wada test scores were 5/5 using the left hemisphere ( right carotid injection ) and 3/5 using the right hemisphere . at the age of 21
, she underwent invasive eeg monitoring , which captured 10 seizures arising from the right hippocampus and 1 from the left .
convulsive seizures resolved with surgery , but both complex partial seizures and nonepileptic events continued .
( a ) section stained with luxol fast blue for orientation ( original magnification 20 ) .
( b ) a neun immunohistochemical preparation reveals very few brown - stained neurons in ca4 .
( c ) immunohistochemistry for astrocytes using glial fibrillary acidic protein shows gliosis ( original magnification 20 ) .
( d ) a dysplastic neuron expressing neurofilament protein from ca4 ( original magnification 400 ) . at the age of 24 , she began to have gait difficulties with mild leg stiffness .
two years later left arm dysmetria and gait ataxia become prominent , consistent with cerebellar dysfunction .
her anti - gad level was found to be greater than 300 u / ml ( radioimmunoassay , normal range 01.1 ) .
csf studies showed oligoclonal bands and an igg / total protein ratio of 0.01 but were otherwise normal .
she is now on regular iv immunoglobulin ( ivig ) infusions with mild improvement in gait .
immunohistochemical studies using antibodies for t cells ( cd3 ) , t cell subsets ( cd4 and cd8 ) , b lymphocytes ( cd20 ) , plasma cells ( cd138 ) , and granzyme were performed and did not reveal lymphocytes or plasma cells in the parenchyma or subarachnoid space .
( a ) section stained with luxol fast blue for orientation ; ca4 is seen in the center between the blades of the fascia dentata ( original magnification 20 ) .
( d ) high - power ( original magnification 200 ) view of the fascia dentata showing dispersion and migration of neurons stained with neun .
five months after surgery , he began to report stiffness and spasms of the back .
on examination at that time , he was found to have increased muscle tone in the lower extremities and myoclonic jerks .
findings later included gaze - evoked diplopia and respiratory dysfunction due to stiffness of the respiratory musculature . on laboratory testing ,
serum anti - gad level was found to be greater than 300 u / ml .
approximately 3 years after surgery , he developed a cerebellar syndrome with speech changes , diplopia , dysmetria , and ataxia .
initial mri showed decreased volume in the left hippocampus without signal abnormality and abnormal t2 signal in the right hippocampus without volume loss .
wada test scores were 5/5 using the left hemisphere ( right carotid injection ) and 3/5 using the right hemisphere . at the age of 21
, she underwent invasive eeg monitoring , which captured 10 seizures arising from the right hippocampus and 1 from the left .
convulsive seizures resolved with surgery , but both complex partial seizures and nonepileptic events continued .
( a ) section stained with luxol fast blue for orientation ( original magnification 20 ) .
( b ) a neun immunohistochemical preparation reveals very few brown - stained neurons in ca4 .
( c ) immunohistochemistry for astrocytes using glial fibrillary acidic protein shows gliosis ( original magnification 20 ) .
( d ) a dysplastic neuron expressing neurofilament protein from ca4 ( original magnification 400 ) . at the age of 24 , she began to have gait difficulties with mild leg stiffness .
two years later left arm dysmetria and gait ataxia become prominent , consistent with cerebellar dysfunction .
her anti - gad level was found to be greater than 300 u / ml ( radioimmunoassay , normal range 01.1 ) .
csf studies showed oligoclonal bands and an igg / total protein ratio of 0.01 but were otherwise normal .
she is now on regular iv immunoglobulin ( ivig ) infusions with mild improvement in gait .
immunohistochemical studies using antibodies for t cells ( cd3 ) , t cell subsets ( cd4 and cd8 ) , b lymphocytes ( cd20 ) , plasma cells ( cd138 ) , and granzyme were performed and did not reveal lymphocytes or plasma cells in the parenchyma or subarachnoid space .
( a ) section stained with luxol fast blue for orientation ; ca4 is seen in the center between the blades of the fascia dentata ( original magnification 20 ) . (
( d ) high - power ( original magnification 200 ) view of the fascia dentata showing dispersion and migration of neurons stained with neun .
five months after surgery , he began to report stiffness and spasms of the back .
on examination at that time , he was found to have increased muscle tone in the lower extremities and myoclonic jerks .
findings later included gaze - evoked diplopia and respiratory dysfunction due to stiffness of the respiratory musculature . on laboratory testing ,
serum anti - gad level was found to be greater than 300 u / ml .
approximately 3 years after surgery , he developed a cerebellar syndrome with speech changes , diplopia , dysmetria , and ataxia .
we describe 2 patients who initially presented with medically refractory tle due to ilae type 3 hs , were found to have high levels of anti - gad antibodies , and later developed sps and cerebellar syndromes .
one of the patients remains free of seizures after temporal lobectomy ; the other continues to have seizures , the frequency of which has not clearly been altered by immune modulatory treatment .
however , in both patients , sps and cerebellar syndromes did respond to immune modulatory treatment .
high gad antibody levels were found in 2.8% of patients with epilepsy in a recent study that included patients with both well - controlled and uncontrolled epilepsy .
ilae type 3 hs has been described in a small number of specimens from other patients with presumed autoimmune - related epilepsy , including a patient with suspected anti - gad  related limbic encephalitis .
bien et al . described pathologic specimens from 3 patients with anti - gad encephalitis in which there was no immunoglobulin or complement deposition , arguing against an antibody - mediated mechanism . on the other hand ,
markers of a t cell  mediated cytotoxic process , while present , reflected less - intense activation than that seen in other forms of autoimmune encephalitis due to intracellular antigens .
the rarity of ilae type 3 hs and the overlap between the pathologic findings in these cases and previously published descriptions of specimens from patients with anti - gad  related epilepsy strongly suggest that anti - gad antibodies underlie these patients ' epilepsy and sps with cerebellar ataxia .
the cases described here contribute to our understanding of the phenomenon of anti - gad  related epilepsy in 2 ways .
first , they illustrate the evolution of anti - gad  related neurologic syndromes from epilepsy to other branches of the condition , which has been less well - described than transitions and overlaps between sps and cerebellar syndromes .
second , there are few descriptions of pathologic specimens from patients with tle and anti - gad antibodies .
these 2 cases strengthen the hypothesis of an association between anti - gad antibodies and some cases of ilae type 3 hs .
they were obtained late in the course of the development of the epilepsy , leaving open the possibility of cytotoxic processes .
the other neurologic manifestations of anti - gad  related autoimmunity , however , developed after these specimens were obtained .
similar to the cases described by bien et al . , the presence of oligoclonal bands in case 1 and anti - thyroid and anti - parietal antibodies in case 2 suggests a possible role for antibody - mediated mechanisms .
if an antibody - mediated process is relevant in these cases , it is unclear whether anti - gad antibodies themselves or coexisting antibodies to an unknown antigen are pathogenic .
although a small sample , these cases suggest that ilae type 3 hs may be immunologically mediated in some cases and that tle due to ilae type 3 hs may be one component of a broader anti - gad  related neurologic syndrome in some patients . if there is a unifying explanation of the mechanisms of anti - gad  related neuropathology , these cases suggest that hypotheses will have to accommodate the development of hs , sps , and cerebellar dysfunction in the same patient .
patrick lasala proofread and edited the document for content , particularly regarding the neurosurgical details .
graber serves on a scientific advisory board for novacure , inc . and a data safety monitoring board for stemedica , inc .
, was formerly on a speakers ' bureau for biogen idec , and received research support from diogenix , novartis , biogen , and radiation therapy oncology group .
 objective : to describe the neuropathologic findings and clinical course of 2 patients who underwent temporal lobectomy for medically refractive epilepsy and were later found to have high anti  
 glutamic acid decarboxylase ( gad ) concentrations.methods:small case series.results:neuropathologic examination of both patients revealed international league against epilepsy ( ilae ) type 3 hippocampal sclerosis . following surgery , both developed signs and symptoms of stiff person syndrome and later cerebellar ataxia . 
 laboratory studies demonstrated high concentrations of anti - gad antibodies in both patients.conclusions:these cases suggest that ilae type 3 hippocampal sclerosis may be immunologically related to and may exist as part of a broader anti - gad  related neurologic syndrome in some instances . 
CASE REPORTS
Case 1.
Case 2.
DISCUSSION
AUTHOR CONTRIBUTIONS
STUDY FUNDING
DISCLOSURE