Macrocephaly, large head, hydrocephalus, benign familial macrocephaly

Macrocephaly is defined as head circumference greater than 2 standard deviations above the normal distribution for age, gender, and gestation.


Hydrocephalus (communicating or non-communicating), megalencephaly, thickening of the skull, cerebral edema, space-occupying lesions, hyperostosis, and hemorrhage into the subdural or epidural spaces may cause macrocephaly. Anatomic megalencephaly includes conditions in which the brain is enlarged because the number or size of cells increases. These children are macrocephalic at birth but have normal intracranial pressure. Children with metabolic megalencephaly are normocephalic at birth and develop megalencephaly during the neonatal period because of storage of abnormal substances or by producing cerebral edema (Table 80).

Table 80

Causes of macrocephaly

I. Hydrocephalus


 Arnold-Chiari malformation

 Aqueductal stenosis

 X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) syndrome (L1CAM)

 Dandy-Walker malformation

 Galenic vein aneurysm or malformation

 Neoplasms, supratentorial, and infratentorial

 Arachnoid cyst, infratentorial

 Holoprosencephaly with dorsal interhemispheric sac


 External or extraventricular obstructive hydrocephalus (dilated subarachnoid space)

 Arachnoid cyst, supratentorial

 Meningeal fibrosis/obstruction



 Neoplastic infiltration


 Arteriovenous malformation

 Intracranial hemorrhage

 Dural sinus thrombosis

 Choroid plexus papilloma

 Neurocutaneous syndromes

 Incontinentia pigmenti

 Destructive lesions



 Familial, autosomal-dominant, autosomal-recessive, X-linked

II. Subdural Fluid




III. Brain Edema (Toxic-Metabolic)



 Vitamin A


 Endocrine (hypoparathyroidism, hypoadrenocorticism)


 Idiopathic (pseudotumorcerebri)

IV. Thick Skull or Scalp (Hyperostosis)

 Familial variation


 Osteoporosis, severe precocious autosomal-recessive osteoporosis (CLCN7, TCIRG1)

 Pycnodysostosis (CTSK)

 Craniometaphyseal dysplasia (ANKH)

 Craniodiaphyseal dysplasia

 Pyle dysplasia

 Sclerosteosis (SOST)

 Juvenile Paget disease

 Idiopathic hyperphosphatasia

 Familial osteoectasia

 Osteogenesis imperfecta


 Cleidocranial dysostosis

 Hyperostosis corticalis generalisata (van Buchem disease)

 Proteus syndrome

V. Megalencephaly and hemimegalencephaly

Table 80

From Swaiman, K. F., Ashwal, S., et al. (2012). Swaiman’s pediatric neurology: principles and practice, ed 5. Philadelphia: Elsevier.

The causes of anatomic megalencephaly include genetic megalencephaly or megalencephaly (with gigantism, typical facial changes, and learning difficulties, as seen in Sotos syndrome or associated with mutations or deletions in the nuclear receptor-binding SET domain containing protein), neurocutaneous disorders (e.g., macrocephaly cutis marmorata telangiectatica congenital), or other neurologic disorders.

Examples of metabolic megalencephalies include leukodystrophies. Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) may present with macrocephaly before the individual goes on to develop severe leukoencephalopathy, at a potentially treatable stage. Megalencephalic leukoencephalopathy with subcortical cysts is a rare leukodystrophy characterized by macrocephaly and a slowly progressive clinical course marked by spasticity and cognitive decline. Macrocephaly is also frequently seen in autism, but its relationship to the pathogenesis is unclear.


Evaluation involves review of prior head circumference measurements to assess rate of head growth (a rapidly growing head that is crossing percentile lines suggests hydrocephalus), assessment of head shape (frontal bossing is associated with hydrocephalus, lateral bulging with infantile subdural hematoma), measurement of head circumference of parents and siblings (benign familial megalencephaly), and computed tomography (CT) scan, magnetic resonance imaging (MRI), or ultrasound. If the infant is neurologically and developmentally normal, close observation may be all that is necessary.

A useful rule of thumb for normal rate of head growth follows:

  •  Premature infants: 1 cm/week
  •  1 to 3 months: 2 cm/month
  •  3 to 6 months: 1 cm/month
  •  6 to 12 months: 0.5 cm/month

Magnetic Resonance Imaging



Magnetic resonance imaging (MRI) creates images based on the behavior of various tissues exposed to strong magnetic fields, controlled magnetic field gradients, and radiofrequency (RF) pulses. Image intensity and contrast depends upon the concentration of unpaired protons, typically the motion of the hydrogen nuclei, nuclear magnetic relaxation parameters, and the type of sequence or acquisition being performed.

When tissue protons are placed in a magnetic field, they tend to align themselves either parallel in a low-energy state or antiparallel in a high-energy state to the vector of the imposed magnetic field, although they periodically flip between the two states. Because low-energy states are preferred, more protons align parallel than antiparallel at any given moment, creating a net magnetization vector. An RF pulse can then be applied, exciting the protons and changing them from longitudinal to transverse alignment. As these protons return to equilibrium within the magnetic field (i.e., longitudinal alignment), they emit energy (as an RF signal) that can be detected and converted into meaningful data—the image—by means of certain manipulations.

Technical parameters

Repetition time (TR) defines the duration of a cycle as the time between successive RF pulses.

Echo time (TE) defines a sampling interval during the cycle and is the time between giving the RF pulse and measuring the amount of RF signal being emitted by the tissue, the “echo.” There may be single or multiple echoes sampled during a given cycle.

Relaxation time is the time it takes the protons to return to equilibrium within the magnetic field after an RF pulse has been given.

Common magnetic resonance imaging sequences

  1. I. T1 relaxation is based upon how fast protons return to equilibrium (longitudinal alignment) after being excited by an RF pulse. At any given time after the RF pulse is given TE, substances whose protons re-equilibrate fastest (lipids, for example, with the highest percentage of protons in the longitudinal position) appear brightest on T1-weighted images (T1WI) where the T1 characteristics are emphasized. Substances whose protons re-equilibrate slower (water, for example) will appear darker (Table 81). The shorter the TE, the greater the difference between various substances and tissues. At short TE, a large percentage of the lipid protons have regained their longitudinal position, whereas few water protons have done so. At longer TE, a greater percentage of both lipid and water protons have regained their longitudinal position. The greater the difference between the two substances (the shorter the TE), the greater the contrast on T1WI. Therefore, T1WI have both short TR and short TE.

  2. II. T2 relaxation is determined by how fast transverse magnetization decays. The longer transverse alignment is maintained, the stronger the signal that is emitted on T2-weighted images (T2WI) (Table 82). At shorter TE, a higher percentage of both lipid and water protons are in transverse alignment. At a longer TE, most of the lipid protons have lost their transverse magnetization (fast decay), whereas most of the water protons remain in transverse alignment (slow decay). Therefore, for greatest contrast on T2WI images, a longer TE should be chosen. Consequently, T2WI have long TE and long TR.

The degree of brightness or darkness on T1WI and T2WI can thus be determined by tissue content (Tables 8183). In general, pathologic conditions are dark on T1WI, bright on T2WI, and bright on proton density images. The acquisition of data may be performed in a variety of patterns or sequences, which emphasize differences in tissue properties.

  1. III. Spin echo (SE) sequence: an initial 90-degree pulse is given, and the echo is assessed at a predetermined point with an additional 180-degree pulse. The 180-degree pulse is necessary because of “dephasing” or spreading of the magnetic vectors of individual protons as they decay. If dephasing is not corrected, the vectors would eventually cancel each other out until the net vector becomes weak enough that the signal emitted would be undetectable. The 180-degree pulse “rephases” or brings back together the individual proton vectors so the echo emitted can be detected. T1WI images, T2WI images, and proton density images (PDIs) may be obtained with this sequence. PDIs emphasize tissue characteristics.
  2. IV. Another frequently used acquisition sequence is the gradient echo (GRE), a relatively fast scanning technique. The sequence takes less scanning time and is useful for imaging flowing blood (flow-related enhancement), for detecting calcification or hemorrhage, and for moderate myelogram effect (white cerebrospinal fluid [CSF]) in the spinal canal. GRE images, like SE, may be either T1-weighted or T2-weighted, but usually only T2WI or PDIs are obtained.
  3. V. Short tau inversion recovery (STIR) and fluid attenuated inversion recovery (FLAIR) are sequences where an inversion recovery preparation is used. A 180-degree RF pulse inverts the longitudinal magnetization, and then T1 recovery takes place. Depending on tissue, all longitudinal magnetization will have 0 magnitude in a specific time. If the excitation follows such time, the corresponding tissue is nulled: in STIR sequence, fat is dark; in FLAIR sequence, fluid (e.g. CSF) is dark.
  4. VI. Perfusion-weighted images (PWIs) are useful in evaluating cerebral blood flow using a bolus-tracking method whereby repeated images are acquired at the same location during the passage of a high volume of intravenous gadolinium. These are T2-weighted sequences and because gadolinium produces decreased signal intensity on T2-weighted scans, areas of diminished blood flow are bright on PWI.
  5. VII. Diffusion-weighted images (DWIs) are reflective of water motion in brain tissue. Areas with low diffusion appear bright. For example, DWI reveals cerebral infarcts as bright areas within 30 minutes of onset, with the increased signal intensity lasting 7 to 21 days.
  6. VIII. Quantitative measurement using apparent diffusion coefficient (ADC) maps can be performed. ADC maps may be helpful in cases of suspected T2 shine-through artifact on DWI, where bright signal on T2 appears bright on DWI and ADC versus acute infarct (bright on DWI and dark in ADC).
  7. IX. Susceptibility weighted imaging is a corrected GRE 3D high velocity MRI sequence, which is sensitive to detecting a very subtle amount of intracranial hemorrhage.

Clinical uses of MRI

  1. I. Vascular: Strokes appear earlier and in better detail on MRI (particularly DWI) than on computed tomography (CT). DWI and PWI images are vital in taking care of acute stroke patients. Combining both imaging sequences enables the clinician to identify the penumbra area, which represents potentially salvageable tissue. For vascular malformations, MRI and magnetic resonance angiography (MRA) are fine diagnostic tools. For aneurysms, MRA/computed tomography angiography (CTA) is excellent for screening, but a small aneurysm (< 3 mm) could be missed. Conventional digital subtraction angiography is the gold standard for evaluating aneurysms. MR venography is superb for diagnosing dural venous sinus thrombosis. Although MRI can detect all types of hemorrhage, unenhanced CT is the appropriate screening examination due to quick exam time and easier access. In cases of suspected diffuse axonal injury, MRI may prove of diagnostic value, especially with the addition of a GRE pulse sequence.
  2. II. Tumors: MRI is the procedure of choice to rule out small tumors or for tumor delineation. The ability to map the extent of a tumor (especially with the use of gadolinium) and the multiplanar capability of MRI make it very useful in surgical planning.
  3. III. Infections: Cerebritis is well visualized with MRI. Abscess is well delineated with MRI (particularly DWI).
  4. IV. Meningeal processes: MRI is more sensitive than CT for visualizing both infected and neoplasm-infiltrated meninges.
  5. V. Trauma: MRI is not the examination of choice because of the lack of bony detail and the length of time needed. CT should be used.
  6. VI. Demyelinating disease: MRI is the procedure of choice because of the excellent delineation of white matter disease. Active lesions of multiple sclerosis will enhance with gadolinium.
  7. VII. Congenital/structural abnormalities: Multiplanar MRI is excellent for showing heterotopias and other anatomic abnormalities.
  8. VIII. Spine imaging: Because the spinal cord is a thin, inherently low-contrast structure, MRI is the noninvasive examination of choice for the spine. Vertebral bone is well imaged on spinal MRI because it contains fatty marrow. However, small spinal column fractures are better seen on CT. MRI also allows good visualization of the soft tissue and ligaments.
  9. IX. Pregnancy: The safety of MRI in pregnancy has yet to be determined; therefore, risk versus benefit must be considered. Gadolinium should not be administered during pregnancy.

Advantages of magnetic resonance imaging

  1. I. Multiplanar capability: The magnetic field can be adjusted to image in any plane without moving the patient.
  2. II. No ionizing radiation.
  3. III. Superior soft tissue contrast: Subtle differences in soft tissue proton relaxation characteristics enable visual distinction between soft tissues. This is considered “inherent” contrast of the soft tissue that can be significantly better appreciated with MRI than with any other modality.
  4. IV. Vascular anatomy: Flowing blood has different characteristics than stationary soft tissue. Vessels can be imaged in detail with MRI. Magnetic resonance angiograms and magnetic resonance venograms can be reconstructed by subtracting out the background tissue signal.
  5. V. MRI can easily image areas that are poorly visualized by CT (e.g., areas encased in thick bones, such as the posterior fossa and anterior temporal lobes).
  6. VI. Gadolinium is a paramagnetic IV contrast agent, which enhances tissues that are highly vascular or have a damaged blood–brain barrier. Unlike traditional contrast agents, gadolinium has very few contraindications. Adverse reactions are extremely rare. Contrast-enhanced MRI is generally obtained with T1WI, where gadolinium enhancement appears bright.

Disadvantages and limitations of magnetic resonance imaging

  1. I. MRI has a longer imaging time than CT. This has improved markedly with newer generation machines.
  2. II. Sensitivity to motion is very high, resulting in degraded image quality with patient movement. Chloral hydrate, benzodiazepines, barbiturates, or other medications can be used as a sedative, but timing and dosage and possible respiratory depression are important parameters to monitor.
  3. III. Claustrophobia is often due to tighter confinement and longer imaging times than CT. Sedation may be necessary. Consider using an open MRI or benzodiazepine administration prior to the MRI.
  4. IV. Metal and electronic devices, such as pacemakers, cochlear implants, and foreign bodies, often contraindicate MRI. A list may be obtained from the manufacturer, but it is becoming less problematic since the newest metal devices are being made MRI compatible.
  5. V. Calcium is not well visualized. Dense cortical bone appears as a signal void. Therefore, bone signal is restricted to that given off by marrow fat. Areas of parenchymal calcification identified on CT may not be seen on MRI and, if seen, are often of variable signal intensity.
  6. VI. Artifacts are common on MRI because of the complex interactions of several types of information, any of which can distort the final image.

Intraoperative magnetic resonance imaging

The use of open MRI units in the operating room has contributed to an increased extent of tumor removal and a parallel improvement in survival times. In addition, preoperative MRI with the patient’s head in a stereotactic frame or with fiducial markers can be used for surgical planning.



MEG, Magnetoencephalogram, EEG, electroencephalogram, Tumor, Surgery, Epilepsy

Magnetoencephalography (MEG) records the extracranial magnetic fields produced by electrical current which is the basis of electroencephalogram (EEG), and measures vectors tangential to the cortical surface. MEG signal is very small, but it is not subject to distortion from dura, skull, or the scalp. MEG and EEG are complementary in obtaining cerebral electrical activity. MEG can assess the neural activity underlying cognitive processes in the brain and is widely used in neuropsychology research due to its excellent temporal resolution with good spatial resolution. In clinical neurology, MEG is used in localizing epileptiform activity in patients and in localizing eloquent areas of the cortex for surgical planning in patients with brain tumors or intractable epilepsy. The availability of MEG is limited by its cost and it is largely used in research settings.


Gross J., et al. Good practice for conducting and reporting MEG research. Neuroimage. 2013;65:349–363.

Marburg Disease


Marburg variant, Balo concentric sclerosis, fulminant variants of MS

Approximately 7% of patients presenting with multiple sclerosis (MS) have radiographic features of fulminant disease. Among the recognized variants are Marburg variant and Balo concentric sclerosis. There is a great amount of clinical and radiological overlap among them, which makes a specific diagnosis challenging.

Marburg variant

Marburg first described a variant of MS in 1906, and most cases subsequently reported followed an aggressive course leading to death within 1 year. Lesions demonstrate significant mass effect and edema and may overlap with findings of acute disseminated encephalomyelitis. Marburg variant may be best thought of as an extreme end of the demyelinating disease spectrum and distinguishing it from other fulminant variants may be difficult in the clinical setting.

Balo Concentric Sclerosis

Presentation is usually monophasic, although it may follow a relapsing or progressive, and sometimes fulminant, course.

The characteristic feature is the development of alternating bands of demyelinated and myelinated white matter, which is seen on MRI as concentric rings, often described as “onion bulbs” due to their appearance, with rings of T2 hyperintensity surrounded by T2 hypointensity.

Mechanical Thrombectomy for Acute Ischemic Stroke (See Thrombectomy)


Embolectomy, thrombectomy, ischemic stroke, endovascular intervention, revascularization

Recent clinical advances established mechanical thrombectomy (MT) as the standard of care for acute ischemic stroke (AIS) secondary to large vessel occlusion (LVO) up to 24 hours of symptoms onset. Several clinical trials of endovascular treatment in AIS patients (MR CLEAN, ESCAPE, SWIFT PRIME, EXTEND-IA, and REVASCAT) demonstrated superior outcomes with endovascular therapy using second-generation MT devices (stent-retrievers) compared to intravenous recombinant tissue plasminogen activator (r-tPA) alone for patients with proximal LVO in the anterior circulation. Based on these data, the American Stroke Association/American Heart Association (ASA/AHA) in 2015 recommended MT as the standard of care (Class I, level of evidence A recommendation) for AIS patients who meet the following criteria:

(a) Pre-stroke modified Rankin score 0 to 1, (b) AIS receiving intravenous r-tPA within 4.5 hours of onset, (c) causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1), (d) age ≥ 18 years, (e) National Institutes of Health Stroke Scale (NIHSS) score of ≥ 6, (f) ASPECTS of ≥ 6, and (g) treatment can be initiated (groin puncture) within 6 hours of symptom onset.

Furthermore, in 2017 and 2018 two hallmark trials (DAWN and DEFUSE 3) were published, extending the time windows up to 24 hours for AIS patients presenting with favorable imaging findings with small to moderate completed infarction and the presence of salvageable tissue on penumbra imaging. Based on these findings, the ASA/AHA updated their guidelines and recommended MT up to 16 hours (Class IA) and met both DEFUSE 3 and DAWN trials criteria of significant mismatch and small to moderate core volume, and up to 24 hours from symptoms onset (Class IB) if they met DAWN trial criteria of core infarct size less than 70 mL and significant mismatch.

The efficacy and safety of MT for patients who do not meet top-tier evidence criteria are under investigation. Patients with confirmed LVO on computed tomography angiography who did not meet top-tier evidence for MT—most commonly those with distal anterior circulation occlusion (M2, M3, or anterior cerebral artery [ACA] occlusions) or in the posterior circulation, NIHSS score < 6, ASPECTS score < 6, and pre-stroke baseline modified Rankin scale (mRS) score of > 1—appear to have similarly high rates of good clinical outcome with no apparent increased risk. Given these results and the potential for devastating disability associated with emergent LVOs, when considering MT, clinicians should not defer sound clinical judgment in favor of a top-tier evidence-based checklist of inclusion/exclusion criteria. The suggested algorithm is below.

Minimizing the time to intervention is important to achieve the best possible outcomes and requires streamlined workflow, plus efficient triage and teamwork (Fig. 39). Treatment with intravenous r-tPA within 4.5 hours remains central to the management of patients with AIS; there is no evidence supporting bypassing it in favor of MT.

Fig. 39
Figure 39 Proposed acute ischemic stroke presenting within 24 hours triage algorithm.


Powers W.J., et al. American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment: a Guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:3020–3035.

Powers W.J., et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46–e110.



MELAS, mitochondrial disorders

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystem disorder that typically presents in childhood. It is a maternally inherited genetic syndrome caused by mutations in mitochondrial DNA, predominantly complex I of the electron transport chain. The most common mutation causing MELAS involves the A3243G gene (approximately 80%) which encodes for transfer RNA. In childhood, the first symptoms may manifest as developmental delay. This disease process manifests as encephalopathy which presents either as dementia or seizures, stroke-like episodes (appearing before the age of 40), recurrent vomiting, and headaches (typically recurring migraines). Other findings include ocular symptoms such as pigmentary retinopathy and ophthalmoplegia.

Due to the fact that it is a mitochondrial disorder, other diagnostic characteristics include other mitochondrial disorders such as myoclonic epilepsy with ragged red fibers on muscle biopsy (MERRF), elevated serum lactic acid, and with associated muscle weakness. Other non-neurologic signs include diabetes mellitus, renal disease, short stature, cardiomyopathy, and deafness. On magnetic resonance imaging (MRI) of the brain, lesions often are confined to the cortex (mainly occipital lobes) and are not localized to a vascular distribution. Discrete areas of lactic acidosis may be identified on magnetic resonance spectroscopy. Cerebrospinal fluid (CSF) protein is often elevated.

Therapeutic management includes supportive care and genetic counseling. Medication therapy includes anticonvulsants for seizures. Of note, in MELAS, use of valproic acid is associated with paradoxical convulsions, therefore, other medications should be used as an alternative for seizure prophylaxis. Physicians should refrain from statins, given their adverse effects of myopathy, when choosing a cholesterol-lowering medication. Other treatments include Coenzyme Q10 and other agents such as L-arginine and levocarnitine which decrease oxidative stress.


Johnson M. Encephalopathies; mitochondrial encephalopathies. In: Kliegman R., et al., eds. Nelson textbook of pediatrics. ed 20 Elsevier; 2016:2901.

Werring D., Meschia J., Woo D. Genetic basis of stroke occurrence, prevention and outcome. In: Grotta J., et al., eds. Stroke: pathophysiology, diagnosis, and management. Philadelphia: Elsevier; 2016:271.



Memory, Short-term memory, long-term memory, procedural memory, episodic memory, Alzheimer’s disease, Kluver-Bucy syndrome, medial temporal lobe, Papez circuit, Hippocampus, amygdala, nondeclarative memory, declarative memory, implicit memory, explicit memory, semantic memory, working memory

Memory comprises the mental processes of registration, encoding, and storage of experiences and information. It has been traditionally divided into short-term or working memory (active holding and manipulation of information) and long-term memory (information stored for periods of minutes to decades). Memory systems can utilize a conscious awareness and recall (explicit, declarative) or unconscious awareness (implicit, nondeclarative). Episodic memory, for example, utilizes the explicit and declarative memory systems to narrate an experience or a story in our own context. Procedural memory of riding a motor bike or learning the sequence of numbers on a smartphone without conscious effort, on the other hand, utilizes implicit (nondeclarative) memory. Table 84 summarizes the features of some important memory systems.

The anatomy of memory involves many widely distributed neural structures. The medial temporal lobe memory system—comprising the hippocampus, the amygdala, and adjacent related entorhinal, perirhinal, and parahippocampal cortices and their connections to the neocortex—is involved in the processing and storage of long-term memory. Papez circuit plays a critical role in the transfer of information into long-term memory and its emotional components.

Damage to basal forebrain structures (septum, nucleus basalis of Meynert, and orbitofrontal regions), as occurs in Alzheimer disease, is associated with memory disorder, which is often accompanied by other frontal lobe abnormalities. Damage to diencephalic structures—particularly dorsomedial and other thalamic nuclei, as in Korsakoff syndrome—leads to amnesia, possibly by the disconnection of cortical areas involved in memory processing. Bilateral damage of the limbic system causes severe memory disturbance. Bilateral damage to the amygdaloid region and anterior temporal lobes may produce the Klüver-Bucy syndrome, which is characterized by behavioral and cognitive deficits, placidity, apathy, hypersexuality, hyperorality, and visual and auditory agnosia.

Amnestic syndromes include retrograde or antegrade amnesia. Retrograde amnesia commonly follows head injury and involves loss of memory for a variable time before the event. Antegrade amnesia, the inability to incorporate ongoing experience into memory stores, is seen in head trauma, Wernicke-Korsakoff psychosis, or bilateral limbic lesions to the hippocampal-amygdala complex. The latter is usually due to occlusive vascular disease, hypoxic encephalopathy, or encephalitis. Total global retrograde amnesia, in which an individual loses all prior memory, is never due to organic dysfunction.


Budson A.E., Kowall N.W., eds. The handbook of Alzheimer’s disease and other dementiasWest Sussex, UK. John Wiley & Sons; . 2011;Vol. 7.

Budson A.E., Price B.H. Memory dysfunction in neurological practice. Pract Neurol. 2007;7(1):42–47.

Meningitis (See also Neurologic Emergency Appendix)




Meningitis is an infectious or inflammatory process that affects the leptomeninges. Most cases are secondary to a viral infection, while other causes include bacterial, fungal, and parasitic infections. In rare instances, meningitis can be secondary to chemical reactions or drug allergies.

Clinical presentation

Meningitis should be suspected in any patient with an acute onset of nuchal rigidity, headache, altered mental status, fever, emesis, and photophobia. Meningeal signs are often absent in infants younger than 6 months of age, elderly individuals, or immunosuppressed patients.

The classic triad includes fever, neck rigidity, and mental status changes. Physical examination can show evidence of meningismus—classic meningeal signs such as Brudzinski sign (spontaneous flexion of the hips during attempted passive flexion of the neck) or Kernig sign (the inability or reluctance to allow full extension of the knee when the hip is flexed 90 degrees).

Diagnosis and evaluation

If the diagnosis of acute bacterial meningitis is suspected, blood cultures and head computed tomography (CT) are obtained immediately. Antibiotic therapy should begin before the patient leaves the emergency room for the CT. A lumbar puncture should be performed with particular caution in patients with thrombocytopenia, raised intracranial pressure, mass effect on central nervous system imaging, clinical signs of impending herniation, or concomitant spinal epidural abscess. Antibiotics are chosen based on patient age, severity of clinical situation, and possible organisms (Table 85). If the CT result is normal, a cerebrospinal fluid (CSF) examination must be performed and sent for blood cell and differential cell counts, glucose and protein levels, and cultures (bacterial, viral, fungal, and mycobacterial, as appropriate). Organism-specific studies, including cryptococcal antigen studies and counterimmunoelectrophoresis specific for some strains of Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae, fl-hemolytic streptococci, and Escherichia coli are often useful, especially if the results of the initial CSF cultures are negative (Table 86).

Table 86

Causative organisms in meningitis according to patient age and clinical setting
Infants < 6 wk old: group B streptococci, E. coli, S. pneumoniae, L. monocytogenes, Salmonella organisms, P. aeruginosa, S. aureus, H. influenzae, Citrobacter organisms, herpes simplex 2
Children 6 wk to 15 yr old: H. influenzae, S. pneumoniae, N. meningitidis, S. aureus, viruses
Older children and young adults: N. meningitidis, S. pneumoniae, H. influenzae, S. aureus, viruses
Adults > 40 yr old: S. pneumoniae, N. meningitidis, S. aureus, L. monocytogenes, gram-negative bacilli
Diabetes mellitus: S. pneumoniae, gram-negative bacilli, staphylococci, Cryptococcus organisms, Mucor
Alcoholism: S. pneumoniae
Sickle cell anemia: S. pneumoniae
Pneumonia or upper respiratory infection: S. pneumoniae, N. meningitidis, viruses, H. influenzae
AIDS or other abnormal cellular immunity: Toxoplasma, Cryptococcus, Coccidioides, and Candida organisms; L. monocytogenes, M. tuberculosis, and M. avium-intracellulare, T. pallidum, Histoplasma organisms, Nocardia, S. pneumoniae, gram-negative bacilli
Abnormal neutrophils: P. aeruginosa, S. aureus, Candida and Aspergillus organisms, Mucor
Immunoglobulin deficiency: S. pneumoniae, N. meningitidis, H. influenzae
Ventricular shunt infections: S. epidermidis, S. aureus, gram-negative bacilli
Penetrating head trauma, skin lesions, bacterial endocarditis or other heart disease, severe burns, IV drug abuse: S. aureus, streptococci, gram-negative bacilli
Closed head trauma, CSF leak, pericranial infections: S. pneumoniae, gram-negative bacilli
Following neurosurgical procedures: S. aureus, S. epidermidis, gram-negative bacilli
Tick bites: B. burgdorferi
Swimming in fresh water ponds: Naegleria organisms
Contact with water frequented by rodents or domestic animals: Leptospira organisms
Contact with hamsters or mice: Lymphocytic choriomeningitis virus
Exposure to pigeons: Cryptococcus organisms
Travel in southwestern United States: Coccidioides organisms

CSF, Cerebrospinal fluid; IV, intravenous.

Modified from Mandell, G. L., et al. (1985). Principles and practice of infectious diseases, ed 2. New York: John Wiley and Sons.

Laboratory evaluation of CSF includes a Gram stain and India ink examination of centrifuged CSF sediment. Cell counts greater than 100/mm, protein levels greater than 50 mg/dL, and glucose levels less than 30 mg/dL suggest bacterial infection. There is overlap with ranges more typical of fungal, tuberculous, and viral meningitis (see Cerebrospinal Fluid). A polymorphonuclear predominance is more common with bacterial meningitis and a lymphocytosis with aseptic meningitis. Approximately 10% of bacterial meningitides show a lymphocytosis. Hypoglycorrachia (low CSF glucose level) occurs in bacterial, tuberculous, fungal, carcinomatous, or chemical meningitis. In the subacute presentation (more than 24 hours of symptoms), unless mental status is impaired, a more detailed workup may be done before starting antibiotic therapy.

Chronic meningitis is meningoencephalitis lasting for > 4 weeks with a persistently abnormal CSF study.

Recurrent meningitis describes repetitive episodes of meningitis with an abnormal CSF followed by symptom-free periods and normal CSF (Table 87).

Mollaret meningitis is a benign recurrent aseptic meningitis associated with herpes simplex virus, type 2, and may improve on administration of prophylactic acyclovir.


Tailored to the underlying cause, initial broad-spectrum-wide coverage may include ceftriaxone 2 g q 24 hours, ampicillin 2 g IV q 4–6 hours, vancomycin 1 g q 12 hours, and metronidazole 500 mg IV q 6 hours. Glucocorticoid administration suppresses the inflammatory response, with resultant decreased brain edema and lowered intracranial pressure. Children with meningitis who receive treatment with dexamethasone 0.6 mg/kg/day in four divided doses for the initial 4 days of antibiotic therapy have lower rates of sensorineural hearing loss and neurologic sequelae.

Dexamethasone may reduce the rate of neurologic sequelae, such as seizures, focal neurologic deficits, and papilledema, particularly in patients with pneumococcal meningitis.


The major complications from acute meningitis are seizure, stroke, abscess, hydrocephalus, and herniation with death (Fig. 40). Mortality rates for the different forms of meningitis are variable. The three most common bacterial meningitides (pneumococcal, meningococcal, and H. influenzae) have an average mortality rate of 10%; neurologic deficits occur in about 20% of survivors. The frequency of complications correlates with an increased duration of symptoms before treatment. Mental status changes, in particular agitation and confusion, are poor prognostic signs, as is an underlying malignancy, alcoholism, diabetes, or pneumonia. Common sequelae include hearing loss, vestibular dysfunction, cognitive and behavioral changes, and seizures.

Figure 40
Figure 40 Cranial complications in bacterial meningitis. (Adapted van de Beek, D., et al. (2006). Community-acquired bacterial meningitis in adults. N Engl J Med, 354(1), 44–53.


Brouwer M.C., van de Beek D. Management of bacterial central nervous system infections. Handb Clin Neurol. 2017;140:349–364.

Richie M.B., Josephson S.A. A practical approach to meningitis and encephalitis. Semin Neurol. 2015;35(6):611–620.

Mental Status Testing


Memory, MMSE, MoCA, mental status, cognition

Routine clinical mental status examination should allow for quick screening of focal and global abnormalities. Elements of the mental status examination include state of awareness, attention, mood and affect, speech and language, memory, visual spatial function, executive functions (processing speed, attention, judgment, planning abstraction), praxis, and other aspects of cognition such as calculations and thought content. Patients who appear to have difficulties on unstructured testing during neurological examination should have a more detailed survey of their cognitive abilities, using short, standardized omnibus tests such as the Mini-Mental Status Examination or Montreal cognitive assessment (Fig. 41).

Fig. 41
Figure 41 Mini mental state examination (From Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. Psychiatr Res, 12(3), 189–198.)

Interpretation of mental status testing cannot be performed in isolation. Widely used tests may not be valid for those with less than eight grades of education; norms may vary with race/ethnicity, education, and age. An inattentive patient may not perform well on memory tasks or language comprehension, but this is not indicative of primary language or memory disturbance. Aphasic patients may perform significantly worse than their functional status might suggest. Visual impairment may complicate constructional testing and naming. Fund of knowledge and proverb testing, although useful as a screening test, is highly dependent on educational level, socioeconomic status, and cultural background.


Daffner K.R., Gale S.A., Barrett A.M., et al. Improving clinical cognitive testing. Report of the AAN Behavioral Neurology Section Workgroup. Neurology. 2015;85(10):910–918.

Tang-Wai D.F., et al. Comparison of the short test of mental status and the mini-mental state examination in mild cognitive impairment. Arch Neurol. 2003;60:1777–1781.

Metabolic Diseases of Childhood


Metabolic diseases of childhood, maple syrup urine disease, phenylketonuria, glycogen storage disorders, homocystinuria abetalipoproteinemia Galactosemia, hypothyroidism, pyridoxine deficiency

A metabolic disorder should be suspected under the following conditions: (1) neurologic disorder is replicated in sibling or close relative, (2) recurrent episodes of altered consciousness or unexplained vomiting in an infant, (3) recurrent unexplained ataxia or spasticity, (4) progressive central nervous system (CNS) degeneration, (5) mental deterioration in sibling or close relative, and (6) mental retardation in the absence of major congenital anomalies.

The following procedures may be performed: (1) urine screen, (2) serum ammonia, fasting blood glucose, pH, Pco2, and lactic and pyruvic acid, (3) serum amino and organic acids, (4) x-ray, (5) serum lysosomal enzyme screen, (6) tissue biopsy for structural and biochemical alterations, and (7) CT or MRI.

Classification by clinical presentation

  1. I. Acute encephalopathy presents shortly after birth or during early infancy with recurrent vomiting, lethargy, poor feeding, and dehydration. It initially affects the gray matter, and, hence, presents with cognitive impairment, seizures, or vision impairment. Course is rapidly progressive. This presentation is usually caused by “small-molecule diseases” (amino acids, organic acids, and simple sugars) and represents an “intoxication” or toxic encephalopathy. Intoxications result from accumulation of toxic compounds proximal to the metabolic block. Serum lactate and ammonia, blood gas, and urine ketones permit classification of the metabolic disorders into those with (1) ketosis (maple syrup urine disease [MSUD]), (2) ketoacidosis and acidosis (organic acidurias), (3) lactic acidosis, (4) hyperammonemia with ketoacidosis (urea cycle disorders), and (5) no ketoacidosis or hyperammonemia (nonketotic hyperglycinemia, sulfite oxidase deficiency, and peroxisomal/lysosomal disorder) (Table 88).

  2. II. Chronic or progressive encephalopathy manifests during late infancy, childhood, or adolescence. It initially affects white matter and presents with gradual onset of long-tract signs such as spasticity, ataxia, or hyperreflexia. Dementia may develop later. Liver, heart, muscle, or kidneys are frequently involved. This clinical presentation is caused by large-molecule (glycogen, glycoprotein, lipids, and mucopolysaccharides) or storage diseases and represents intoxication, energy deficiency, or both. Glycogen storage diseases, congenital lactic acidosis, fatty acid oxidation defects, mitochondrial respiratory disorders, and peroxisomal disorders belong to this group. Routine metabolic screening tests are seldom helpful. Neuroimaging and EEG, evoked potentials, electromyography and nerve conduction studies, and specialized genetic/metabolic testing are often necessary to elucidate the diagnosis.

The following metabolic disorders require early recognition and prompt treatment:

  1. I. Phenylketonuria: autosomal recessive (AR); defect of phenylalanine hydroxylase; 2 months, vomiting and irritable; 4 to 9 months, mental retardation; later seizures, eczema, reduced hair pigmentation; early treatment with phenylalanine-restricted diet can preserve normal IQ.
  2. II. MSUD: AR; defect in branched-chain amino acids (valine, leucine, isoleucine); first week, opisthotonos, intermittent hypertonia, feeding difficulties, and irregular breathing; 50% with hypoglycemia; sweet-smelling urine; if a diet restricted in branched-chain amino acids is started within first 2 weeks of life, normal or near-normal IQ may be achieved.
  3. III. Homocystinuria: AR; cystathionine synthase defect; presents between 5 and 9 months; strokes, seizures, and psychiatric disturbances; ectopia lentis; sparse, blond, and brittle hair; treatment is methionine-restricted diet with or without pyridoxine 250 to 1200 mg/day. Cysteine-supplemented diet.
  4. IV. Bassen-Kornzweig disease (abetalipoproteinemia): AR; first year, steatorrhea; second year, ataxia, retardation, retinitis pigmentosa; hypocholesterolemia, fat-soluble vitamin deficiencies, acanthocytosis; treat with vitamins E, A, and K.
  5. V. Galactosemia: AR; defect in galactose-1-uridyl transferase; normal at birth and occur when milk feeding begins during first week; listless, jaundice, vomiting, diarrhea, and no weight gain; second week, hepatosplenomegaly; fourth week, cataracts; may be hypotonic and have pseudotumor cerebri; if untreated develops intellectual disability and motor retardation; treat with lactose-free diet; visual-perceptual deficits persist despite early treatment; susceptible to Escherichia coli sepsis.
  6. VI. Hypothyroidism: post-term, macrosomia, jaundice, large posterior fontanel, mottled skin, big belly; second month, hypotonia, grunting cry, macrocephaly, coarse hair; later, developmental delay, deaf-mutism, and spasticity; if thyroid replacement not started within first 3 months of life, cerebellar and speech defects may persist.
  7. VII. Pyridoxine deficiency: neonatal seizures and EEG abnormalities respond only to pyridoxine; requires lifelong treatment.



Microcephaly, small head, intellectual disabilities

Microcephaly refers to head circumference smaller than 2 standard deviations (SD) below the normal distribution for age and sex. It is important to note familial trends (measure the heads of both parents), as it can be a normal variant and normal intelligence and development are not uncommon. Head circumference smaller than 3 SD of age norms usually indicates later mental retardation. About 35 cm is the mean for head circumference at birth.

Microcephaly usually results from a small brain except in the case of craniosynostosis, in which premature closure of sutures occurs despite a normal brain (Fig. 42). Primary microcephaly refers to diminished brain size due to abnormal development early in the pregnancy.

Fig. 42
Figure 42 Algorithm for the diagnostic evaluation of the infant or child with postnatal-onset microcephaly. (Modified from Ashwal, S., et al. (2009). Practice parameter: evaluation of the child with microcephaly [an evidence-based review]: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology, 73, 887–897.)

Causes include inherited disorders (usually autosomal recessive), abnormal structural development (schizencephaly, lissencephaly, pachygyria, micropolygyria, agenesis of corpus collosum), and chromosomal abnormalities. Damage caused by irradiation or TORCH infections early in the pregnancy are also common causes. Secondary microcephaly implies that the brain was forming normally but a disease process impaired further growth. It usually occurs late in the pregnancy. Causes include intrauterine disorders (infection, toxins, vascular), perinatal brain injuries (hypoxic-ischemic encephalopathy, intracranial hemorrhage, encephalitis, stroke), and postnatal systemic diseases (chronic cardiopulmonary or renal disease, malnutrition).

Evaluation involves determining primary versus secondary causes, with special attention to identifying infectious causes (i.e., TORCH infections). Magnetic resonance imaging (MRI) is useful to distinguish the two forms, as secondary microcephaly often has identifiable abnormalities.


Daroff R.B., Jankovic J., Mazziotta J.C., et al., eds. Bradley’s neurology in clinical practice. ed 7 Elsevier; 2015.

Dulac O., Lassonde M., Sarnat H.B., eds. Pediatric neurology, Part I/II/III. ed 1 Elsevier; . Handbook of Clinical Neurology. 2013;vol. 111/112/113.

Mitochondrial Disorders


Mitochondria, MELAS, MERRF, ophthalmoplegia, Kearns-Sayre syndrome, growth, CoQ10

Mitochondrial diseases (MDs) are a clinically heterogeneous group of disorders that arise because of dysfunction of the mitochondrial respiratory chain as a result of nuclear or mitochondrial DNA (MDNA) mutation. MD may affect a single organ, but most involve multiple organ systems and often present with prominent neurologic and myopathic features. Because the sperm do not contribute mitochondria to the developing embryo, mitochondrial disorders involving MDNA mutations do not show male-to-male transmission. Nuclear MD presents commonly in childhood and MDNA presents in late childhood or adult life.

Clinical features

Many MDs display a cluster of clinical features constituting a known clinical syndrome, such as the Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERFF), neurogenic weakness with ataxia and retinitis pigmentosa, or Leigh syndrome (LS). However, the diagnostic criteria for many of these rare disorders have not been fully formalized. An alternative approach is to consider “red flags” for recognizing mitochondrial disorders.

Red-flag neurologic symptoms and red-flag symptoms in other organ systems include:

  1. 1. Stroke: Nonvascular distribution; on magnetic resonance imaging the apparent diffusion coefficient (ADC) map shows a mixture of hyperintensity and hypointensity
  2. 2. Basal ganglia lesions: Bilateral symmetric (characteristic of LS); also with brainstem lesions
  3. 3. Encephalopathy-hepatopathy: Precipitated by valproic acid exposure; associated hepatic failure epilepsy, epilepsia partialis continua, myoclonus, and status epilepticus
  4. 4. Cognitive decline: Regression with illness
  5. 5. Ataxia: Associated with epilepsy or other systemic symptoms; neuroimaging may show cerebellar atrophy, white matter lesions, and basal ganglia lesion
  6. 6. Ocular signs: Optic nerve atrophy, ophthalmoplegia, and ptosis; retinopathy
  7. 7. Sensorineural hearing loss: At early age, accompanied by other systemic symptoms
  8. 8. Cardiovascular: Hypertrophic cardiomyopathy with rhythm disturbance; unexplained heart block; cardiomyopathy with lactic acidosis; dilated cardiomyopathy with muscle weakness; Wolff-Parkinson-White arrhythmia
  9. 9. Ophthalmologic: Fluctuating, dysconjugate eye movements, sudden or insidious onset optic neuropathy/atrophy
  10. 10. Gastrointestinal (GI): Unexplained or valproate-induced liver failure; severe dysmotility; pseudo-obstructive episodes
  11. 11. Other: Unexplained hypotonia, weakness, failure to thrive, and a metabolic acidosis in infant or young child; exercise intolerance disproportional to weakness; hypersensitivity to general anesthesia; episodes of acute rhabdomyolysis; early onset diabetes mellitus

Symptoms can then be identified, family history obtained (note that clinical variability exists within families and many individuals do not fit neatly into one particular category), metabolic assessment (serum or cerebrospinal fluid [CSF] lactate and pyruvate, organic acids, carnitine, CoQ10), neuroimaging, muscle biopsy, and directed genetic testing can be obtained.

Management of mitochondrial disorders

The management of MD is often multidisciplinary and presents some important challenges regarding diverse issues such as exercise and anesthesia, acute illnesses, genetic counselling, and supportive care. A major management issue is recognizing these disorders in a timely manner before organ damage or while symptoms can be prevented. More chronic management issues may include treatment of diabetes mellitus, cardiac pacing, ptosis correction, intraocular lens replacement for cataracts, and vision support services. Patients with mitochondrial cytopathies may benefit from oral administration of alpha lipoic acid and riboflavin and/or CoEnzyme Q10 (especially in CoQ10 deficiencies) but much of the data is anecdotal.

A special recommendation from a recent consensus document is the use of intravenous arginine hydrochloride to be administered urgently in the acute setting of a stroke-like episode associated with the MELAS m.3243 A > G mutation in the MTTL1 gene and considered in a stroke-like episode associated with other primary mitochondrial cytopathies, while other etiologies are being excluded.

Aug 12, 2020 | Posted by in NEUROLOGY | Comments Off on M
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