Cytotoxic lesions of the corpus callosum (CLOCCs)
Updates to Article Attributes
Cytotoxic lesions of the corpus callosum (CLOCCs) represent a collection of disparate conditions that can cause signal change in the corpus callosum, usually involving the splenium.
Terminology
The term cytotoxic lesions of the corpus callosum (CLOCCs) has been proposed recently 12 as a more precise description of this phenomenon which has previously been known by a variety of terms including transient lesions of the splenium of the corpus callosum, mild encephalitis/encephalopathy with a reversible isolated SCC lesion (MERS), reversible splenial lesions and reversible splenial lesion syndrome (RESLES). CLOCCs not only better reflects current understanding of the underlying pathophysiology of these lesions but also does not explicitly imply that these lesions are confined to the splenium. As such it is probably a better term to use.
Clinical presentation
Clinical presentation relates to the underlying pathology (see below) rather than to the callosal lesion itself. Unlike many other lesions of the corpus callosum, CLOCCs do not demonstrate convincing signs or symptoms of hemispheric disconnection, such as pseudoneglect, alien hand syndrome, apraxia of the left hand, agraphia, alexia, and visual apraxias 4.
Pathology
Although numerous underlying aetiologies have been identified, these lesions appear to result from a stereotyped cascade of cytokines and stimulated cells. An initial insult results in macrophages releasing inflammatory cytokines (IL-1 and IL-6) which in turn leads to a cascade of changes including recruitment of T-cells, break-down of the blood-brain barrier, production of TNF-α, and activation of astrocytes. The end result is a massive increase in glutamate in the extracellular fluid which, via interactions with a number of cell membrane receptors, results in an influx of water into both astrocytes and neurones which manifests macroscopically as cytotoxic oedema 12.
It appears that the reason the splenium of the corpus callosum is preferentially affected is the presence of a high density of oligodendrocytes expressing large numbers of glutamate affected receptors 12.
Aetiology
Cytotoxic lesions of the corpus callosum are seen in a wide variety of clinical settings, although exactly which conditions are listed in any one publication varies. Classically CLOCCs are seen in patients with seizures or metabolic disturbances, although many other aetiologies are recognised. Reported aetiologies include 1-5,12:
-
seizures
-
complex relationship – CLOCCs seen in a variety of settings:
antiepileptic medications (with or without seizures)
sudden cessation of antiepileptic drugs (classic)
seizures with or without antiepileptic medications
-
-
metabolic disturbance
electrolyte imbalance (e.g. hyperammonaemia, hyper- and hyponatraemia)
osmotic demyelination (e.g. extrapontine myelinolysis 10-12)
-
infections
-
reported in a wide range of cerebral infections, including cerebral abscess, encephalitis and meningitis
viral (e.g. influenza, measles, herpes, mumps, adenovirus, varicella zoster, rotavirus, SARS-CoV-2)
bacterial (e.g. salmonella, Legionnaires' disease)
mycobacterial (e.g. tuberculous meningitis)
-
-
CNS malignancy
many are associated with chemotherapy and/or seizures
-
drugs and toxins
antidepressants (e.g amitriptyline)
antiepileptics (e.g. carbamazepine, lamotrigine, phenytoin)
antipsychotics (e.g. clozapine)
chemotherapy (e.g. ciclosporin, fluorouracil)
corticosteroids
pesticide (e.g. methyl bromide)
-
especially if large volume
not the result of vasospasm
Radiographic features
Transient lesions of the splenium are only really appreciable on MRI where they have three distinct patterns 4,12:
well-circumscribed, small, oval lesions in the midline within the substance of the splenium (most common)
more extensive less well-defined irregular lesions extending throughout the splenium and into the adjacent hemispheres (boomerang sign)
more extensive extension anteriorly into the body of the corpus callosum
The smaller well-circumscribed lesions are the typical lesion seen in the setting of seizures/cessation of antiepileptic medication, whereas the larger lesion is more typical of other aetiologies.
MRI
These lesions demonstrate the expected features of cytotoxic oedema 4,12:
T1: hypointense
T2: hyperintense
DWI/ADC: restricted diffusion (ADC typically 300–500 x 10-6 mm2/s)
T1 C+ (Gd): no enhancement
Some studies have shown that patients generally recover completely on MRI studies within 1 month, mostly within 1 week following the neurological recovery 7.
Treatment and prognosis
The prognosis generally depends on the underlying cause, but in the setting of epilepsy or antiepileptic drug-related lesions, it is very good.
Differential diagnosis
Depending on the publication, some of the differentials to contemplate are included in the list of aetiologies of CLOCCs. In any case, when confronted with a splenial lesion consider:
infarction (e.g. pericallosal artery occlusion)
trauma (e.g. diffuse axonal injury)
tumours (e.g. diffuse glioma, lymphoma)
-<p><strong>Cytotoxic lesions of the corpus callosum (CLOCCs) </strong>represent a collection of disparate conditions that can cause signal change in the <a href="/articles/corpus-callosum">corpus callosum</a>, usually involving the splenium. </p><h4>Terminology</h4><p>The term cytotoxic lesions of the corpus callosum (CLOCCs) has been proposed recently <sup>12</sup> as a more precise description of this phenomenon which has previously been known by a variety of terms including<strong> transient lesions of the splenium of the corpus callosum</strong>,<strong> mild encephalitis/encephalopathy with a reversible isolated SCC lesion (MERS)</strong>, <strong>reversible splenial lesions</strong> and <strong>reversible splenial lesion syndrome (RESLES)</strong>. CLOCCs not only better reflects current understanding of the underlying pathophysiology of these lesions but also does not explicitly imply that these lesions are confined to the splenium. As such it is probably a better term to use. </p><h4>Clinical presentation</h4><p>Clinical presentation relates to the underlying pathology (see below) rather than to the callosal lesion itself. Unlike many other <a href="/articles/lesions-of-the-corpus-callosum-1">lesions of the corpus callosum</a>, CLOCCs do not demonstrate convincing signs or symptoms of hemispheric disconnection, such as <a href="/articles/pseudo-neglect">pseudoneglect</a>, <a href="/articles/alien-hand-syndrome">alien hand syndrome</a>, <a href="/articles/apraxia-1">apraxia</a> of the left hand, <a href="/articles/agraphia">agraphia</a>, <a href="/articles/alexia">alexia</a>, and visual apraxias <sup>4</sup>. </p><h4>Pathology</h4><p>Although numerous underlying aetiologies have been identified, these lesions appear to result from a stereotyped cascade of cytokines and stimulated cells. An initial insult results in macrophages releasing inflammatory cytokines (IL-1 and IL-6) which in turn leads to a cascade of changes including recruitment of T-cells, break-down of the blood-brain barrier, production of TNF-α, and activation of astrocytes. The end result is a massive increase in glutamate in the extracellular fluid which, via interactions with a number of cell membrane receptors, results in an influx of water into both astrocytes and neurones which manifests macroscopically as <a href="/articles/cytotoxic-cerebral-oedema">cytotoxic oedema</a> <sup>12</sup>. </p><p>It appears that the reason the splenium of the corpus callosum is preferentially affected is the presence of a high density of oligodendrocytes expressing large numbers of glutamate affected receptors <sup>12</sup>. </p><h5>Aetiology</h5><p>Cytotoxic lesions of the corpus callosum are seen in a wide variety of clinical settings, although exactly which conditions are listed in any one publication varies. Classically CLOCCs are seen in patients with seizures or metabolic disturbances, although many other aetiologies are recognised. Reported aetiologies include <sup>1-5,12</sup>: </p><ul>-<li>-<p>seizures</p>-<ul><li>-<p>complex relationship – CLOCCs seen in a variety of settings:</p>-<ul>-<li><p>antiepileptic medications (with or without seizures)</p></li>-<li><p>sudden cessation of antiepileptic drugs (classic)</p></li>-<li><p>seizures with or without antiepileptic medications</p></li>-</ul>-</li></ul>-</li>-<li>-<p>metabolic disturbance</p>-<ul>-<li><p>electrolyte imbalance (e.g. hyperammonaemia, hyper- and hyponatraemia)</p></li>-<li><p><a href="/articles/haemolytic-uraemic-syndrome">haemolytic-uraemic syndrome</a></p></li>-<li><p><a href="/articles/hepatic-encephalopathy">hepatic encephalopathy</a></p></li>-<li><p><a href="/articles/hypoglycaemic-encephalopathy">hypoglycaemia</a></p></li>-<li><p><a href="/articles/marchiafava-bignami-disease-1">Marchiafava-Bignami disease</a></p></li>-<li><p><a href="/articles/osmotic-demyelination-syndrome">osmotic demyelination</a> (e.g. <a href="/articles/extrapontine-myelinolysis-1">extrapontine myelinolysis</a> <sup>10-12</sup>)</p></li>-<li><p><a href="/articles/wernicke-encephalopathy">Wernicke encephalopathy</a></p></li>-<li><p><a href="/articles/wilson-disease-cns-manifestations-1">Wilson disease</a></p></li>-</ul>-</li>-<li>-<p>infections</p>-<ul><li>-<p>reported in a wide range of cerebral infections, including <a href="/articles/cerebral-abscess-1">cerebral abscess</a>, <a href="/articles/viral-encephalitides">encephalitis</a> and <a href="/articles/leptomeningitis">meningitis</a></p>-<ul>-<li><p>viral (e.g. influenza, <a href="/articles/measles" title="Measles">measles</a>, <a href="/articles/herpes-simplex-encephalitis">herpes</a>, <a href="/articles/mumps">mumps</a>, adenovirus, varicella zoster, rotavirus, <a href="/articles/covid-19-4" title="SARS-CoV-2">SARS-CoV-2</a>)</p></li>-<li><p>bacterial (e.g. salmonella, <a href="/articles/legionella-pneumonia">Legionnaires' disease</a>)</p></li>-<li><p>mycobacterial (e.g. <a href="/articles/tuberculous-meningitis">tuberculous meningitis</a>)</p></li>-</ul>-</li></ul>-</li>-<li>-<p>CNS malignancy</p>-<ul><li><p>many are associated with chemotherapy and/or seizures</p></li></ul>-</li>-<li>-<p>drugs and toxins</p>-<ul>-<li><p>antidepressants (e.g amitriptyline)</p></li>-<li><p>antiepileptics (e.g. carbamazepine, lamotrigine, phenytoin)</p></li>-<li><p>antipsychotics (e.g. clozapine)</p></li>-<li><p>chemotherapy (e.g. ciclosporin, fluorouracil)</p></li>-<li><p>corticosteroids</p></li>-<li><p>pesticide (e.g. methyl bromide)</p></li>-</ul>-</li>-<li>-<p><a href="/articles/subarachnoid-haemorrhage">subarachnoid haemorrhage</a></p>-<ul>-<li><p>especially if large volume</p></li>-<li><p>not the result of <a href="/articles/cerebral-vasospasm-following-subarachnoid-haemorrhage">vasospasm</a></p></li>-</ul>-</li>-</ul><h4>Radiographic features</h4><p>Transient lesions of the splenium are only really appreciable on MRI where they have three distinct patterns <sup>4,12</sup>: </p><ol>-<li><p>well-circumscribed, small, oval lesions in the midline within the substance of the splenium (most common)</p></li>-<li><p>more extensive less well-defined irregular lesions extending throughout the splenium and into the adjacent hemispheres (<a href="/articles/boomerang-sign-splenium">boomerang sign</a>) </p></li>-<li><p>more extensive extension anteriorly into the body of the corpus callosum</p></li>-</ol><p>The smaller well-circumscribed lesions are the typical lesion seen in the setting of seizures/cessation of antiepileptic medication, whereas the larger lesion is more typical of other aetiologies. </p><h5>MRI</h5><p>These lesions demonstrate the expected features of <a href="/articles/cytotoxic-cerebral-oedema">cytotoxic oedema</a> <sup>4,12</sup>: </p><ul>-<li><p><strong>T1:</strong> hypointense</p></li>-<li><p><strong>T2:</strong> hyperintense</p></li>-<li><p><strong>DWI/ADC: </strong>restricted diffusion (ADC typically 300–500 x 10<sup>-6</sup> mm<sup>2</sup>/s)</p></li>-<li><p><strong>T1 C+ (Gd):</strong> no enhancement</p></li>-</ul><p>Some studies have shown that patients generally recover completely on MRI studies within 1 month, mostly within 1 week following the neurological recovery <sup>7</sup>.</p><h4>Treatment and prognosis</h4><p>The prognosis generally depends on the underlying cause, but in the setting of epilepsy or antiepileptic drug-related lesions, it is very good. </p><h4>Differential diagnosis</h4><p>Depending on the publication, some of the differentials to contemplate are included in the list of aetiologies of CLOCCs. In any case, when confronted with a splenial lesion consider:</p><ul>-<li>-<p><a href="/articles/demyelination">demyelination</a></p>-<ul>-<li><p><a href="/articles/multiple-sclerosis">multiple sclerosis (MS)</a></p></li>-<li><p><a href="/articles/acute-disseminated-encephalomyelitis-adem-1">acute disseminated encephalomyelitis (ADEM)</a></p></li>-</ul>-</li>-<li><p>infarction (e.g. <a href="/articles/pericallosal-artery">pericallosal artery</a> occlusion)</p></li>-<li><p><a href="/articles/posterior-reversible-encephalopathy-syndrome-1">posterior reversible encephalopathy syndrome (PRES)</a></p></li>-<li><p>trauma (e.g. <a href="/articles/diffuse-axonal-injury">diffuse axonal injury</a>)</p></li>-<li><p>tumours (e.g. <a href="/articles/diffuse-glioma">diffuse glioma</a>, <a href="/articles/lymphomas-of-the-central-nervous-system" title="PCNSL">lymphoma</a>)</p></li>-<li><p><a href="/articles/sandwich-sign-marchiafava-bignami-disease">Marchiafava-Bignami disease</a></p></li>-<li><p><a href="/articles/cerebral-fat-embolism">cerebral fat embolism</a></p></li>- +<p><strong>Cytotoxic lesions of the corpus callosum (CLOCCs) </strong>represent a collection of disparate conditions that can cause signal change in the <a href="/articles/corpus-callosum">corpus callosum</a>, usually involving the splenium. </p><h4>Terminology</h4><p>The term cytotoxic lesions of the corpus callosum (CLOCCs) has been proposed recently <sup>12</sup> as a more precise description of this phenomenon which has previously been known by a variety of terms including<strong> transient lesions of the splenium of the corpus callosum</strong>,<strong> mild encephalitis/encephalopathy with a reversible isolated SCC lesion (MERS)</strong>, <strong>reversible splenial lesions</strong> and <strong>reversible splenial lesion syndrome (RESLES)</strong>. CLOCCs not only better reflects current understanding of the underlying pathophysiology of these lesions but also does not explicitly imply that these lesions are confined to the splenium. As such it is probably a better term to use. </p><h4>Clinical presentation</h4><p>Clinical presentation relates to the underlying pathology (see below) rather than to the callosal lesion itself. Unlike many other <a href="/articles/lesions-of-the-corpus-callosum-1">lesions of the corpus callosum</a>, CLOCCs do not demonstrate convincing signs or symptoms of hemispheric disconnection, such as <a href="/articles/pseudo-neglect">pseudoneglect</a>, <a href="/articles/alien-hand-syndrome">alien hand syndrome</a>, <a href="/articles/apraxia-1">apraxia</a> of the left hand, <a href="/articles/agraphia">agraphia</a>, <a href="/articles/alexia">alexia</a>, and visual apraxias <sup>4</sup>. </p><h4>Pathology</h4><p>Although numerous underlying aetiologies have been identified, these lesions appear to result from a stereotyped cascade of cytokines and stimulated cells. An initial insult results in macrophages releasing inflammatory cytokines (IL-1 and IL-6) which in turn leads to a cascade of changes including recruitment of T-cells, break-down of the blood-brain barrier, production of TNF-α, and activation of astrocytes. The end result is a massive increase in glutamate in the extracellular fluid which, via interactions with a number of cell membrane receptors, results in an influx of water into both astrocytes and neurones which manifests macroscopically as <a href="/articles/cytotoxic-cerebral-oedema">cytotoxic oedema</a> <sup>12</sup>. </p><p>It appears that the reason the splenium of the corpus callosum is preferentially affected is the presence of a high density of oligodendrocytes expressing large numbers of glutamate affected receptors <sup>12</sup>. </p><h5>Aetiology</h5><p>Cytotoxic lesions of the corpus callosum are seen in a wide variety of clinical settings, although exactly which conditions are listed in any one publication varies. Classically CLOCCs are seen in patients with seizures or metabolic disturbances, although many other aetiologies are recognised. Reported aetiologies include <sup>1-5,12</sup>: </p><ul>
- +<li>
- +<p>seizures</p>
- +<ul><li>
- +<p>complex relationship – CLOCCs seen in a variety of settings:</p>
- +<ul>
- +<li><p>antiepileptic medications (with or without seizures)</p></li>
- +<li><p>sudden cessation of antiepileptic drugs (classic)</p></li>
- +<li><p>seizures with or without antiepileptic medications</p></li>
- +</ul>
- +</li></ul>
- +</li>
- +<li>
- +<p>metabolic disturbance</p>
- +<ul>
- +<li><p>electrolyte imbalance (e.g. hyperammonaemia, hyper- and hyponatraemia)</p></li>
- +<li><p><a href="/articles/haemolytic-uraemic-syndrome">haemolytic-uraemic syndrome</a></p></li>
- +<li><p><a href="/articles/hepatic-encephalopathy">hepatic encephalopathy</a></p></li>
- +<li><p><a href="/articles/hypoglycaemic-encephalopathy">hypoglycaemia</a></p></li>
- +<li><p><a href="/articles/marchiafava-bignami-disease-1">Marchiafava-Bignami disease</a></p></li>
- +<li><p><a href="/articles/osmotic-demyelination-syndrome">osmotic demyelination</a> (e.g. <a href="/articles/extrapontine-myelinolysis-1">extrapontine myelinolysis</a> <sup>10-12</sup>)</p></li>
- +<li><p><a href="/articles/wernicke-encephalopathy">Wernicke encephalopathy</a></p></li>
- +<li><p><a href="/articles/wilson-disease-cns-manifestations-1">Wilson disease</a></p></li>
- +</ul>
- +</li>
- +<li>
- +<p>infections</p>
- +<ul><li>
- +<p>reported in a wide range of cerebral infections, including <a href="/articles/cerebral-abscess-1">cerebral abscess</a>, <a href="/articles/viral-encephalitides">encephalitis</a> and <a href="/articles/leptomeningitis">meningitis</a></p>
- +<ul>
- +<li><p>viral (e.g. influenza, <a href="/articles/measles" title="Measles">measles</a>, <a href="/articles/herpes-simplex-encephalitis">herpes</a>, <a href="/articles/mumps">mumps</a>, adenovirus, varicella zoster, rotavirus, <a href="/articles/covid-19-4" title="SARS-CoV-2">SARS-CoV-2</a>)</p></li>
- +<li><p>bacterial (e.g. salmonella, <a href="/articles/legionella-pneumonia">Legionnaires' disease</a>)</p></li>
- +<li><p>mycobacterial (e.g. <a href="/articles/tuberculous-meningitis">tuberculous meningitis</a>)</p></li>
- +</ul>
- +</li></ul>
- +</li>
- +<li>
- +<p>CNS malignancy</p>
- +<ul><li><p>many are associated with chemotherapy and/or seizures</p></li></ul>
- +</li>
- +<li>
- +<p>drugs and toxins</p>
- +<ul>
- +<li><p>antidepressants (e.g amitriptyline)</p></li>
- +<li><p>antiepileptics (e.g. carbamazepine, lamotrigine, phenytoin)</p></li>
- +<li><p>antipsychotics (e.g. clozapine)</p></li>
- +<li><p>chemotherapy (e.g. ciclosporin, fluorouracil)</p></li>
- +<li><p>corticosteroids</p></li>
- +<li><p>pesticide (e.g. methyl bromide)</p></li>
- +</ul>
- +</li>
- +<li>
- +<p><a href="/articles/subarachnoid-haemorrhage">subarachnoid haemorrhage</a></p>
- +<ul>
- +<li><p>especially if large volume</p></li>
- +<li><p>not the result of <a href="/articles/cerebral-vasospasm-following-subarachnoid-haemorrhage">vasospasm</a></p></li>
- +</ul>
- +</li>
- +</ul><h4>Radiographic features</h4><p>Transient lesions of the splenium are only really appreciable on MRI where they have three distinct patterns <sup>4,12</sup>: </p><ol>
- +<li><p>well-circumscribed, small, oval lesions in the midline within the substance of the splenium (most common)</p></li>
- +<li><p>more extensive less well-defined irregular lesions extending throughout the splenium and into the adjacent hemispheres (<a href="/articles/boomerang-sign-splenium">boomerang sign</a>) </p></li>
- +<li><p>more extensive extension anteriorly into the body of the corpus callosum</p></li>
- +</ol><p>The smaller well-circumscribed lesions are the typical lesion seen in the setting of seizures/cessation of antiepileptic medication, whereas the larger lesion is more typical of other aetiologies. </p><h5>MRI</h5><p>These lesions demonstrate the expected features of <a href="/articles/cytotoxic-cerebral-oedema">cytotoxic oedema</a> <sup>4,12</sup>: </p><ul>
- +<li><p><strong>T1:</strong> hypointense</p></li>
- +<li><p><strong>T2:</strong> hyperintense</p></li>
- +<li><p><strong>DWI/ADC: </strong>restricted diffusion (ADC typically 300–500 x 10<sup>-6</sup> mm<sup>2</sup>/s)</p></li>
- +<li><p><strong>T1 C+ (Gd):</strong> no enhancement</p></li>
- +</ul><p>Some studies have shown that patients generally recover completely on MRI studies within 1 month, mostly within 1 week following the neurological recovery <sup>7</sup>.</p><h4>Treatment and prognosis</h4><p>The prognosis generally depends on the underlying cause, but in the setting of epilepsy or antiepileptic drug-related lesions, it is very good. </p><h4>Differential diagnosis</h4><p>Depending on the publication, some of the differentials to contemplate are included in the list of aetiologies of CLOCCs. In any case, when confronted with a splenial lesion consider:</p><ul>
- +<li>
- +<p><a href="/articles/demyelination">demyelination</a></p>
- +<ul>
- +<li><p><a href="/articles/multiple-sclerosis">multiple sclerosis (MS)</a></p></li>
- +<li><p><a href="/articles/acute-disseminated-encephalomyelitis-adem-1">acute disseminated encephalomyelitis (ADEM)</a></p></li>
- +</ul>
- +</li>
- +<li><p>infarction (e.g. <a href="/articles/pericallosal-artery">pericallosal artery</a> occlusion)</p></li>
- +<li><p><a href="/articles/posterior-reversible-encephalopathy-syndrome-1">posterior reversible encephalopathy syndrome (PRES)</a></p></li>
- +<li><p>trauma (e.g. <a href="/articles/diffuse-axonal-injury">diffuse axonal injury</a>)</p></li>
- +<li><p>tumours (e.g. <a href="/articles/diffuse-glioma">diffuse glioma</a>, <a href="/articles/lymphomas-of-the-central-nervous-system" title="PCNSL">lymphoma</a>)</p></li>
- +<li><p><a href="/articles/sandwich-sign-marchiafava-bignami-disease">Marchiafava-Bignami disease</a></p></li>
- +<li><p><a href="/articles/cerebral-fat-embolism">cerebral fat embolism</a></p></li>
Image 1 MRI (DWI) ( create )
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