disorders include:
Intoxications (e.g., alcohol, quinine, aminoglycosides, NSAID)
4.9.3 Dizziness and Light-Headedness
The differential diagnoses of dizziness and light-headedness are vast and include (Fig. 4.6):
Postural hypotension, e.g., dehydration and autonomic dysfunction
Cardiological disorders, e.g., congestive heart failure and arrhythmias
Psychiatric disorders, e.g., depression and anxiety
Trauma, e.g., concussion and whiplash
Medication, e.g., antidepressants, AED, aminoglycosides and other antibiotics, antihypertensive drugs, anxiolytics, sedating drugs, chemotherapeutic agents, diuretics, and salicylic acids
4.10 The Differential Diagnosis of Sleep Disorders
Sleep disorders are best categorized into those that are common and those that are not.
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The most common sleep disturbances are due to poor sleep hygiene, simple worries, depression, anxiety, alcohol, medication side effects, shift work, jet lag, sleep apnea syndrome, chronic pain, restless legs syndrome, periodic leg movements in sleep, and chronic diseases of neurological (MS, parkinsonism), and non-neurological origin (e.g., anemia, congestive heart failure, hepatitis, diabetes, hypo- and hyperthyroidism).
Somewhat less common are:
REM sleep behavior disorder. Patients have vivid dreams, and during the stage of REM sleep, they may violently act out their dreams. Following a prolonged interval that may last years or even decades, most patients with idiopathic REM sleep behavior disorder will eventually develop a neurodegenerative disorder, most commonly one of the synucleinopathies (Parkinson’s disease, DLB, and MSA). The prevalence of REM sleep behavior disorder is approximately 0.5% but is much higher among patients with neurodegenerative disease or narcolepsy and among patients taking antidepressants.
Epileptic seizures arising from sleep, e.g., nocturnal frontal lobe epilepsy (NFLE).
Parasomnias (e.g., somnambulism, sleep automatism, and sleep terrors). Accurately diagnosing sleep-related events, and particularly distinguishing parasomnias from other sleep disorders such as NFLE, can be challenging. Important clues from the history pointing to a parasomnia include the time of onset during the night (NREM parasomnias typically occur 1–2 h after falling asleep, whereas seizures tend to occur soon thereafter or just before wakening in the morning), the number of events per night (only once or twice for parasomnias), and duration (several minutes, whereas typically less than 1 min for seizures). Patients (exceptionally) reporting a clear recall of events are more likely to have NFLE, and while both groups of disorders frequently arise during childhood, onset from mid-teens to age 50 years suggests NFLE. Even later onset raises the possibility of REM sleep behavior disorder. Lastly, whereas complex motor phenomena can occur with both NFLE and parasomnias, prominent bipedal (“cycling”) automatisms strongly suggest NFLE. Using the Frontal Lobe Epilepsy and Parasomnias scale (Derry et al. 2006) and admitting the patient to the epilepsy monitoring unit (if available) may help to clarify the situation.
Narcolepsy has a prevalence of approximately 0.025–0.05%. The symptoms of narcolepsy are due to instability of the transition of sleep and wake, as well as of REM sleep and non-REM sleep. The classic tetrad consists of excessive daytime sleepiness with imperative sleep attacks, cataplexy, sleep paralysis, and hallucinations upon falling asleep or upon awaking. Cataplexy is triggered by sudden emotions and can be socially stigmatizing (e.g., jaw sagging and facial slackening with laughter). However, the degree of cataplexy ranges from frequent, complete loss of muscle tone leading to sudden collapse to very mild symptoms, hardly noticed by the patient and only occurring a few times in a lifetime. (See Sect. 4.8 for a detailed description of cataplexy.) Further, some patients with otherwise typical features of narcolepsy lack cataplexy entirely (the so-called monosymptomatic narcolepsy or narcolepsy without cataplexy). Indeed, the complete tetrad of symptoms is present in only a minority of patients (ca. 15%).
It is less well appreciated that narcoleptics may experience episodes of automatic behavior and amnesia, lasting for seconds to hours, usually when the patient is alone and performing monotonous tasks such as driving. The patient gradually loses track of what is going on but continues to perform routine tasks automatically, until he is interrupted by a concerned observer. Characteristically, the patient has complete amnesia for the attack.
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