Periodic Paralysis, Brain Fog,
Memory and Cognition: Is There a Connection?
By Susan Q Knittle-Hunter - Using AI ChatGPT & Midjourney
Members of the Periodic Paralysis community sometimes describe an
experience they call “brain fog.” They may have difficulty
concentrating, finding a familiar word or name, following a conversation,
thinking clearly, or completing a mental task that ordinarily would be easy.
This raises an important question:
Can Periodic Paralysis affect thinking and memory as well as the muscles?
The answer is not a simple yes or no.
Periodic Paralysis (PP) is primarily a group of ion-channel disorders
affecting skeletal-muscle excitability. For most forms of PP, cognitive
impairment is not considered a defining feature. However, several factors
associated with PP—including fatigue, poor sleep, physiological stress and, in
some circumstances, electrolyte disturbances—could potentially affect how
mentally alert or clear a person feels.
There is also one particularly important exception: Andersen-Tawil
Syndrome (ATS), for which research has demonstrated a specific
neurocognitive phenotype in some affected individuals.
Understanding these distinctions is important.
What Do We Mean by “Brain Fog”?
“Brain fog” is not a medical diagnosis. It is a descriptive term people
use for experiences such as:
- difficulty concentrating
- slower thinking
- trouble retrieving words or names
- difficulty maintaining attention
- forgetfulness
- feeling mentally exhausted or
“foggy”
- difficulty organizing thoughts
- needing more time to process
information
These symptoms do not necessarily mean that a person has a progressive
memory disorder or that brain cells are being damaged.
They can occur temporarily when the body is under physiological stress.
For someone with Periodic Paralysis, therefore, we need to ask two
different questions:
Does the particular PP channelopathy directly affect cognition?
and
Can the circumstances surrounding a PP attack temporarily interfere with
clear thinking?
Those are not the same question.
Hypokalemic Periodic Paralysis
Hypokalemic Periodic Paralysis (HypoKPP) is most commonly associated with
pathogenic variants in CACNA1S and, less frequently, SCN4A.
During a typical attack, potassium moves abnormally from the extracellular
space into cells, producing a fall in measured serum potassium and loss of
skeletal-muscle excitability.
Importantly, this is generally a redistribution of potassium,
rather than a simple loss of total-body potassium.
Current clinical descriptions of primary HypoKPP focus predominantly on
episodic and sometimes permanent muscle weakness. Cognitive impairment is not
recognized as a characteristic neurological manifestation of primary HypoKPP.
Standard descriptions even emphasize that individuals ordinarily remain alert
during attacks.
That does not mean a person with HypoKPP can never experience mental
fogginess.
Severe hypokalemia from any cause can produce systemic and neurological
symptoms, and medical literature has described confusion, disorientation and
memory disturbances in association with significant hypokalemia.
However, caution is necessary here.
Evidence that severe hypokalemia can affect mental functioning is
not evidence that inherited HypoKPP routinely causes cognitive impairment.
Those are very different conclusions.
Hyperkalemic Periodic Paralysis
Hyperkalemic Periodic Paralysis (HyperKPP) is primarily associated with
pathogenic variants in SCN4A, which encodes the skeletal-muscle sodium
channel NaV1.4.
Attacks may be associated with elevated serum potassium or a significant
rise from the person's baseline, although potassium does not necessarily reach
dramatically abnormal levels. Between attacks, potassium is generally normal.
As with HypoKPP, a specific cognitive syndrome has not been
established as a feature of HyperKPP.
Research does, however, show that the effects of HyperKPP can extend
beyond the period of obvious paralysis.
In a survey of genetically confirmed individuals with HyperKPP, people
frequently reported extreme fatigue, weakness, clumsiness and irritability
following attacks.
Extreme fatigue by itself can make concentration, word retrieval and
mental processing more difficult.
Therefore, a person may quite genuinely feel mentally “foggy” following
an attack without that necessarily indicating that the SCN4A mutation is
directly impairing memory or cognition.
Normokalemic Periodic Paralysis
Normokalemic Periodic Paralysis (NormoKPP) deserves special attention
because its classification has been controversial.
Some families historically diagnosed with NormoKPP were later found to
carry SCN4A variants associated with the HyperKPP spectrum. This led
some investigators to conclude that NormoKPP was not a completely separate
disease but rather a variant within the HyperKPP spectrum.
However, the story did not end there.
In 2013, Fan, Lehmann-Horn and colleagues described a two-generation
family with complicated normokalemic periodic paralysis caused by a mutation
in CACNA1S, the gene encoding the skeletal-muscle calcium channel
CaV1.1.
The mutation, R1242G, affected a voltage-sensor region of the
channel and produced an abnormal omega—or gating-pore—current. The affected
individuals had a complicated phenotype that included NormoKPP,
exercise-induced contractures, muscle edema and progressive muscle abnormalities.
Imaging demonstrated abnormal sodium accumulation within muscle.
Later reviews of CaV1.1 channelopathies continued to recognize this
R1242G-associated normokalemic phenotype.
This is an important reminder:
A normal serum potassium result does not mean that ion handling and
electrical activity within affected muscle cells are normal.
At present, however, there is not good evidence establishing a distinct
cognitive impairment syndrome caused by NormoKPP itself.
Therefore, if someone with NormoKPP experiences difficulty remembering
names, concentrating or thinking clearly, the symptom should be taken
seriously—but it should not automatically be attributed directly to NormoKPP.
Andersen-Tawil Syndrome Is
Different
Andersen-Tawil Syndrome is also a form of Periodic Paralysis, but it is a
multisystem ion-channel disorder.
Most genetically confirmed ATS is associated with pathogenic variants in KCNJ2,
which encodes the inward-rectifier potassium channel Kir2.1.
Kir2.1 is expressed not only in skeletal muscle and the heart, but also
in the brain.
This provides an important biological reason to investigate cognition in
ATS—and researchers have done so.
The 2006 Neurocognitive Study
Yoon and colleagues studied ten individuals with KCNJ2 mutations
and compared them with their unaffected siblings using formal
neuropsychological testing.
The results were fascinating.
Overall IQ was similar between the groups, and researchers found no
significant difference in verbal or visual memory.
However, individuals with ATS demonstrated differences in areas involving
executive functioning and abstract reasoning, as well as greater
difficulties with some academic abilities.
The investigators concluded that KCNJ2 mutations were associated
with a distinct neurocognitive phenotype characterized particularly by deficits
in executive function and abstract reasoning.
That distinction is extremely important.
The research did not show that people with ATS simply “lose their
memory.”
Rather, certain aspects of how information is organized, processed,
reasoned through and acted upon may be affected in some individuals.
Later Research Supports the Finding
A much larger deep-phenotyping study published in Brain examined
69 people with Andersen-Tawil Syndrome.
Among the individuals receiving formal neuropsychological evaluation,
researchers again identified problems involving executive function and
processing speed. Five patients were specifically reported to have executive
dysfunction and slowed processing, which investigators suggested might relate
to the central nervous system expression of KCNJ2.
This provides stronger support for the idea that ATS can involve the
central nervous system as well as skeletal muscle and the heart.
At the same time, not every person with ATS has cognitive difficulties.
ATS varies tremendously from one individual to another, even among
members of the same family.
Fatigue May Be an Important Part of
the Puzzle
Fatigue is extremely common in Periodic Paralysis.
A survey involving people with several forms of PP reported muscle
fatigue in 89% of respondents.
A more recent study of genetically confirmed CACNA1S HypoKPP
similarly found weakness and fatigue among the symptoms having the greatest
effect on quality of life.
Anyone who has experienced profound physical exhaustion knows that
thinking can become more difficult when the body is exhausted.
This does not establish a PP-specific cognitive disorder.
It does, however, provide one possible explanation for why some people
report that their minds do not seem to work normally before, during or after an
attack.
Sleep May Matter Too
Sleep problems have also been documented in people with Periodic
Paralysis.
An early survey examining sleep in PP found greater self-reported
insufficient sleep quality and more nocturnal awakenings among people with
Periodic Paralysis than among healthy controls.
A later study examining pain in people with PP also found increased
fatigue and poor sleep quality among those experiencing pain.
Poor or fragmented sleep can affect attention, processing speed and
memory retrieval in anyone.
Therefore, when someone with PP reports “brain fog,” sleep quality
deserves consideration along with the attack itself.
So, Can Periodic Paralysis Cause
Brain Fog?
The most scientifically accurate answer at present is:
Possibly indirectly in some circumstances—but we should not describe
cognitive impairment as a general symptom of all forms of Periodic Paralysis.
For HypoKPP, HyperKPP and NormoKPP, current evidence does not
establish a characteristic disease-specific cognitive syndrome.
Temporary mental fogginess may instead occur alongside factors such as:
- profound fatigue
- inadequate or disrupted sleep
- pain
- physiological stress during an
attack
- significant electrolyte
abnormalities
- inadequate food or fluid intake
- illness or other attack triggers
- other medical conditions
occurring at the same time
Some of these possibilities are supported more strongly than others, and
not every episode of “brain fog” in someone with PP is necessarily caused by
PP.
Andersen-Tawil Syndrome is the important exception.
Research has demonstrated a neurocognitive phenotype associated with KCNJ2,
particularly involving executive function, abstract reasoning and, in some
individuals, processing speed. This appears to represent an aspect of ATS
itself rather than merely the consequence of a potassium shift during an
attack.
What About Forgetting People's
Names?
This brings us back to the question that prompted this article:
Can NormoKPP cause someone to have trouble remembering people's names?
There is currently insufficient evidence to say that difficulty
retrieving names is a direct symptom of NormoKPP.
If it happens primarily before, during or after an attack, however, it
may be useful to document the pattern.
Record:
- when the cognitive symptom begins
- whether weakness is occurring at
the same time
- what preceded the episode
- sleep the night before
- food and fluid intake
- other symptoms occurring with it
- how long the mental fogginess
lasts
- whether it disappears as the
attack resolves
Patterns can sometimes tell us more than a single laboratory value.
Persistent, progressive or newly developing cognitive problems should not
automatically be blamed on Periodic Paralysis. Other neurological,
metabolic, cardiovascular, sleep-related and medical causes may need to be
considered.
Sudden confusion, loss of awareness, new difficulty speaking, one-sided
weakness or another abrupt neurological change should not simply be assumed to
be a PP attack and warrants urgent medical evaluation.
The Bigger Picture
For many years, Periodic Paralysis was described primarily in terms of
episodes of muscle weakness.
Research has increasingly shown that the lived experience can be
considerably broader.
Permanent weakness, fatigue, pain, impaired sleep and reduced quality of
life have all been documented in PP populations.
And in Andersen-Tawil Syndrome, research demonstrates that the
channelopathy itself can extend beyond skeletal and cardiac muscle into
neurocognitive function.
There is still much we do not know.
Perhaps one of the most important lessons is this:
When a person with Periodic Paralysis reports a symptom that is not in
the traditional textbook description, we should neither automatically attribute
it to PP nor automatically dismiss it because it is not in the textbook.
We document it.
We look for patterns.
We investigate other possible causes.
And we continue asking questions.
That is how knowledge about rare diseases grows.
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Morrow JM, et al. Andersen-Tawil syndrome: deep phenotyping reveals
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